Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is reportedly the second most common cause of idiopathic parkinsonism. Generally, there is no family history and no strong genetic component is known in this idiopathic condition. However, some rare familial clusters have been reported. The disease usually begins when patients are in their 50s to mid 60s. However, the youngest autopsy-proven case began when the patient was 43 years old. Approximately one third of cases begin when the patient is younger than 60 years.
In the Olmsted County Database, the average annual incidence for individuals aged 50-99 was 5.3 per 100,000 population. Overall, estimates suggest that PSP is about as common as motor neuron disease. A high incidence of PSP has been reported in the French Antilles, approaching 14 cases per 100,000 population in Guadeloupe. This high incidence might be related to environmental neurotoxins found in herbal teas and fruits that are commonly consumed there. PSP with tau doublets was found in all 3 cases of probable PSP in which autopsy was performed.
PSP is associated with neuronal loss, gliosis, and neurofibrillary tangles in the pretectal area, substantia nigra, subthalamic nucleus, globus pallidus, superior colliculus, and substantia innominata. Degeneration of multiple neurotransmitter systems leads to a more diffuse disorder than idiopathic PD. The cholinergic and adrenergic systems are involved in addition to the dopaminergic system. Tau-positive glial inclusions are a consistent pathologic finding (see the images below). Coiled bodies, which are small round cells of oligodendrocytic origin found in white matter, are also seen in a widespread distribution.
Abnormality of tau protein
PSP has been considered to be a tau protein disorder. Cortical fibrillary tangles of PSP are similar to those observed in Alzheimer disease with regard to the presence of an abnormally phosphorylated tau protein. Tau is a component of a microtubule-associated protein that is responsible for axonal transport of vesicles. The mechanism whereby this is involved in PSP has yet to be determined. PSP overlaps with corticobasal degeneration (CBD) in this regard, and the latter may have a stronger association with tau protein abnormalities than does PSP.
Tau proteins exist in 6 isoforms encoded by a single gene. Different electrophoretic patterns have been identified in the various disorders associated with tau abnormalities. Thirty-two mutations have been identified in more than 100 families. About half of the known mutations have their primary effect at the protein level. They reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level and perturb the normal ratio of 3-repeat to 4-repeat tau isoforms. When studied, this change resulted in a relative overproduction of tau protein with 4 microtubule-binding domains in the brain.
In Alzheimer disease, the pattern consists of a paired helical fragment triplet (55/64/69), whereas in PSP and CBGD, a tau doublet (64/69) is observed. In Pick disease, a different tau doublet (55/64) is observed. Tau protein abnormalities also have been found in frontotemporal dementia, with parkinsonism linked to chromosome 17 (FTDP-17). The chromosomal region containing MAPT has been shown to evolve into 2 major haplotypes, H1 and H2. The more common haplotype, H1, is overrepresented in patients with PSP and CBD. A study of these abnormalities promises further insights into the pathogenesis of these diseases. However, clinical applications are limited at this time.
Clinical presentation and diagnosis
Onset of PSP typically begins in the sixth or seventh decade of life. The patient develops bradykinesia, rigidity, dysarthria, dysphagia, and dementia, as in patients with idiopathic PD. However, tremor is rare, and the patient has severe postural instability. Axial rigidity appears to be more prominent than limb rigidity. Consistently, patients have downgaze ophthalmoparesis and pseduobulbar palsy. Eyelid problems are present including eyelid freezing and difficult with either opening or closing the eyes. The association of dementia in PSP is contentious. Dystonia is present in about 13% of patients with pathologically proven PSP.
The supranuclear component of the disorder is ocular paresis, which can be overcome by vertical doll’s-eyes maneuvers. The combination of vertical paresis and a history of frequent falls due postural instability is central to the diagnosis of PSP. Some patients develop severe palilalia, emotional incontinence, and other evidence of bilateral frontal lobe dysfunction. Occasionally, patients present with akinesia of gait, speech, and handwriting, without rigidity, tremor, dementia, or gaze paresis. Blepharospasm and dry eyes have been reported. Dubois et al noted that the applause sign was useful in the clinical diagnosis of PSP.
The National Institute of Neurological Disorders and Stroke and the Foundation for PSP/CBD and Related Brain Diseases (CurePSP) have published formal criteria for the diagnosis of PSP. In 2003, the Movement Disorders Society Scientific Issues Committee Report (MDSSICR) reviewed these criteria. Postural instability leading to falls in the first year of disease onset and a vertical supranuclear gaze paresis have good discriminatory value, according to these criteria. Findings from a comparison of neuropsychiatric features suggest that patients with PSP have significantly more apathy and disinhibition than those with PD.
