Parkinsonism Plus Syndromes

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In addition to Parkinson's disease, parkinsonism is one of the major clinical features in several other primary neurodegenerative conditions. However, because they all have additional features not typical of Parkinson's disease and share an overall worse prognosis and poorer response to antiparkinsonian therapy, they are often grouped together under the conglomerate term parkinsonism-plus syndromes. Within this group, each condition has distinctive characteristics that must be recognized and distinguished from one another and from PD.

PROGRESSIVE SUPRANUCLEAR PALSY

Pathogenesis and Pathophysiology. Progressive supranuclear palsy (PSP) is the most common and best recognized entity among the parkinsonism-plus syndromes. PSP is an idiopathic condition with no known precipitant or strong genetic component. Postmortem analysis of the brains of PSP patients show neuronal loss, gliosis, and neurofibrillary tangles composed of straight and paired helical filaments. y The SN, subthalamic nucleus, globus pallidus, superior colliculus, pretectal area, and substantia innominata are the sites of maximum involvement. Dopaminergic, cholinergic, and adrenergic neurotransmitter systems are affected, provoking a far more diffuse degenerative process than that seen in Parkinson's disease. '6

Epidemiology and Risk Factors. A medically based survey in central New Jersey found that the age-adjusted prevalence of PSP was 1.38 per 100,000 population, and men appeared to be slightly more frequently affected than women. y Most patients experience the initial symptoms during their sixth and seventh decades. No clear geographical, occupational, or temporal clusters of PSP have been found. Although PSP is not considered a genetic disorder, rare familial clusters have been reported and Conrad and colleagues have identified an association with a particular tau genetic factor.

Clinical Features and Associated Disorders. PSP shares some clinical features with PD, such as bradykinesia, rigidity, dysarthria, dysphagia, and dementia. However, PSP patients rarely exhibit tremor and usually have much more profound postural instability. In addition, axial rigidity is more prominent than limb rigidity. Some patients with PSP also develop severe palilalia, emotional incontinence, and other evidence of bilateral frontal lobe dysfunction. y

The best known feature of PSP, vertical ocular gaze paresis, may be overcome by passive head movement, which activates the oculocephalic reflexes (hence the designation supranuclear). Riley and colleagues y reported five patients who presented with "pure akinesia" of gait, speech, and handwriting without rigidity, tremor, dementia, or eye movement abnormalities on clinical examination. None of the patients responded to levodopa, and four demonstrated subtle changes in vertical saccades on eyelid movement recordings.y The diagnostic criteria for PSP have been recently refined as a result of careful clinical-pathological correlative studies, and the greatest diagnostic confidence is placed in the combined clinical features of early frequent falls within the first year of clinical disease and vertical downward supranuclear paresis on examination. y

Differential Diagnosis. Whereas PSP is idiopathic, the same clinical syndrome has been associated with Alzheimer's disease, multiple strokes, multiple system atrophy (MSA), posthypoxic encephalopathy, and Whipple's disease. Parkinson's disease itself and the other parkinsonism-plus syndromes, including corticobasal ganglionic degeneration, Lewy body dementia, normal pressure hydrocephalus, and "multi-infarct parkinsonism" must also be considered. Rarely, other conditions such as dentato-rubro-pallido-luysian atrophy (DRPLA), neuroacanthocytosis, progressive external ophthalmoplegia, and hydrocephalus may present with oculomotility disorders that are suggestive of PSP.

Evaluation. Magnetic resonance imaging (MRI) should be performed in patients in whom PSP is suspected to rule out a multi-infarct state or hydrocephalus. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) demonstrate prefrontal hypoactivity and show evidence of severe involvement of the dopaminergic terminals as well as the postsynaptic DA receptors in the striatum. y

Management. Although PSP is associated with loss of multiple neurotransmitters, pharmacological therapies remain disappointing. Levodopa ameliorates the bradykinesia and rigidity in about a third of cases, but the benefit rarely persists beyond 1 or 2 years. DA agonists rarely provide additional benefit. If, however, the dopaminergic drugs improve the bradykinesia but have no impact on poor balance, the medicated patient may feel more agile and independent, only to fall more frequently, leading to consequently greater disability. Anticholinergic drugs and tricyclic antidepressants with anticholinergic effects (e.g., amitriptyline) may be helpful in treating emotional incontinence. Idazoxan, a noradrenergic drug, produced modest improvement in a small number of patients, but sympathomimetic and other side effects have limited further development of this drug.y Blepharospasm, occasionally associated

with PSP, responds to botulinum toxin injection, and dry eyes may be treated with topical lubricants. Although physical, occupational, and speech therapy are of limited potential, these options may be beneficial in some patients and their families. Electroconvulsive therapy, adrenal implantation, and pallidotomy have been of no benefit.

Prognosis and Future Perspectives. The median interval from onset of the initial symptom, regardless of its nature, to onset of gait difficulty is estimated at 0.3 years; to the need for gait assistance, 3.1 years; to confinement to bed or wheelchair, 8.2 years; and to death, 9.7 years. y The problems that most frequently cause complications or death are falls and aspiration.

