Summary and Discussion ka Simpson, M.D. Resident, Department of Neurology

[Guest guest]

<A HREF= " http://www.bcm.tmc.edu/neurol/challeng/pat22/summary.html " >Baylor

Neurology Case of the Month</A> Patient #22 presented with typical

parkinsonian features of bradykinesia, rigidity, and postural instability.

This localizes the responsible lesion(s) to basal ganglia or subcortical

frontal lobe structures. The most common cause of parkinsonism worldwide is

idiopathic Parkinson's disease (IPD), a progressive neurodegenerative

condition due to dopaminergic neuronal loss in the substantia nigra, pars

compacta. Clinical features include a resting supination-pronation tremor,

cogwheel rigidity, bradykinesia, loss of postural reflexes, the freezing

phenomenon, and a good therapeutic response to levodopa therapy. Other

features seen later in the course of the disease include hypophonia,

autonomic dysfunction, and bradyphrenia. Diagnostic confusion arises, as in

this case, when patients present with parkinsonism associated with atypical

features, such as oculomotor abnormalities, marked autonomic dysfunction,

cerebellar involvement, apraxias, and/or pyramidal tract involvement. The

coexistence of these features with parkinsonism implies involvement of

multiple neurological systems. In this case, parkinsonism accompanied

features of pyramidal, autonomic, intellectual (mild subcortical dementia),

and cerebellar dysfunction. Several distinct clinical entities with mixtures

of parkinsonism and degeneration of other neurological systems are now

recognized. Distinguishing among these processes is more than an academic

exercise, since accurate diagnosis carries therapeutic and prognostic

significance. In part, this is due to differences in the pathophysiology and

anatomy of the different diseases. The prognosis for successful treatment of

Parkinson's disease is quite good, since the primary defect lies in loss of

the dopaminergic cells of the substantia nigra. Replacement of dopamine

effectively treats the underlying physiologic abnormality, though it does not

address the pathophysiology of disease progression. Prognosis in conditions

resulting from degeneration of the striatum or other basal ganglionic

structures is much worse, since the primary defect lies in loss of cells

carrying dopaminergic receptors. Dopamine replacement is not as effective in

helping these patients.The differential diagnosis of parkinsonism accompanied

by atypical features is broad and includes the Parkinsonism Plus syndromes

(multisystem atrophies, progressive supranuclear palsy, cortical-basal

ganglionic degeneration, progressive pallidal atrophy, diffuse Lewy body

disease), Alzheimer's disease with parkinsonian features, Pick's disease,

hederodegenerative diseases ('s, Hallervorden-Spatz, Huntington's

disease, etc.), and secondary parkinsonism (vascular, drug induced,

infection, prion disease, toxins, trauma, mass lesions, hydrocephalus,

hypothyroidism, paraneoplastic, hepatocerebral degeneration, and

syringomesencephalia). Of the various causes, the Parkinsonism Plus syndromes

and secondary parkinsonism are the most common. Hederodegenerative diseases

are relatively uncommon, and this patient did not fit into any of the

recognized patterns of hederodegenerative disease. The patient's mild

