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Parkinson-Plus Syndromes
Last Updated: October 5, 2005
(http://www.emedicine.com/neuro/topic596.htm)
Synonyms and related keywords: Parkinson disease, PD, Parkinson's disease, atypical
parkinsonism, multiple system atrophy, MSA, progressive supranuclear palsy, PSP,
parkinsonism-dementia-amyotrophic lateral sclerosis complex, PDALS,
corticobasalganglionic degeneration, CBGD, diffuse Lewy body disease, DLBD,
parkinsonian features
AUTHOR INFORMATION
Section 1 of 9

Author: Arif Dalvi, MD , Program Director, Assistant Professor, Department of
Neurology, University of Chicago, Co-director of Parkinson's Disease and Movement
Disorders Center
Coauthor(s): Stephen M Bloomfield, MD , Assistant Professor, Department of
Neurosurgery, West Virginia University
Arif Dalvi, MD, is a member of the following medical societies: Movement Disorders
Society
Editor(s): Christopher C Luzzio, MD , Clinical Assistant Professor, Department of
Neurology, University of Wisconsin at Madison; Francisco Talavera, PharmD, PhD ,
Senior Pharmacy Editor, eMedicine; Nestor Galvez-Jimenez, MD , Program Director of
Movement Disorders, Director of Neurology Residency Training Program, Department
of Neurology, Division of Medicine, Cleveland Clinic Florida; Matthew J Baker, MD ,
Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and
Nicholas Lorenzo, MD , Chief Editor, eMedicine Neurology; Consulting Staff,
Neurology Specialists and Consultants
DEFINITION
Section 2 of 9
Several primary neurodegenerative disorders have parkinsonian features, such as bradykinesia, rigidity, tremor, and gait disturbances, in common. These neurologic conditions are associated with complex clinical presentations that reflect degeneration in various neuronal systems. However, because of the common parkinsonian features, the disorders have been collectively named Parkinson-plus syndromes. Although separate clinical syndromes have been identified, modern immunocytochemical techniques and genetic findings suggest many underlying similarities broadly grouped into 2 types: synucleinopathies and tauopathies. Patients with Parkinson-plus syndromes typically have a worse prognosis than those with Parkinson disease (PD), and Parkinson-plus syndrome responds poorly to the standard anti-Parkinson treatments. An adequate response to treatment in a patient with parkinsonian symptoms may indicate that a Parkinson-plus syndrome is developing, and searching for the signs and symptoms of degeneration in other neuronal systems is important. Clinical clues suggestive of Parkinson-plus syndromes include the following:
• Lack of response to levodopa/carbidopa (Sinemet) or dopamine agonists in the • Early onset of dementia • Early onset of postural instability • Early onset of hallucinations or psychosis with low doses of levodopa/carbidopa • Ocular signs, such as impaired vertical gaze, blinking on saccade, square-wave jerks, nystagmus, blepharospasm, and apraxia of eyelid opening or closure • Pyramidal tract signs not explained by previous stroke or spinal cord lesions • Autonomic symptoms such as postural hypotension and incontinence early in the • Prominent motor apraxia • Alien-limb phenomenon • Marked symmetry of signs in early stages of the disease • Truncal symptoms more prominent than appendicular symptoms • Absence of structural etiology such as a normal-pressure hydrocephalus (NPH) MULTIPLE-SYSTEM ATROPHY
Section 3 of 9
Historical developments
Dejerine and Thomas first used the term olivopontocerebellar atrophy (OPCA) in 1900 when they described 2 patients with a degenerative disorder leading to progressive cerebellar dysfunction and parkinsonism. In 1960, van de Eecken, Adams, and van Bogaert reported 3 patients with striatonigral degeneration (SND) with atrophy of the caudate nucleus and putamen. In 1960, Shy and Drager described a neurologic syndrome (Shy-Drager syndrome [SDS]) of orthostatic hypotension with parkinsonian features. In 1969, Graham and Oppenheimer noted that the clinical and pathologic findings of OPCA, SND, and SDS overlapped significantly. They advanced the term multiple-system atrophy (MSA) to describe these disorders. OPCA, SND, and SDS were considered distinct entities reflecting degeneration of separate neuronal subsystems. Because patients shared many signs and symptoms, the clinical distinction may be unclear. Recent neurobiologic research has justified the grouping of these conditions under a common pathophysiologic definition as variants of MSA. Definition
The clinical definition of MSA is a progressive, idiopathic, degenerative process beginning in adulthood. Patients present with various degrees of parkinsonism, autonomic failure, cerebellar dysfunction, and, pyramidal signs that are poorly responsive to levodopa or dopamine agonists. Glial cytoplasmic inclusions (GCIs) and a neuronal multisystem degeneration are the pathologic hallmarks of this clinically variable disorder. Diagnosis