MULTIPLE SYSTEM ATROPHY

Pathogenesis and Pathophysiology. The pathogenic mechanisms of MSA remain unknown, and in contrast to PD, there is no evidence that genetic factors play a role. Whereas the initial neurodegenerative events are unclear, in well-established cases, the staining characteristics and distribution of oligodendroglial fibrillary cytoplasmic inclusions are distinctively different from the neurofibrillary tangles of Alzheimer's disease, PSP, postencephalitic parkinsonism, and others. y Highly variable neuronal loss and gliosis are seen in the substantia nigra, caudate, putamen, cerebellar cortex, pyramidal tract, Edinger-Westphal nucleus, locus ceruleus, inferior olives, dorsal motor nucleus of the vagus, Purkinje cells, intermediolateral cell column of the spinal cord, spinocerebellar tracts, and Onuf's nucleus. Reduced dopamine or norepinephrine levels occur in the nigra, nucleus accumbens, septum, hypothalamus, and locus ceruleus. y

Epidemiology and Risk Factors. In a review of autopsies of parkinsonism, Quinn reported frequencies ranging from 3.6 to 22 percent, with a mean of 8.2 percent (68/833 cases).y However, no study has been undertaken to determine the population prevalence of MSA. At one large referral center, 100 patients with MSA reported a median age at onset of 53 years (range, 33 to 76 years). y

Clinical Features and Associated Disorders. MSA encompasses three neurodegenerative syndromes, which in the past were considered clinically distinct: striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome (SDS). All these conditions share similarities with one another and with PD. The hallmark features of MSA are parkinsonism that is poorly responsive to levodopa therapy and varying degrees of autonomic, cerebellar, and pyramidal dysfunction. SDS is diagnosed clinically when dysautonomia far outweighs the other signs, SND is designated when anterocollis and pyramidal dysfunction are prominent, and OPCA is used to characterize the patient with prominent cerebellar features of ataxia, limb dyssynergia, and kinetic tremor. For all MSA patients, autonomic insufficiencies include orthostatic hypotension, postprandial hypotension, anhidrosis with thermoregulatory disturbances, poor lacrimation and salivation, constipation, and impotence. Disturbances in bladder emptying and incontinence may also occur. In addition, emotional lability, pyramidal signs, supranuclear ophthalmoplegia, anterocollis, myoclonus, sleep apnea and other ventilatory dysrhythmias, respiratory stridor, polyneuropathy, amyotrophy, and dementia may be present in any of the forms.y The variety of clinical presentations is wide, and pure autonomic failure, sleep apnea syndromes, some forms of peripheral neuropathies, and conditions that clinically resemble amyotrophic lateral sclerosis all may represent forms of underlying MSA.

Differential Diagnosis. Parkinson's disease, particularly in patients with prominent postural instability and gait disturbance, may be difficult to distinguish from MSA.[34] PSP and other parkinsonism-plus syndromes can be particularly difficult to separate, especially in the first 5 years of clinical illness. Vascular encephalopathies with multiple subcortical strokes may produce a similar constellation of signs, and the condition of pure autonomic failure can be difficult to differentiate from MSA in the early course of illness.

Evaluation.MRI may be useful to rule out a multi-infarct state, normal pressure hydrocephalus, or other causes of parkinsonism. An MRI scan demonstrating marked hypointensity of the striatum and linear hyperintensity lateral to the putamen on T2 weighted images suggests iron deposition and supports the diagnosis of MSA. y PET scans of MSA are similar to those of PSP and usually confirm a decreased density of striatal D2 receptors. y External urethral and rectal sphincter electromyography (EMG) is abnormal in almost all patients with MSA. Resting, supine, and standing norepinephrine levels are of questionable value, but supine and standing norepinephrine levels have been found to be slightly elevated in patients with MSA, whereas in those with pure autonomic failure they are usually decreased.y

Management. Levodopa may provide some relief, usually short-term, for the rigidity, bradykinesia, and postural instability typical of MSA. y Patients with MSA usually require larger doses of levodopa than patients with PD, but side effects, such as increased orthostatic hypotension and facial dystonia, often limit the usefulness of levodopa. Patients rarely derive any meaningful benefit from DA agonists, anticholinergics, amantadine, or other antiparkinsonian drugs. Symptomatic orthostatic hypotension can be treated with sodium and volume repletion unless the patient is at risk of congestive heart failure or renal insufficiency. Ancillary measures such as wearing elastic stockings to increase central venous volume and elevating the head of the bed 6 inches may also be attempted but often prove uncomfortable. Fludrocortisone, a mineralocorticoid, often improves orthostatic symptoms by increasing vascular volume. Some patients benefit from the inhibition of vasodilator prostaglandin synthesis brought about by indomethacin, and from the use of the alpha-adrenergic agonist clonidine and the peripheral vasoconstrictor ephedrine. Midodrine, an alpha-adrenergic agonist, has benefited some patients with moderate and severe orthostatic hypotension of various causes. y Urinary frequency or incontinence, if due to detrusor hyperreflexia, may respond to peripherally acting anticholinergic agents such as oxybutinin or propantheline given at bedtime. Intranasal desmopressin at bedtime may offer relief from nocturnal urinary frequency. Impotence may respond to yohimbine, papaverine, or a penile implant. Constipation can be treated with cisapride, stool softeners, and bulk-forming agents. Hallucinations caused by dopaminergic therapeutic agents usually respond to a lower

dose of dopaminergic medications or to clozapine at bedtime. y This latter therapy must be used cautiously, however, in patients with hypotension. All patients receiving this drug must be monitored for agranulocytosis with weekly white blood cell counts.