subcortical dementia and the presence of cerebellar signs did not fit the

pattern expected for either Alzheimer's or Pick's disease. Infectious

possibilities include encephalitis lethargica, HIV, syphilis, and SSPE. In

this case, serologic tests excluded syphilis and HIV infection, and the

clinical course and features were not consistent with encephalitis lethargica

or SSPE (which are rapidly progressive conditions). There was no history of

anti-psychotic or anti-emetic drug exposure, toxin (CO, Mn, Hg, MPTP, CS2,

methanol, cyanide) exposure, multiple head traumas, multiple strokes, or

metabolic abnormalities. Prion diseases, especially Creutzfeldt-Jakob and

Gerstmann-Straussler-Scheinker disease, present with a more rapid, aggressive

course and more profound dementia. Neuroimaging excluded the possibility of

hydrocephalus and mass lesions. One might consider the possibility of normal

pressure hydrocephalus, consisting of the triad of dementia, gait

disturbance, and urinary incontinence. The mild subcortical dementia is

consistent with this diagnosis, but the lack of improvement of this patient's

leg function on lying down argues against it. Neuroimaging was not consistent

with this diagnosis. The Parkinsonism Plus syndromes include an array of

neurodegenerative conditions characterized by parkinsonism plus other

evidence of neurological dysfunction as seen in our patient. In Diffuse Lewy

Body disease, parkinsonism is accompanied by cortical dementia with varying

levels of attention, early hallucinations, and psychosis. Autonomic

dysfunction is common, and pyramidal signs may be seen, but cerebellar

dysfunction is not found. This patient's mild subcortical dementia is also

not consistent with this diagnosis. In cortical-basal ganglionic

degeneration, parkinsonism is accompanied by ideomotor apraxias, the alien

limb phenomenon, cortical reflex myoclonus, cortical sensory loss, marked

asymmetry of involvement, and focal rigidity and dystonia with contractures.

None of these features was seen in this patient. In progressive supranuclear

palsy, parkinsonism is accompanied by a prominent supranuclear gaze

disturbance not seen in this patient. Multisystem atrophy (MSA) is a

progressive, sporadic disorder characterized by parkinsonism in association

with varying degrees of cerebellar, pyramidal, intellectual, and autonomic

dysfunction. Classically, this includes three separate entities -

Striatonigral degeneration (parkinsonism poorly responsive to levodopa and

frequently associated with cervical dystonia), Olivopontocerebellar atrophy

(parkinsonism with cerebellar dysfunction), and Shy-Drager syndrome

(parkinsonism with autonomic dysfunction). Because of the clinical overlap

and common pathologic finding of an intracytoplasmic oligodendroglial

inclusion body, these entities are now lumped together. This patient best fit

the diagnosis of multisystem atrophy with evidence of parkinsonism,

cerebellar dysfunction, autonomic dysfunction, mild dementia, and long-tract

signs. The patient was treated with low dose levodopa and physical therapy.

He noted only mild initial improvement in his parkinsonian symptoms. His mild

orthostasis was treated with increased fluid intake, and he reported

improvement in these symptoms. He declined any further treatment regarding

his urinary incontinence and erectile dysfunction at this time.