In 2003, the Movement Disorders Society Scientific Issues Committee Report (MDSSICR) revised the diagnostic criteria for MSA. These criteria allowed for the classification of MSA by different levels of diagnostic certainty, such as possible, probable, and definite. The report recommended that MSA be subdivided into 2 categories on the basis of the neurosystem predominantly involved. Patients with predominant parkinsonian features are identified as having MSA-P, which replaces the term SND, whereas patients with prominent cerebellar dysfunction have MSA-C, which replaces the term OPCA. Patients with idiopathic PD are distinguished from patients with MSA by the lack of autonomic and cerebellar features as well as by their response to levodopa/carbidopa. Patients with MSA typically do not substantially benefit from trials of levodopa/carbidopa. Distinguishing patients with MSA from patients with progressive supranuclear palsy (PSP) can be difficult; the latter sometimes have cerebellar features or diffuse Lewy body disease (DLBD) and orthostatic hypotension. The conference recommended that patients with MSA and predominant cerebellar features be designated having MSA-C, which replaces the term sporadic OPCA. Autonomic dysfunction appears in all forms of MSA. Therefore, the term SDS is not useful. Differential diagnosis
MSA is most likely to be confused with idiopathic PD. In a prospective clinicopathologic study, the initial diagnosis of PD was correct in 65% of patients, a rate which improved to 76% with follow-up care. MSA was correctly diagnosed in 69% of patients who had been observed for at least 5 years. Clinical clues indicating the Parkinson-plus syndromes are discussed in Definition above. In MSA, autonomic insufficiency and cerebellar signs are the features most helpful with differential diagnosis. Epidemiology
The exact incidence of MSA is not known clearly owing to the opinion that it is underrecognized. Some authors estimate that 3-10% of patients with Parkinson syndrome actually have MSA-P, and a prevalence of 16.4 cases per 100,000 population has been reported. In a study in Minnesota in 1976-1990, researchers estimated the average annual incidence of MSA was 3 cases per 100,000 population. A study in rural Bavaria showed a prevalence of 0.31% in the population older than 65 years, a group in which 0.71% had PD. The disease has a male predominance, as documented in 3 of 4 large studies. One study of 203 patients with histopathologically confirmed MSA demonstrated a male-to-female ratio of 1.3:1.0. The mean patient age at onset is 54.3 years with a range of 33-78 years. Clinical presentation
The MDSSICR recognizes 4 clinical domains in MSA: autonomic and urinary dysfunction, parkinsonism, cerebellar dysfunction, and corticospinal dysfunction. In 1 study of 100 patients, initial symptoms were orthostatic hypotension (68%), parkinsonism (46%), autonomic symptoms (41%), and cerebellar signs and symptoms (5%). Nearly all patients eventually develop parkinsonism and autonomic symptoms. Orthostatic hypotension develops in 66% of patients. Cerebellar symptoms develop in 50% of patients during the course of the disease. Patients with autonomic failure develop urinary dysfunction, orthostatic hypotension, erectile dysfunction, or impotence, which are observed early in nearly all men with MSA. Other common problems are urinary frequency, urgency, incontinence, or incomplete bladder emptying. On electromyelography (EMG), abnormal sphincteric results have been noted in MSA and can be useful ancillary findings. Patients with parkinsonism typically have asymmetric tremor, bradykinesia, rigidity, and postural instability. The tremor tends to be postural, irregular, and jerky, unlike the typical pill-rolling tremor of idiopathic parkinsonism. The dysarthria observed in patients with MSA tends to be hypokinetic. Patients with cerebellar features present with gait and limb ataxia, ataxic dysarthria, and sustained gaze-evoked nystagmus. They also tend to develop saccadic pursuit movements. Patients with corticospinal dysfunction present with extensor plantar responses and hyperreflexia. Respiratory stridor is observed in 33% of patients. However, they rarely require a tracheostomy. Cognitive dysfunction is less common than in other Parkinson-plus syndromes such as PSP or corticobasalganglionic degeneration (CBGD). Neuroimaging
Neuroimaging findings in patients with MSA are partially correlated with the neuronal subsystems involved. All clinical subtypes tend to cause atrophy of the cerebellum, brainstem, putamen, and caudate nucleus. The globus pallidus tends to be spared in MSA. The cerebellum and brainstem tends to be atrophied in patients who present with predominantly cerebellar features, whereas the putamen and caudate nucleus tends to be involved in patients who present with parkinsonian features. Slitlike hyperintensities are noted on T2- and proton density–weighted MRIs of the pons, middle cerebellar peduncle, and cerebellum. An autopsy-proven case of MSA had hyperintensities in the pyramidal system on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI. Correlations between MRI and histopathologic findings support the theory that iron deposition, microgliosis, astrocytosis, and severe neuronal loss appear to contribute to the abnormal hyperintensities. The most reliable findings specific to MSA are putaminal atrophy, hyperintensity in the rim of