Neurology: Case of the Month

Check Your Diagnosis — Patient 22

Ericka Simpson, M.D.

Diagnosis

Multi-System Atrophy (MSA)

Clinical Summary

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 (Wilson'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.

Discussion

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 1-2 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 six 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.

References

  1. Stocchi F, Carbone A, Monge A, Ruggieri S, Bernadelli A, Manfredi M. Urodynamic and neurophysiological evaluation in Parkinson's disease and multiple system atrophy. J Neurol Neurosurg Psych. 1997:62:507-11.
  2. Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: A meta-analysis. Neurology. 1997;48(2):384-93.
  3. Wenning Gk, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: A review of 203 pathologically proven cases. Mov Dis. 1997;12(2):133-47.
  4. Fahn S, Marsden CD, Jankovic J. A comprehensive review of movement disorders for the clinical practitioner. The Parkinson-plus syndromes. Aspen, Colorado; Aug 1-4, 1995.
  5. Quinn NP, Wenning GK. Multiple system atrophy. In Battistin L, Scarlato G, Caraceni T, Ruggieri S, editors. Advances in neurology, Vol 69. Lippincott-Taven Publishers, Philadelphia, 1996.
  6. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple sytem atrophy. An analysis of 100 cases. Brain. 1994;117:834-45.
  7. Quinn, N. Multiple system atrophy. In Marsden CD, Fahn S, editors. Movement Disorder 3, Vol 13. Butterworth-Heinemann Publishers, Boston. 1994.

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