Introduction

Graham and Oppenheimer coined the term multisystem atrophy (MSA) in 1969 to

reflect the clinical relationships among three previously described

parkinsonian syndromes: Shy-Drager syndrome (SDS), olivopontocerebellar

atrophy (OPCA), and striatonigral degeneration (SND). Each shares features of

parkinsonism along with variable degrees of pyramidal, cerebellar, and

autonomic dysfunction. Subsequent pathological studies demonstrated a shared

intracytoplasmic, eosinophilic oligodendroglial inclusion in each of these

conditions, further supporting their clinical relationship. Though many

neurologists still diagnose the individual syndromes, the generic term,

multisystem atrophy, is now considered the preferred designation by most

movement disorder specialists. However, the oligodendroglial cystoplasmic

inclusions and intraneuronal cytoplasmic inclusions that are characteristic

of the condition may be found in some patients with cortical basal-ganglionic

degeneration (CBGD) and progressive supranuclear palsy (PSP). It is unclear

if these " markers " simply represents non-specific " tombstones " without any

clear pathophysiologic significance. Epidemiology

The true prevalence of this condition is not known. Various studies have

suggested an incidence of 3.6% to 22% among patients diagnosed with

parkinsonism. The mean age of disease onset is 52.5 years with a mean age of

death ranging from 60-65 years. Fewer than 4% of cases begin between the ages

of 30-39 years and 70-79 years respectively. The vast majority (92%) of cases

begin between the ages of 40-69. Survival from the age of symptom onset to

death ranges from 5.5-9.4 years. There is a slight male predominance with a

gender ratio of 1.1:1 to 1.9:1.Clinical Features

Patients with MSA may present with a variety of clinical manifestations,

either fitting one of the distinct subtypes (SND, OPCA, SDS) or with a

combination of signs reflecting involvement of pyramidal, basal ganglia,

cerebellar, and autonomic systems. Traditionally, the designation

striatonigral degenearation was given to patients with predominant

parkinsonism and pathological demonstration of striatal degeneration at

autopsy. There is no clinical feature that clearly distinguishes SND from

idiopathic Parkinson's disease (IPD), but tremor is less prominent, response

to levodopa therapy is poor, and cervical dystonia (usually presenting as

anterocollis) is more prominent in the former. OPCA was diagnosed in patients

with parkinsonism associated with ataxia and any number of added findings

including dyskinesias, cranial nerve palsies, optic atrophy, retinal

degeneration, amyotrophy, peripheral neuropathy, supranuclear

ophthalmoplegia, and/or dementia. Shy-Drager syndrome was diagnosed in

patients with parkinsonism and prominent autonomic failure. Currently, the

designation of MSA with a particular subtype (SND, OPCA, SDS) is used. In

some cases, the designation MSA alone is used, when the patient does not fit

into a clear subtype.Autonomic symptoms are present in 74-97% of patients

with MSA with 55% showing urinary incontinence, 18% with urinary retention,

80% with impotence, and 68% with postural hypotension (usually mild to

moderate with rare syncope). Three-fourths of patients develop autonomic

symptoms up to four years before the onset of other neurological compromise.

Parkinsonism is present in 90-100% of patients diagnosed with MSA, with

bradykinesia and rigidity found in 74% and tremor in 66%. Tremor is more

common in MSA of SND subtype, though the classic pill-rolling tremor at rest

is uncommon. Cerebellar ataxia is present in 49% of patients diagnosed with

MSA, including 79% of those diagnosed with the OPCA subtype, 60% of those

with the SDS subtype, and 20% with the SND subtype. Dysmetria of the upper

extremities is less common. Nystagmus has been documented in 25% of patients.