A study of 103 consecutive cases of pathologically proved PSP revealed 2 clinical subtypes. The first, called the Richardson syndrome, occurred in 54% of the cases and was associated with an early onset of postural instability, supranuclear gaze palsy, and cognitive dysfunction. The second, called PSP-Parkinsonism, occurred in 32% of cases and had features more typical of idiopathic PD, including a moderate response to levodopa. Fourteen cases (14%) could not be classified according to these criteria. At the molecular level, the 2 subtypes were characterized by distinct tau isoforms, suggesting that they are discrete nosologic entities.
MRI can help exclude NPH and multi-infarction syndromes. MRI can also be helpful in distinguishing PSP from MSA and CBD. Atrophy in the midbrain or cerebellum, whether general or focal, is the most common. Due to disproportionate atrophy of the dorsal midbrain relative to the pons, sagittal views on MRI can give the appearance of a “hummingbird”. Still, up to a quarter of patients with PSP have no abnormality on computed tomography (CT) or MRI imaging of the brain. Midbrain diameter of less than 17 mm, hyperintensity in the midbrain, atrophy or hyperintensity of the red nucleus, and hyperintensity in the globus pallidus are especially useful findings. PET and single-photon emission CT (SPECT) demonstrate prefrontal hypometabolism. Specialized PET scans can depict severe involvement of the dopaminergic system.
The most characteristic feature of PSP is the supranuclear downgaze palsy. Some patients who never develop this finding are found to have PSP at autopsy. There is an average delay in making a proper diagnosis of 3.6 years after symptom onset. The measurement of midbrain atrophy ratio on MRI is a useful tool in distinguishing early PSP from PD and age-matched controls.
Pharmacologic agents remain the mainstay of treatment of PSP, though the results are frequently disappointing.
Carbidopa/levodopa reduces bradykinesia and rigidity in perhaps one third of patients. However, even at high doses dopaminergic therapies usually provide only a mild, temporary improvement of parkinsonian symptoms. This is likely due to the loss of dopamine receptors in the striatum. At present, no medication provides contued relief in such patients. Dopamine agonists rarely help and are most likely to cause hallucinations and confusion. Sometimes, the reduction of bradykinesia may lead to an increase in falling because of postural instability. Therefore, physical therapy and rehabilitation should focus on gait training, and the use of assistive devices such as walkers should be considered.
Emotional incontinence may respond to anticholinergic agents and tricyclic antidepressants. A small controlled study of donepezil reported modest benefit for the cognitive symptoms at the expense of worsening activities of daily living (ADL) and motor scores. Zolpidem has been reported to improve both motor symptoms and ocular findings, but this effect was transient.
Blepharospasm can be treated with botulinum toxin injections. Botulinum toxin injections can also be useful if drooling of saliva is a disabling symptom. Dry eyes can be treated with topical lubricants. Noradrenergic agonists such as idazoxan may benefit some patients. However, sympathomimetic and other adverse effects commonly limit its usefulness. Adrenal transplantation and pallidotomy have not been helpful. Monitoring for swallowing difficulties with a modified barium swallow test allows for appropriate dietary modification or percutaneous endoscopic gastrostomy tube placement to reduce aspiration risk.
Patients with PSP tend to have progressive deterioration, with a 9.7-year median survival from the onset of symptoms. Gait difficulties occur early, and patients require assistance within 3 years. Confinement to bed or a wheelchair is typically necessary within 8 years. Eventual death usually follows a severe fall, pulmonary embolus, or aspiration pneumonia.
Parkinsonism – dementia – amyotrophic lateral sclerosis complex (PDALS) is a condition well described on the island of Guam and is known there as Lytico-Bodig disease. The latter term is derived from the local Guamanian dialect, with lytico referring to the paralysis caused by the ALS component and with bodig referring to the “laziness” that describes the parkinsonian component.
Extensive genetic and environmental research has been performed on this disorder in the last 50 years. The incidence of PDALS peaked in the 1950s and has declined since then. Dietary toxins in native flour were once considered the source of a potential neurotoxin. However, this hypothesis has been ruled out. The flour is obtained from the seeds of the cycad tree. Because the seed contains a potent hepatotoxin, the flour must be washed many times before consumption. Cycasin and beta-N -methyl-amino-L-alanine (BMAA) are putative neurotoxins in the seed. If the seeds are repeatedly washed, ingestion of an estimated 70 kg of flour is required to receive a toxic dose; therefore, this hypothesis is unlikely. Toxic effects of manganese and aluminum are also being considered.