the putamen, and infratentorial changes. However, these findings are not observed in all patients with MSA. Altered size of the inferior olivary nuclei and putaminal isointensity or hypointensity relative to the globus pallidus are not useful findings. Reduced metabolic activity in the putamen and decreased dopaminergic function in the striatonigral system has been demonstrated on positron emission tomography (PET) in patients with the parkinsonian subtype of MSA. However, these findings also are observed in idiopathic PD. Decreased metabolic activity in the cerebellum has been noted in the cerebellar subtype of MSA. PET studies may be useful in the differential diagnosis of MSA, PSP, and CBGD. Routine MRI can be somewhat helpful in distinguishing MSA, PSP, and CBGD. Putaminal involvement and vermian cerebellar atrophy are significantly most common in MSA, but cortical atrophy, midbrain atrophy, and third ventricle enlargement are most common in PSP and CBGD. Pathologic findings
Macroscopic findings of patients with MSA are correlated with neuroimaging and clinical findings. Each MSA subtype demonstrates various degrees of atrophy in the extrapyramidal, spinocerebellar, pyramidal, and autonomic nervous systems. Some depigmentation of the substantia nigra and locus ceruleus is noted in all MSA subtypes. Atrophy of the motor and premotor cortices has also been noted. The intermediolateral cell column of the spinal cord is preferentially involved. Patients with MSA-P primarily develop extrapyramidal system atrophy such that the posterolateral putamen and ventrolateral substantia nigra appear atrophic and discolored. Patients with MSA-C primarily have shrinkage of the cerebellum, middle cerebellar peduncles, inferior olives, and basis pontis. Histopathologic findings include neuronal loss, gliosis, and microvacuolation in the involved neuronal systems. These findings are present in varying degrees proportional to the volume loss on gross inspection. Even in regions where atrophy is not noted, these changes are present to some extent. Demyelination eventually ensues in the white matter in the involved regions. An epitope of myelin basic protein was discovered only in degenerating myelin. Monoclonal antibody probes for this aberrant myelin demonstrate that these white matter lesions are more widespread than previously demonstrated with routine myelin stains. Autonomic and endocrine manifestations of MSA may be related to neuronal loss in the hypothalamus, spinal cord, and medulla. Cell loss has been found in histaminergic neurons in the tuberomammillary nucleus, arginine-vasopressin neurons in the suprachiasmatic nucleus, and tyrosine hydrolase neurons in the medulla, arcuate nucleus, and spinal cord lateral horns and intermediate zone of the anterior horns. Abnormalities in peripheral nerves and muscles that are absent in patients with idiopathic PD have been found in patients with MSA. Sural nerve biopsy demonstrates a 23% reduction in unmyelinated nerve fibers. Nerve conduction studies are abnormal in 40% of patients with MSA. Abnormal electromyography findings suggesting partial denervation have been found in 22.5% of patients with MSA. Neurodegeneration affecting axons may be a distinctive characteristic that can differentiate patients with MSA or PSP patients from patients with idiopathic PD. Neurofilament proteins reflecting axonal degeneration are increased in the CSF of patients with MSA or PSP. Pathophysiology of MSA
Although the exact cause of MSA evades understanding, many pathophysiologic mechanisms have been uncovered. Iron and ferritin levels appear to be increased in the substantia nigra and striatum. Oligodendroglial and microglial cells are predominantly involved, with neurons and astrocytes relatively spared. Iron levels in the putamen are 5 times higher than normal and associated with coarse electron-dense granules and fine granular and fibrillary material in lamellated structures. This excessive iron accumulation is correlated with the signal voids noted in these structures on MRI. Excessive iron may produce neurotoxicity because of its role in oxidation and reduction reactions. This type of oxidative stress is speculated to be involved in various neurodegenerative disorders. Iron also promotes fibril formation from alpha-synuclein that may be responsible for the formation of GCIs (see Glial cytoplasmic inclusions below). Genetic susceptibility involving various genetic markers has been examined without confirmation. Genetic markers for previously identified spinocerebellar disorders are not found in patients with MSA. Mitochondrial chain function in the substantia nigra and platelets of patients with MSA are similar to that of age-matched controls. Glial cytoplasmic inclusions