Pyramidal signs occur in 61% of patient diagnosed with MSA, with extensor

plantar responses and hyper-reflexia seen in 41% and 46% of patients,

respectively. A smaller percentage (10%) of patients demonstrate spasticity,

though spastic paraparesis does not appear to occur. Intellectual impairment

is usually mild, corresponding to a mild subcortical dementia. Severe

intellectual impairment is rare, seen in approximately 2% of cases. Emotional

lability may be seen in advanced disease. Other clinical features include

dysarthria (present in virtually all patients), respiratory stridor (34% of

patients), anisocoria (in 8% of patients and associated with a Horner's

syndrome in 5%), excessive snoring and vocal cord abductor palsy, and

dystonia (including anterocollis, torticollis, focal limb dystonia, axial

dystonia, and orofacial dystonia in 12% of untreated cases). Oculomotor

dysfunction is common and includes saccadic pursuit in 68%, hypometric

saccades in 65%, limitation of upgaze in 39%, limitation of downgaze in 7%,

and limitation of horizontal gaze in 7% of cases.Diagnosis

In diagnosing parkinsonian syndromes, one must first attempt to distinguish

IPD from other causes. At times, this is extremely difficult; but the

exercise has prognostic and therapeutic implications. Factors that help make

this distinction include symmetry of symptoms, absent or minimal tremor,

early autonomic dysfunction, early falling, prominent postural instability,

and a poor response to levodopa therapy, with each of these features seen

more prominently in non-IPD parkinsonism. Definitive diagnosis of MSA

requires autopsy, but clinical criteria for diagnosis of SND and OPCA

subtypes have been developed. The diagnosis of possible MSA, SND subtype may

be made in any patient with parkinsonism and a poor response to levodopa

therapy. The diagnosis of probable MSA, SND subtype also includes evidence of

autonomic dysfunction, cerebellar signs, pyramidal signs, dystonia, or

abnormal responses to sphincter EMG. The diagnosis of possible MSA, OPCA

subtype may be made in any patient with a sporadic, adult-onset cerebellar

syndrome associated with parkinsonism. The diagnosis of probable MSA, OPCA

subtype also includes evidence of pyramidal signs, autonomic failure,

oculomotor disturbances and/or pathologic sphincter EMG.Diagnostic testing is

aimed at supporting the clinical diagnosis, by demonstrating evidence of

autonomic dysfunction and/or radiological clues, and excluding other

potential causes of parkinsonism, such as toxin exposure, hydrocephalus,

cerebral infarction, brain tumors, and infections. Tests of autonomic

function (tilt table, plasma catecholamine levels) help to confirm suspicions

of autonomic failure, but do not reliably distinguish the autonomic failure

seen in MSA from that seen in IPD. However, external urethral or rectal

sphincter EMG appears to be a relatively specific test for MSA, in that 98.7%

of patients with MSA show signs of denervation and reinnervation while other

patients with parkinsonism show normal responses to sphincter EMG.

Neuroimaging is generally unrevealing and used primarily to eliminate other

causes for parkinsonism. In some cases, putaminal abnormalities are seen on

T2-weighted images, but this finding is not specific for MSA. In rare cases

of OPCA significant brainstem and cerebellar atrophy may be seen.Definitive

evidence requires pathological confirmation at the time of autopsy. In MSA,

SND subtype one sees atrophy and discoloration in the putamina and

depigmentation of the substantia nigra. Microscopically, there is severe

neuronal loss and gliosis in the putamina, substantia nigra, globus pallidus,

caudate, and subthalamic nucleus. Lewy bodies may rarely be found. In MSA,

OPCA subtype one sees degeneration of the inferior olives, ventral pontine

nuclei, and cerebellar cortex. And in MSA, SDS subtype the major pathologic

lesion is found in the thoracic and upper lumbar intermediolateral gray

column of the spinal cord, where sympathetic preganglionic neurons lie.

Treatment

As in early cases of idiopathic Parkinson's disease, the mainstay of

treatment in patients with MSA is physical and occupational therapy to

maintain mobility. Because of prominent problems with dysarthria and

dysphagia, speech therapy is an important addition to this regimen.

Otherwise, there is no specific therapy for MSA. Medical treatment is aimed

at alleviating the extrapyramidal and autonomic dysfunction, though success

is generally limited. The majority of patients show no or modest improvement

with levodopa therapy. Up to 1/3 of patients with MSA, however, will show a

moderate to good response with levodopa therapy, but this response is

generally short-lived (lasting only 1 to 2 years). Treatment with levodopa is

recommended for all patients, because of the chance for some improvement.

Interestingly, the commonly encountered levodopa-induced dyskinesias seen in

patients with IPD do not commonly occur in patients with MSA.

Anticholinergics and amantadine may provide some symptomatic relief, but

their use is limited by the development of orthostatic hypotension in many

patients. Symptomatic treatment of orthostasis includes elastic stockings,

increased salt and water intake, and mineralocorticoids, but is generally not

very effective. Impotence may be treated with various measures, including

penile implants and intracavernosal papaverine injections. Urinary

incontinence may be treated with peripherally acting anticholinergic drugs.

Urinary retention may be treated with indwelling catheters or intermittent

catheterization. Respiratory stridor may be treated with tracheostomy. Sleep

apnea may be treated with CPAP or tracheostomy in severe cases. Severe

dysphagia may be treated with enteral feeding. Dystonias may be treated with

botulinum toxin injections. Prognosis

MSA is a progressive neurodegenerative disease that is uniformly fatal. Mean

survival is 6 years with a considerable range (2-20 years). Factors

portending a faster progression and shorter survival include older age of

onset and the presence of more than one clinical feature.