Another term used in this setting is disinhibition-dementia-parkinsonism-amyotrophy complex. However, this term is not confined to Guam and may represent tauopathy of the FTDP-17 type.
Pathologic evaluation of the substantia nigra has found depigmentation, basophilic inclusion bodies, cell loss, and neurofibrillary tangles without senile plaques. This last finding also has been observed in the anterior horn cells and pyramidal tracts. Motor neuron disease tends to occur in younger patients, and older patients tend to develop parkinsonism and severe dementia. In Guam, the presentation varies between the 2 cultural groups that have populated the island. Both the ALS form and the parkinsonism-dementia form of PDALS are seen in the Chamorros group, while the Filipino group tends to have the parkinsonism-dementia syndrome.
Consider Alzheimer disease, Lewy body disease, postencephalitic parkinsonism, idiopathic PD, ALS, and motor neuron disorders in the differential diagnosis of PDALS. Regarding treatment, patients do not respond to levodopa, and psychiatric treatment may be indicated. A progressive clinical picture is characteristic of both subtypes of PDALS. Death within 10 years is usual.
Corticobasal degeneration (CBD) is characterized by frontoparietal cortical atrophy in addition to degeneration within the extrapyramidal system. CBD patients exhibit cortical findings such as pyramidal signs, aphasia, and myoclonus apraxia along with subcortical extrapyramidal findings such as dystonia as well as the alien limb sign. In recent studies, there is increasing evidence of an overlapping presentation in some patients of progressive aphasia, supranuclear gaze palsy (mimicking PSP), and frontotemporal dementia. Generally, cognitive decline and dysautonomia do not occur until later stages of the disease. The main neuropathological findings include swollen achromatic neurons, gliosis, and neuronal loss in the cerebral cortex, substantia nigra, lateral nuclei of the thalamus, locus cerleus, striatum, and Purkinje layer of the cerebellum. The disease tends to occur in those aged 60-80 years, with a mean age of onset of 63 years. CBD is a rare syndrome, with an estimated incidence of 0.02-0.92 per 100,000 population per year. No familial or environmental factors appear to influence CBD. Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) may initially be confused with CBD. However, the true diagnosis becomes clear as the apraxia and dystonia develop. Again, the clinical and pathologic features of PSP and CBD can overlap considerably.
Cortical atrophy of the frontal and parietal lobes has been described, with ballooned (see the image below) and enlarged cells seen on microscopy. The substantia nigra is depigmented. However, Lewy bodies and diffuse neuronal loss are conspicuously absent.
CBD is now classified as a 4-repeat tauopathy. Neuropathologic diagnostic criteria include tau-immunoreactive lesions in neurons, glia, and cell processes. The minimal pathologic features for diagnosis are cortical and striatal tau-positive neuronal and glial lesions, especially astrocytic plaques and threadlike structures in both white matter and gray matter combined with neuronal loss both in focal cortical lesions and substantia nigra. These criteria help distinguish the disease from other tauopathies, with the exception of frontotemporal dementia and parkinsonism related to chromosome 17 mutations (FTDP-17). Of note, patients meeting these pathologic criteria may not have had the classic clinical presentation of CBD.
Clinical onset of CBD occurs in the sixth decade of life. Rinne et al reported 5 initial presentations, including a “useless” arm (55%), gait disorder (27%), prominent sensory symptoms, isolated speech disturbance, and behavioral disturbance.
Symptoms on long-term follow-up include focal or asymmetric rigidity, bradykinesia, postural and action tremor, and marked dystonia. These problems usually arise predominantly in one upper extremity. Limb apraxia may become a serious problem, with independent movements occasionally as severe as an alien limb. The incidence of limb apraxia is far higher in CBD than in PSP, with a similar level of cognitive impairment.
Current clinical criteria tend to be biased in terms of motor symptoms. However, they are shifting toward criteria that include the important cognitive element. The dissociation between pathological criteria and clinical presentations has led to the term corticobasal syndrome (CBS), which distinguishes CBD from the classic clinical picture just described.
Treatment and prognosis
The rigidity, bradykinesia, and tremor sometimes can benefit from levodopa therapy. However, the marked disability from the limb apraxia is progressive and generally remains unresponsive to rehabilitation efforts. Injections of botulinum toxin often relieve dystonia. In particular, the dystonic clenched fist may respond to injections of botulinum toxin, which helps relieve the pain and prevent skin breakdown. CBGD usually progresses to severe disability and death within 10 years.