Microscopic findings in patients with MSA are distinctive for the cytoplasmic inclusions in the oligodendroglial cells, as well as for neuronal loss, astrocytosis, and loss of myelin. These lesions are predominantly located in the substantia nigra, locus ceruleus, putamen, inferior olives, pontine nuclei, Purkinje cells, and intermediolateral columns of the spinal cord. The globus pallidus, caudate nucleus, corticospinal tracts, anterior horn cells of the cord, dentate nucleus, and vestibular nuclei are relatively spared. Many neurodegenerative disorders have been associated with a distinctive pathognomonic histopathologic lesion that can assist in diagnosis. Until 1989, no distinctive lesion was associated with MSA did not have any distinctive lesion was associated with MSA, and the histopathologic diagnosis was based on nonspecific and variable neuronal-system atrophy, cell loss, myelin pallor, and astrocytosis. In 1989, GCIs were described in patients with MSA. GCIs are argyrophilic and have various shapes (eg, triangular, sickle, half-moon, oval, conical). They are occasionally flame shaped and may superficially resemble neurofibrillary tangles. However, cytoplasmic location, size, ultrastructure, immunocytochemical profile, and regional distribution of GCIs are distinctive. GCIs vary in size; they may fill the cytoplasm completely and push the nucleus to the side. The distribution of GCIs follows the suprasegmental motor system, supraspinal autonomic system, and their targets. This distribution includes the primary and secondary motor cortices, the pyramidal and extrapyramidal tracts, and the corticocerebellar systems. The density of GCIs is correlated with the severity of symptoms of patients with MSA. The distribution of GCIs is correlated with the subtypes of MSA, with putaminal lesions prevalent in patients with the MSA-P subtype and corticopontine lesions prevalent in patients with the MSA-C subtype. Pyramidal lesions correlate with the severity of symptoms in both subtypes. Ultrastructural studies of GCIs with electron microscopy and monoclonal antibody probes have confirmed their location in oligodendroglial cells and revealed them to be composed of ubiquitin, tau, microtubule-associated protein-5, cyclin-dependent kinase 5 (cdk5), mitogen-activated protein kinase (MAPK), and alpha synuclein. The tau component in GCIs appears to be immunologically distinct from the tau protein found in patients with Alzheimer disease, PSP, or corticobasal degeneration (CBD). MAPK and cdk5 are usually found in neurons and not oligodendroglial cells. Phosphorylation of these microtubular proteins of the cytoskeleton by these aberrantly located or expressed protein kinases may lead to the formation of GCIs. Other neuronal inclusions have been observed in both the cytoplasm and nucleus of both oligodendroglial cells and neurons in patients with MSA. However, these findings are seen less commonly than GCIs, which remain the hallmark lesion of MSA. The density of GCIs appears to be correlated with the severity of oligodendroglial degeneration and not with the potential degeneration of axons or neurons. The finding of GCIs within oligodendroglial cells of patients with MSA has led to a shift in research interest from neurons to glial cells in patients with various neurodegenerative disorders. A variety of cellular alterations in glial cells of patients with various neurodegenerative disorders has been described. However, none have resembled GCIs, and the clinical significance of these markers remains unclear. Further research in glial pathology may help uncover the pathophysiology in patients with neurodegenerative disorders. Treatment and prognosis of MSA
Patients who develop MSA routinely are faced with a progressive disorder that eventually culminates in disability and death. Median survival in one study of 100 patients was 6.2 years with a range of 0.5-24 years. Patients with the cerebellar subtype of MSA survived longer. Response to drug therapy is poor. The ataxia is particularly resistant to therapy. Levodopa replacement is the mainstay of therapy for the parkinsonian features. Responses tend to be less clear-cut and may be transient. Dopamine agonists are not effective and are more likely to cause hallucinations and psychosis. Blepharospasm and limb dystonia can be reduced with botulinum toxin injections. Autonomic dysfunction is a prominent feature of the disease. Initial treatment includes reduction of antihypertensive agents, increased salt and water intake, and use of elastic stockings. Florinef and Midodrine can be helpful when other measures fail. PROGRESSIVE SUPRANUCLEAR PALSY
Section 4 of 9
PSP is the most common Parkinson-plus syndrome. 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 aged 43 years. 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. 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 on the island of Guadeloupe. This high incidence might be related to environmental neurotoxins that are found in herbal teas and fruits that are in common consumption on this island. PSP with tau doublets was found in all 3 cases of probable PSP in which autopsy was performed. Pathology
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. 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
Of late, PSP has been considered 1 of the tau protein disorders. Cortical fibrillary tangles of PSP are similar to those observed in Alzheimer disease with regard to 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 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