Prognosis and Future Perspectives. Based on autopsy-proven cases of MSA, the average survival time is expected to be less than a decade (mean survival 8.0 years,y median survival 9.5 years.y Future studies may focus on the role of iron and oxidative stress in this disorder and the pathological hallmark of glial cytoplasmic inclusion bodies.

OTHER PARKINSONISM-PLUS SYNDROMES

Corticobasal Ganglionic Degeneration. Corticobasal ganglionic degeneration (CBGD) is a distinctive parkinsonism-plus syndrome because specific cortical signs are associated with it and it has a particular pathological picture. Autopsy in patients with CBGD reveals asymmetrical, focal frontoparietal atrophy, "ballooned" and enlarged cells in the cortex, depigmentation of the substantia nigra without Lewy bodies, and diffuse neuronal loss. y There is no familial predisposition, and no environmental factors increase the risk of disease. Clinically, patients usually develop symptoms after age 60, and neurological signs of CBGD include focal or asymmetrical rigidity, bradykinesia, postural and action tremor, and marked dystonia, usually predominantly in one upper extremity. The most characteristic symptom, however, is limb apraxia, and the involved extremity can become so dysfunctional that it moves completely by itself and can be considered an "alien limb." y In most instances, the condition starts as an apparent case of PD, but the cortical sensory loss, dystonia, and apraxia are noticed quickly as distinctive. PSP and MSA can present with these signs and therefore must always be considered in the differential diagnosis. The parkinsonism can be treated with modest success in some cases by introducing levodopa or DA agonists, but the marked disability resulting from the limb dyspraxia is progressive, untreatable, and markedly disabling. Botulinum toxin can relieve elements of the dystonia. The condition usually progresses steadily, and death occurs within 10 years of diagnosis. y

Parkinsonism-Dementia Amyotrophic Lateral Sclerosis Complex (PDALS). This distinctive condition occurs on the island of Guam (locally known as Lytico-Bodig disease) and has been the focus of significant research because of the possibility that genetic and environmental causes may be contributive. y A study of over 2000 affected and nonaffected individuals in Guam showed that the incidence of this disorder peaked in the 1950s and has gradually declined since that time. Early studies focusing on possible environmental dietary toxins were encouraging, but recent work has failed to identify any agent consistently, and the once-held hypothesis that native flour contains a causative neurotoxin is no longer considered tenable. y Pathologically, depigmentation, basophilic inclusion bodies, and cell loss in the substantia nigra are apparent in cases of PDALS. Neurofibrillary tangles without senile plaques are present in the substantia nigra, anterior horn cells, and pyramidal tracts.y Clinical findings in PDALS range from motor neuron disease in younger patients to parkinsonism with severe dementia in the older population. The amyotrophic lateral sclerosis (ALS) form is seen predominantly in the Chamorros, while the parkinsonism-dementia presentation may be seen in both Chamorro and Filipino residents. The amyotrophic lateral sclerosis seen in Guam does not differ clinically from the motor neuron disease seen in the remainder of the world. Although no cause has been established, the coexistence of these neurodegenerative conditions in one population with overlapping signs supports the continuation of hypotheses based on a common cause. The differential diagnosis for PDALS includes Alzheimer's disease, diffuse Lewy body disease, postencephalitic parkinsonism, PD, the parkinsonism-plus syndromes, lower body parkinsonism and other causes of parkinsonism, as well as ALS and the various forms of motor neuron disease.y Regardless of its form of clinical presentation, the disorder is relentlessly progressive, and death usually occurs within 10 years of diagnosis.

Hemiatrophy/Hemiparkinsonism. Hemiatrophy/ hemiparkinsonism (HA/HP) is an uncommon disorder that involves the onset of parkinsonism on one side of the body in association with a hemiatrophic face, arm, or leg in varying combinations. First described by Klawans, y the disease presents with unilateral parkinsonism; the hemiatrophy is completely unnoticed by the patient. In a hemiparkinsonian patient, therefore, comparative examination of the size of the hands and feet may be necessary to diagnose the condition. Compared to PD, the parkinsonism of HA/ HP usually begins at a younger age and generally remains on the hemiatrophic side for several years before it sometimes becomes bilateral. Unilateral dystonic movements are a common early feature and may respond well to levodopa. The cause is unknown, but early birth injury from hypoxia or trauma has been suggested as a possibility, and there may be some relationship between this syndrome and a distinct form of dystonia termed dopa-responsive dystonia. y Hemiatrophy of the contralateral cortex may be seen on MR in some patients.

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