Dementia with Lewy Bodies (DLB)
Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder characterized by the presence of parkinsonian symptoms and neuropsychiatric disturbances commonly accompanied by dementia. Progressive dementia is often the first and predominant symptom. Of note, longitudinal studies show that after a decade of motor symptoms, 78% of patients with Parkinson disease meet the criteria for dementia, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), as opposed to the 25-30% estimate in patients with DLBD, as derived from cross-sectional studies. Therefore, considering DLBD and Parkinson disease as representing a continuum along a spectrum of cognitive dysfunction is useful.[40, 41, 42]
See the images below showing cortical Lewy bodies.
No familial disposition for DLB has been reported. Some have proposed that DLB represents an extended form of Parkinson disease. However, other authors view this as a clinically distinct entity.
The common thread to DLB and Parkinson disease is the presence of Lewy bodies. These are rounded inclusion bodies containing ubiquitin as the main component. In Parkinson disease, they are mainly observed in the substantia nigra. In contrast, in DLB they are scattered throughout the cerebral cortex and also are seen in the nigra and other subcortical regions. In contrast to Alzheimer disease and CBD, cortical atrophy is not prominent. Two distinct forms of DLB have been described. The pure form occurs with Lewy bodies in the cortical and subcortical structures, whereas the common form has Lewy bodies accompanied by plaques and tangles.
The clinical features may depend on the underlying form of the disease. In the common form, dementia is the prominent feature, while in the pure form, parkinsonian features are more prominent initially. Approximately 20% of patients do not have any parkinsonian features. Neuropsychological deficits that have been described include aphasia, dyscalculia, and apraxia. A psychotic state develops in approximately 20% of patients. Depression, auditory and visual hallucinations, and paranoid ideation may occur. These patients are more likely to have cognitive adverse effects with levodopa therapy in early stages than patients with Parkinson disease.
The Consortium on Dementia with Lewy bodies (DLB) proposed consensus clinical and pathologic criteria for diagnosis of DLB (ie, DLB criteria) in 1996. Three major clinical criteria were described: (1) visual hallucinations, (2) fluctuating cognition, and (3) spontaneous motor features of parkinsonism. One of the 3 criteria is required to diagnose possible DLB, and 2 of the 3 are needed for probable DLB. The minor criteria include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, and hallucinations in other modalities (auditory, olfactory, tactile).
Verghese et al tested the validity of these criteria. If DLB criteria were applied to the 18 patients with DLB and the 76 patients with non-Lewy body dementias in their sample, the definition for possible DLB had excellent sensitivity (89%) but poor specificity (28%), and the criteria for probable DLB had moderate sensitivity (61%) and good specificity (84%).
Parkinson disease is the main entity to be considered. Alzheimer disease in combination with extrapyramidal signs may resemble DLB. Neuroimaging is not especially helpful in making the differential diagnosis. While occipital hypometabolism is a characteristic feature on PET scans, Cordery et al showed that this is not always present.
Parkinsonian features may respond somewhat to levodopa therapy in some patients. Hallucinations and confusion are limiting factors.
Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with Parkinson disease psychosis. It is the first drug to be approved for this condition. Pimavanserin is a selective serotonin inverse agonists (SSIA) which preferentially targets 5-HT2A receptors, but avoids activity at dopamine and other receptors commonly targeted by antipsychotics. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson disease psychosis. Efficacy was shown in a 6-week clinical trial (n=199), where it was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor Parkinson disease symptoms (p=0.001).
Other novel neuroleptic medications (eg, quetiapine and clozapine) may be helpful in controlling hallucinations without exacerbating parkinsonian symptoms. However, these agents are not approved for dementia-related psychosis and their prescribing information include a boxed warning. Elderly patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials. Deaths in these trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.
Centrally acting cholinesterase inhibitors (eg, rivastigmine, donepezil, galantamine) partially reverse decreased cortical cholinergic activity and may improve cognition and neuropsychiatric symptoms in DLB. Rivastigmine improves cognition and neuropsychiatric symptoms in patients with DLB without worsening parkinsonian features. Prognosis is poor, as with the other syndromes already described.