[Guest guest]

<A HREF= " http://www.bcm.tmc.edu/neurol/challeng/pat22/summary.html " >Baylor

Neurology Case of the Month</A> Patient #22 presented with typical

parkinsonian features of bradykinesia, rigidity, and postural instability.

This localizes the responsible lesion(s) to basal ganglia or subcortical

frontal lobe structures. The most common cause of parkinsonism worldwide is

idiopathic Parkinson's disease (IPD), a progressive neurodegenerative

condition due to dopaminergic neuronal loss in the substantia nigra, pars

compacta. Clinical features include a resting supination-pronation tremor,

cogwheel rigidity, bradykinesia, loss of postural reflexes, the freezing

phenomenon, and a good therapeutic response to levodopa therapy. Other

features seen later in the course of the disease include hypophonia,

autonomic dysfunction, and bradyphrenia. Diagnostic confusion arises, as in

this case, when patients present with parkinsonism associated with atypical

features, such as oculomotor abnormalities, marked autonomic dysfunction,

cerebellar involvement, apraxias, and/or pyramidal tract involvement. The

coexistence of these features with parkinsonism implies involvement of

multiple neurological systems. In this case, parkinsonism accompanied

features of pyramidal, autonomic, intellectual (mild subcortical dementia),

and cerebellar dysfunction. Several distinct clinical entities with mixtures

of parkinsonism and degeneration of other neurological systems are now

recognized. Distinguishing among these processes is more than an academic

exercise, since accurate diagnosis carries therapeutic and prognostic

significance. In part, this is due to differences in the pathophysiology and

anatomy of the different diseases. The prognosis for successful treatment of

Parkinson's disease is quite good, since the primary defect lies in loss of

the dopaminergic cells of the substantia nigra. Replacement of dopamine

effectively treats the underlying physiologic abnormality, though it does not

address the pathophysiology of disease progression. Prognosis in conditions

resulting from degeneration of the striatum or other basal ganglionic

structures is much worse, since the primary defect lies in loss of cells

carrying dopaminergic receptors. Dopamine replacement is not as effective in

helping these patients.The differential diagnosis of parkinsonism accompanied

by atypical features is broad and includes the Parkinsonism Plus syndromes

(multisystem atrophies, progressive supranuclear palsy, cortical-basal

ganglionic degeneration, progressive pallidal atrophy, diffuse Lewy body

disease), Alzheimer's disease with parkinsonian features, Pick's disease,

hederodegenerative diseases ('s, Hallervorden-Spatz, Huntington's

disease, etc.), and secondary parkinsonism (vascular, drug induced,

infection, prion disease, toxins, trauma, mass lesions, hydrocephalus,

hypothyroidism, paraneoplastic, hepatocerebral degeneration, and

syringomesencephalia). Of the various causes, the Parkinsonism Plus syndromes

and secondary parkinsonism are the most common. Hederodegenerative diseases

are relatively uncommon, and this patient did not fit into any of the

recognized patterns of hederodegenerative disease. The patient's mild

subcortical dementia and the presence of cerebellar signs did not fit the