The typical patient develops symptoms in the sixth and seventh decades of life. The patient develops bradykinesia, rigidity, dysarthria, dysphagia, and dementia, like 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. The supranuclear component of the disorder is vertical ocular gaze paresis, which can be overcome by vertical doll's-eyes maneuvers. The feature of vertical gaze paresis with a history of frequent falls due to postural instability is central to the diagnosis of PSP. Some patients develop severe palilalia, emotional incontinence, and other evidence of bilateral frontal lobe dysfunction. Occasional 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 Society for Progressive Supranuclear Palsy have published formal criteria for the diagnosis of PSP. In 2003, the 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 compared with those with PD. A study of 103 consecutive cases of pathologically proved PSP revealed 2 clinical subtypes (Williams, 2005). 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 for 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. Differential diagnosis
Consider many of the Parkinson-plus syndromes, such as Alzheimer disease, MSA, CBGD, Lewy body dementia, and PD. Also consider other conditions such as multi-infarct dementia, vascular parkinsonism, NPH, posthypoxic encephalopathy, Whipple disease, neuroacanthocytosis, progressive external ophthalmoplegia, and dentatorubropallidoluysian atrophy. Diagnostic tests
MRI can help exclude NPH and multi-infarction syndromes. As noted above, MRI can also be helpful in distinguishing PSP from MSA and CBGD. 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. Clinical management
Pharmacologic agents remain the mainstay of treatment of PSP, though the results are frequently disappointing. Levodopa/carbidopa reduces bradykinesia and rigidity in one third of patients for approximately 2 years. 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 ADLs and motor scores. Zolpidem was reported to improve both motor symptoms and ocular findings, but this effect was transient. If present, 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 gastronomy tube placement to reduce aspiration risk. Prognosis
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
Section 5 of 9
SCLEROSIS COMPLEX
Parkinsonism-dementia-amyotrophic lateral sclerosis complex (PDALS) is a condition well described on the island of Guam and locally 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 amyotrophic lateral sclerosis (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 recently 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. Pathology
Pathologic evaluation of the substantia nigra has found depigmentation, basophilic inclusion bodies, cell loss, and neurofibrillary tangles without senile plaques. This latter finding also has been observed in the anterior horn cells and pyramidal tracts. Clinical presentation
Motor neuron disease tends to occur in younger patients. Older patients tend to develop parkinsonism and severe dementia. Two cultural groups have populated the island of Guam: The Chamorros group tends to have the ALS form, both the Chamorros and Filipino groups tend to have parkinsonism-dementia syndrome. Differential diagnosis
Consider Alzheimer disease, Lewy body disease, postencephalitic parkinsonism, idiopathic PD, ALS, and motor neuron disorders in the differential diagnosis of PDALS. Treatment
Patients do not respond to levodopa. Psychiatric treatment may be indicated. Prognosis
A progressive clinical picture is characteristic of both subtypes of PDALS. Death within 10 years is usual. CORTICOBASALGANGLIONIC DEGENERATION
Section 6 of 9
CBGD is characterized by frontoparietal cortical atrophy in addition to degeneration within the extrapyramidal system. The disease tends to occur in those aged 60-80 years, with a mean age of onset of 63 years. CBGD is a rare syndrome with an estimated incidence of 0.02-0.92 per 100,000 population per year. Pathology
Cortical atrophy of the frontal and parietal lobes has been described, with ballooned and enlarged cells seen on microscopy. The substantia nigra is depigmented. However, Lewy bodies and diffuse neuronal loss are conspicuously absent. The concept of CBD as a tau protein disorder is mentioned in Abnormality of the tau protein . The disease 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 description described below. Clinical presentation
No familial or environmental factors appear to influence CBGD. Symptoms develop in the sixth decade of life. Rinne et al reported 5 initial presentations including a “useless” arm (55%), gait disorder (27%), and 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 1 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 CBGD 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 that the term corticobasal syndrome (CBS), which distinguishes CBD from the classic clinical picture just described. PET may be useful in the diagnosis of CBGD, as discussed below. Differential diagnosis
PSP and MSA may initially be confused with CBGD. However, the true diagnosis becomes clear as the apraxia and dystonia develop. Again, the clinical and pathologic features of PSP and CBGD can overlap considerably. Treatment
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. Prognosis