Management of Parkinson-Plus Syndromes
Comprehensive face-to-face counseling with the patient and caregivers is indicated. Although the relatively poor prognosis must be outlined, it is also important to emphasize positive supportive measures. These include the use of appropriate walkers (preferably with wheels and brakes), occupational therapy, assessment of the home environment, physical therapy, and exercise. Ask specifically about swallowing ability and, when indicated, obtain a modified barium swallow study.
When difficulties with aspiration are detected, consider a change in diet and, in advanced cases, placement of a percutaneous endoscopic gastrostomy tube to maintain nutritional status. Patients may exhibit an interest in surgical treatments, such as deep brain stimulation, pallidotomy, or transplantation, but these are not indicated for Parkinson-plus syndromes.
Levodopa and Dopamine agonists
In general, patients with Parkinson-plus syndromes do not tolerate dopamine agonists well. The mainstay is a trial of levodopa at doses higher than those commonly used in Parkinson disease. A typical regimen begins with carbidopa/levodopa 25/100 twice daily, with the dose increased by 0.5-1 tablet every week to a target daily dose of approximately 1000 mg of levodopa.
If adverse effects occur at any point in the titration, lower the dose and reassess the plan. Although most patients do not have a positive response, some may respond to high doses, with reduced rigidity, easing of transfers, or mild improvements in balance or gait. If high doses of levodopa do not help the patient, gradually lower the dose with an aim to discontinue the medication. Some patients may find that a low dose helps them stay mobile or improve rigidity, and this dose can be maintained. The patient and caregiver should have easy access to the physician during the trial of levodopa.
Treatment of cognitive problems
Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with Parkinson disease psychosis. It is the first drug to be approved for this condition. It is a selective serotonin inverse agonist (SSIA). It not only preferentially targets 5-HT2A receptors, but also avoids activity at dopamine and other receptors commonly targeted by antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199) where it was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor Parkinson disease symptoms (p=0.001).
Hallucinations can also be alleviated to some extent with older neuroleptics (eg, quetiapine, clozapine), but these can cause marked increase in rigidity and are best avoided. Dementia is the most difficult symptom to treat in this setting. Donepezil and rivastigmine can be tried but do not have any dramatic effect and potentially can worsen motor symptoms. A comprehensive neuropsychological evaluation repeated at intervals of 1 year can help in assessing the progression of cognitive symptoms in a quantitative way and can suggest coping methods.
Treatment of eye involvement
Some patients with PSP may benefit from prismatic lenses that compensate to some extent for the vertical gaze problems. Blepharospasm, facial dystonia, and apraxia of eyelid opening may respond to botulinum toxin injections.
Patients with parkinsonian syndromes unresponsive to dopamine agonists or levodopa should have an imaging study of the brain. MRI of the brain is preferred to CT, as it provides better visualization of midbrain and brainstem structures. PET imaging with fluorine-18-fluorodeoxyglucose (FDG) has been used to identify characteristic patterns of regional glucose metabolism in patients with idiopathic PD or variants of parkinsonism, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).
In a longitudinal study, Eckert et al compared PET diagnosis with a clinical diagnosis by a movement disorders specialist with 2-year follow-up. Diagnoses based on blinded computerized assessment of PET scans agreed with clinical diagnosis in 92.4% of all subjects (97.7% with early PD, 91.6% with late PD, 96% with MSA, 85% with PSP, 90.1% with CBGD) and in 86.5% of healthy control subjects. At present, PET and SPECT scans remain research tools and are not routinely used for diagnosis.
Transcranial sonography (TCS) has been used as a tool for the differential diagnosis of these syndromes. Characteristic findings include hyperechogenicity in the substantia nigra in Parkinson disease, while hyperechogenicity in the lentiform nucleus is seen in MSA and PSP. Walter et al observed that lenticular nuclei hvperechogenicity is observed in 72-82% of patients with MSA and PSP but in only 10-25% of patients with Parkinson disease. Further studies are required to validate these findings.
Magnetic resonance diffusion-weighted imaging regional apparent diffusion coefficients (rADCs) may also be helpful. Middle cerebellar peduncle and rostral pons rADCs in MSA are significantly greater than in PSP and Parkinson disease. Pavior et al reported that middle cerebellar peduncle rADC distinguishes MSA from PSP with a sensitivity of 91% and a specificity of 84%.
An exciting development is the possible application of deep brain stimulation (DBS) to Parkinson-plus syndromes. In an open label trial, Stefani et al reported an improvement in gait and balance in patients with PSP undergoing DBS with the pedeculopontine nucleus and the subthalamic nucleus in combination. Further studies are warranted to validate this result.
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