pattern expected for either Alzheimer's or Pick's disease. Infectious

possibilities include encephalitis lethargica, HIV, syphilis, and SSPE. In

this case, serologic tests excluded syphilis and HIV infection, and the

clinical course and features were not consistent with encephalitis lethargica

or SSPE (which are rapidly progressive conditions). There was no history of

anti-psychotic or anti-emetic drug exposure, toxin (CO, Mn, Hg, MPTP, CS2,

methanol, cyanide) exposure, multiple head traumas, multiple strokes, or

metabolic abnormalities. Prion diseases, especially Creutzfeldt-Jakob and

Gerstmann-Straussler-Scheinker disease, present with a more rapid, aggressive

course and more profound dementia. Neuroimaging excluded the possibility of

hydrocephalus and mass lesions. One might consider the possibility of normal

pressure hydrocephalus, consisting of the triad of dementia, gait

disturbance, and urinary incontinence. The mild subcortical dementia is

consistent with this diagnosis, but the lack of improvement of this patient's

leg function on lying down argues against it. Neuroimaging was not consistent

with this diagnosis. The Parkinsonism Plus syndromes include an array of

neurodegenerative conditions characterized by parkinsonism plus other

evidence of neurological dysfunction as seen in our patient. In Diffuse Lewy

Body disease, parkinsonism is accompanied by cortical dementia with varying

levels of attention, early hallucinations, and psychosis. Autonomic

dysfunction is common, and pyramidal signs may be seen, but cerebellar

dysfunction is not found. This patient's mild subcortical dementia is also

not consistent with this diagnosis. In cortical-basal ganglionic

degeneration, parkinsonism is accompanied by ideomotor apraxias, the alien

limb phenomenon, cortical reflex myoclonus, cortical sensory loss, marked

asymmetry of involvement, and focal rigidity and dystonia with contractures.

None of these features was seen in this patient. In progressive supranuclear

palsy, parkinsonism is accompanied by a prominent supranuclear gaze

disturbance not seen in this patient. Multisystem atrophy (MSA) is a

progressive, sporadic disorder characterized by parkinsonism in association

with varying degrees of cerebellar, pyramidal, intellectual, and autonomic

dysfunction. Classically, this includes three separate entities -

Striatonigral degeneration (parkinsonism poorly responsive to levodopa and

frequently associated with cervical dystonia), Olivopontocerebellar atrophy

(parkinsonism with cerebellar dysfunction), and Shy-Drager syndrome

(parkinsonism with autonomic dysfunction). Because of the clinical overlap

and common pathologic finding of an intracytoplasmic oligodendroglial

inclusion body, these entities are now lumped together. This patient best fit

the diagnosis of multisystem atrophy with evidence of parkinsonism,

cerebellar dysfunction, autonomic dysfunction, mild dementia, and long-tract

signs. The patient was treated with low dose levodopa and physical therapy.

He noted only mild initial improvement in his parkinsonian symptoms. His mild

orthostasis was treated with increased fluid intake, and he reported

improvement in these symptoms. He declined any further treatment regarding

his urinary incontinence and erectile dysfunction at this time.