CBGD usually progresses to severe disability and death within 10 years. DIFFUSE LEWY BODY DISEASE
Section 7 of 9
Definition
DLBD 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 of patients with PD show that 78% meet the criteria for dementia in the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R), after a decade of motor symptoms as opposed to the 25-30% estimate from cross-sectional studies. Therefore, it is useful to consider DLBD and PD as representing a continuum along a spectrum of cognitive dysfunction. Etiology
No familial disposition for DLBD has been reported. Some have proposed that DLBD represents an extended form of PD. However, other authors view this as a clinically distinct entity. Neuropathology
The common thread to DLBD and PD is the presence of Lewy bodies. These are rounded inclusion bodies containing ubiquitin as the main component. In PD, they are mainly observed in the substantia nigra. In contrast, in DLBD they are scattered throughout the cerebral cortex and also are seen in the nigra and other subcortical regions. In contrast to Alzheimer disease and CBGD, cortical atrophy is not prominent. Two distinct forms of the condition 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. Clinical features
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 one fifth of patients do not have any parkinsonian features. Neuropsychological deficits that have been described include aphasia, dyscalculia, and apraxia. A psychotic state is found 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 PD. The Consortium on Dementia with Lewy bodies (CDLB) proposed consensus clinical and pathologic criteria for diagnosis of DLBD (ie, CDLB 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 DLBD, and 2 of the 3 are needed for probable DLBD. 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 CDLB criteria were applied to the 18 patients with DLBD and 76 patients with non-Lewy body dementias in their sample, the definition for possible DLBD had excellent sensitivity (89%) but poor specificity (28%), and the criteria for probable DLBD had moderate sensitivity (61%) and good specificity (84%). Differential diagnosis
PD is the main entity to be considered. Alzheimer disease in combination with extrapyramidal signs may resemble DLBD. Neuroimaging is not especially helpful in making the differential diagnosis. While occipital hypometabolism is a characteristic feature on PET scans, Cordery et al have shown that this is not always present. Treatment
Parkinsonian features may respond somewhat to levodopa therapy in some patients. Hallucinations and confusion are limiting factors. Novel neuroleptic medications, such as quetiapine and clozapine, are helpful in controlling hallucinations without exacerbating parkinsonian symptoms. Centrally acting cholinesterase inhibitors, such as rivastigmine, donepezil, and galantamine partially reverse decreased cortical cholinergic activity and may improve cognition and neuropsychiatric symptoms in DLBD. Rivastigmine improves cognition and neuropsychiatric symptoms in patients with DLBD without worsening parkinsonian features. Prognosis is poor, as with the other syndromes already described. PRACTICAL MANAGEMENT OF PARKINSON-PLUS
Section 8 of 9
SYNDROMES
Investigation
In patients with parkinsonian syndromes unresponsive to dopamine agonists or levodopa, imaging study is warranted. MRI of the brain is preferred to CT, as it improves 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 MSA, PSP, and 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. Counseling and safety measures
Comprehensive face-to-face counseling is indicated with the patient and caregivers involved. Although the relatively poor prognosis must be outlined, give attention to emphasizing positive supportive measures. These include safety measures, such as use of appropriate walkers (preferably with wheels and brakes), occupational therapy, assessment of the home environment, physical therapy, and exercise. Specifically ask questions about swallowing mechanisms, 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 gastronomy tube to maintain nutritional status. Patients may exhibit an interest in surgical techniques such as deep brain stimulation, pallidotomy, or transplantation, but these are not indicated for Parkinson-plus syndromes. Levodopa trial
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 PD. A typical regimen begins with levodopa/carbidopa 25/100 twice per day, with the dose increased by 0.5-1 tablet every week to a target daily dose of approximately 1000 mg based on the levodopa content. 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. Cognitive aspects
Hallucinations can be alleviated to some extent with quetiapine or clozapine. The older neuroleptics 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. Eye signs
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 can respond to botulinum-toxin injections. Patient education
For excellent patient education resources, visit eMedicine's Dementia Center . Also, see eMedicine's patient education article Possible Early Dementia . BIBLIOGRAPHY
Section 9 of 9
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