Introduction

Graham and Oppenheimer coined the term multisystem atrophy (MSA) in 1969 to

reflect the clinical relationships among three previously described

parkinsonian syndromes: Shy-Drager syndrome (SDS), olivopontocerebellar

atrophy (OPCA), and striatonigral degeneration (SND). Each shares features of

parkinsonism along with variable degrees of pyramidal, cerebellar, and

autonomic dysfunction. Subsequent pathological studies demonstrated a shared

intracytoplasmic, eosinophilic oligodendroglial inclusion in each of these

conditions, further supporting their clinical relationship. Though many

neurologists still diagnose the individual syndromes, the generic term,

multisystem atrophy, is now considered the preferred designation by most

movement disorder specialists. However, the oligodendroglial cystoplasmic

inclusions and intraneuronal cytoplasmic inclusions that are characteristic

of the condition may be found in some patients with cortical basal-ganglionic

degeneration (CBGD) and progressive supranuclear palsy (PSP). It is unclear

if these " markers " simply represents non-specific " tombstones " without any

clear pathophysiologic significance. Epidemiology

The true prevalence of this condition is not known. Various studies have

suggested an incidence of 3.6% to 22% among patients diagnosed with

parkinsonism. The mean age of disease onset is 52.5 years with a mean age of

death ranging from 60-65 years. Fewer than 4% of cases begin between the ages

of 30-39 years and 70-79 years respectively. The vast majority (92%) of cases

begin between the ages of 40-69. Survival from the age of symptom onset to

death ranges from 5.5-9.4 years. There is a slight male predominance with a

gender ratio of 1.1:1 to 1.9:1.Clinical Features

Patients with MSA may present with a variety of clinical manifestations,

either fitting one of the distinct subtypes (SND, OPCA, SDS) or with a

combination of signs reflecting involvement of pyramidal, basal ganglia,

cerebellar, and autonomic systems. Traditionally, the designation

striatonigral degenearation was given to patients with predominant

parkinsonism and pathological demonstration of striatal degeneration at

autopsy. There is no clinical feature that clearly distinguishes SND from

idiopathic Parkinson's disease (IPD), but tremor is less prominent, response

to levodopa therapy is poor, and cervical dystonia (usually presenting as

anterocollis) is more prominent in the former. OPCA was diagnosed in patients

with parkinsonism associated with ataxia and any number of added findings

including dyskinesias, cranial nerve palsies, optic atrophy, retinal

degeneration, amyotrophy, peripheral neuropathy, supranuclear

ophthalmoplegia, and/or dementia. Shy-Drager syndrome was diagnosed in

patients with parkinsonism and prominent autonomic failure. Currently, the

designation of MSA with a particular subtype (SND, OPCA, SDS) is used. In

some cases, the designation MSA alone is used, when the patient does not fit

into a clear subtype.Autonomic symptoms are present in 74-97% of patients

with MSA with 55% showing urinary incontinence, 18% with urinary retention,

80% with impotence, and 68% with postural hypotension (usually mild to

moderate with rare syncope). Three-fourths of patients develop autonomic

symptoms up to four years before the onset of other neurological compromise.

Parkinsonism is present in 90-100% of patients diagnosed with MSA, with

bradykinesia and rigidity found in 74% and tremor in 66%. Tremor is more

common in MSA of SND subtype, though the classic pill-rolling tremor at rest

is uncommon. Cerebellar ataxia is present in 49% of patients diagnosed with

MSA, including 79% of those diagnosed with the OPCA subtype, 60% of those

with the SDS subtype, and 20% with the SND subtype. Dysmetria of the upper

extremities is less common. Nystagmus has been documented in 25% of patients.

Pyramidal signs occur in 61% of patient diagnosed with MSA, with extensor

plantar responses and hyper-reflexia seen in 41% and 46% of patients,

respectively. A smaller percentage (10%) of patients demonstrate spasticity,

though spastic paraparesis does not appear to occur. Intellectual impairment

is usually mild, corresponding to a mild subcortical dementia. Severe

intellectual impairment is rare, seen in approximately 2% of cases. Emotional

lability may be seen in advanced disease. Other clinical features include

dysarthria (present in virtually all patients), respiratory stridor (34% of

patients), anisocoria (in 8% of patients and associated with a Horner's

syndrome in 5%), excessive snoring and vocal cord abductor palsy, and

dystonia (including anterocollis, torticollis, focal limb dystonia, axial

dystonia, and orofacial dystonia in 12% of untreated cases). Oculomotor

dysfunction is common and includes saccadic pursuit in 68%, hypometric

saccades in 65%, limitation of upgaze in 39%, limitation of downgaze in 7%,

and limitation of horizontal gaze in 7% of cases.Diagnosis

In diagnosing parkinsonian syndromes, one must first attempt to distinguish

IPD from other causes. At times, this is extremely difficult; but the

exercise has prognostic and therapeutic implications. Factors that help make

this distinction include symmetry of symptoms, absent or minimal tremor,

early autonomic dysfunction, early falling, prominent postural instability,

and a poor response to levodopa therapy, with each of these features seen

more prominently in non-IPD parkinsonism. Definitive diagnosis of MSA

requires autopsy, but clinical criteria for diagnosis of SND and OPCA

subtypes have been developed. The diagnosis of possible MSA, SND subtype may

be made in any patient with parkinsonism and a poor response to levodopa

therapy. The diagnosis of probable MSA, SND subtype also includes evidence of

autonomic dysfunction, cerebellar signs, pyramidal signs, dystonia, or

abnormal responses to sphincter EMG. The diagnosis of possible MSA, OPCA

subtype may be made in any patient with a sporadic, adult-onset cerebellar

syndrome associated with parkinsonism. The diagnosis of probable MSA, OPCA

subtype also includes evidence of pyramidal signs, autonomic failure,

oculomotor disturbances and/or pathologic sphincter EMG.Diagnostic testing is

aimed at supporting the clinical diagnosis, by demonstrating evidence of

autonomic dysfunction and/or radiological clues, and excluding other

potential causes of parkinsonism, such as toxin exposure, hydrocephalus,

cerebral infarction, brain tumors, and infections. Tests of autonomic

function (tilt table, plasma catecholamine levels) help to confirm suspicions

of autonomic failure, but do not reliably distinguish the autonomic failure

seen in MSA from that seen in IPD. However, external urethral or rectal

sphincter EMG appears to be a relatively specific test for MSA, in that 98.7%

of patients with MSA show signs of denervation and reinnervation while other

patients with parkinsonism show normal responses to sphincter EMG.

Neuroimaging is generally unrevealing and used primarily to eliminate other

causes for parkinsonism. In some cases, putaminal abnormalities are seen on

T2-weighted images, but this finding is not specific for MSA. In rare cases

of OPCA significant brainstem and cerebellar atrophy may be seen.Definitive

evidence requires pathological confirmation at the time of autopsy. In MSA,

SND subtype one sees atrophy and discoloration in the putamina and

depigmentation of the substantia nigra. Microscopically, there is severe

neuronal loss and gliosis in the putamina, substantia nigra, globus pallidus,

caudate, and subthalamic nucleus. Lewy bodies may rarely be found. In MSA,

OPCA subtype one sees degeneration of the inferior olives, ventral pontine

nuclei, and cerebellar cortex. And in MSA, SDS subtype the major pathologic

lesion is found in the thoracic and upper lumbar intermediolateral gray

column of the spinal cord, where sympathetic preganglionic neurons lie.

Treatment

As in early cases of idiopathic Parkinson's disease, the mainstay of

treatment in patients with MSA is physical and occupational therapy to

maintain mobility. Because of prominent problems with dysarthria and

dysphagia, speech therapy is an important addition to this regimen.

Otherwise, there is no specific therapy for MSA. Medical treatment is aimed

at alleviating the extrapyramidal and autonomic dysfunction, though success

is generally limited. The majority of patients show no or modest improvement

with levodopa therapy. Up to 1/3 of patients with MSA, however, will show a

moderate to good response with levodopa therapy, but this response is

generally short-lived (lasting only 1 to 2 years). Treatment with levodopa is

recommended for all patients, because of the chance for some improvement.

Interestingly, the commonly encountered levodopa-induced dyskinesias seen in

patients with IPD do not commonly occur in patients with MSA.

Anticholinergics and amantadine may provide some symptomatic relief, but

their use is limited by the development of orthostatic hypotension in many

patients. Symptomatic treatment of orthostasis includes elastic stockings,

increased salt and water intake, and mineralocorticoids, but is generally not

very effective. Impotence may be treated with various measures, including

penile implants and intracavernosal papaverine injections. Urinary

incontinence may be treated with peripherally acting anticholinergic drugs.

Urinary retention may be treated with indwelling catheters or intermittent

catheterization. Respiratory stridor may be treated with tracheostomy. Sleep

apnea may be treated with CPAP or tracheostomy in severe cases. Severe

dysphagia may be treated with enteral feeding. Dystonias may be treated with

botulinum toxin injections. Prognosis

MSA is a progressive neurodegenerative disease that is uniformly fatal. Mean

survival is 6 years with a considerable range (2-20 years). Factors

portending a faster progression and shorter survival include older age of

onset and the presence of more than one clinical feature.