Several primary neurodegenerative disorders share parkinsonian features, such as bradykinesia, rigidity, tremor, and gait disturbances. These disorders have 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.
Parkinson-plus syndromes respond poorly to the standard treatments for Parkinson disease (PD). An inadequate response to treatment in a patient with parkinsonian symptoms suggests the possibility of a Parkinson-plus syndrome and warrants a search for the signs and symptoms of degeneration in other neuronal systems.
In addition to lack of response to carbidopa/levodopa (Sinemet) or dopamine agonists in the early stages of the disease, other clinical clues suggestive of Parkinson-plus syndromes include the following:
- Early onset of dementia
- Early onset of postural instability
- Early onset of hallucinations or psychosis with low doses of carbidopa/levodopa or dopamine agonists
- 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 urinary incontinence early in the course of the disease
- 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)
Modern immunocytochemical techniques and genetic findings suggest that Parkinson-plus syndromes can be broadly grouped into 2 types: synucleinopathies and tauopathies. Clinically, however, 5 separate Parkinson-plus syndromes have been identified, as follows:
- Multiple system atrophy (MSA)
- Progressive supranuclear palsy (PSP)
- Parkinsonism-dementia-amyotrophic lateral sclerosis complex
- Corticobasal ganglionic degeneration (CBD)
- Dementia with Lewy bodies (DLB)
For more information, see the Medscape Reference article Parkinson Disease.
See the related images below regarding Parkinson-plus syndromes.
Multiple System Atrophy
The clinical definition of multiple system atrophy (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 (see the image below).
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. SDS is identified by parkinsonism, which rarely responds to dopaminergic therapy, and autonomic dysfunction. Though the main features of OPCA are cerebellar manifestations, mild parkinsonism and pyramidal signs are also typically present. Patients with SND usually display parkinsonism and pyramidal signs. Somewhat unique for SND is laryngeal stridor. Not uncommonly, it is very difficult to distinguish SND from PD. 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 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.
The Movement Disorders Society Scientific Issues Committee Report (MDSSICR) revised the diagnostic criteria for MSA in 2003. 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 based on 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 carbidopa/levodopa. Autonomic dysfunction appears in all forms of MSA. Therefore, the term SDS is not useful.
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 that improved to 76% with follow-up care. MSA was correctly diagnosed in 69% of patients who had been observed for at least 5 years. In MSA, autonomic insufficiency and cerebellar signs are the features most helpful with differential diagnosis. Distinguishing MSA from progressive supranuclear palsy (PSP) can be difficult; patients with the latter sometimes have cerebellar features and orthostatic hypotension. Some spinocerebellar ataxias (SCA) can manifest with clinical findings suggestive of MSA. SCA-3 and SCA-17 in particular can have these findings.
The exact incidence of MSA is not known; many experts believe that the disorder is underrecognized. Some authors estimate that 3-10% of patients diagnosed with PD actually have MSA-P, and a prevalence of 16.4 cases per 100,000 population has been reported. In a study in Minnesota from 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.
MSA 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.
The MDSSICR recognizes 4 clinical domains in MSA:
- Autonomic and urinary dysfunction
- Cerebellar dysfunction
- Corticospinal dysfunction
In a study of 100 MSA 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.
Autonomic failure manifests as urinary dysfunction, orthostatic hypotension, erectile dysfunction, or impotence, which are observed early in nearly all men with MSA. Other common manifestations 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. The early display of autonomic dysfunction is believed to anticipate a worse prognosis.
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. Those with cerebellar features present with gait and limb ataxia, ataxic dysarthria, and sustained gaze-evoked nystagmus. They also tend to develop saccadic pursuit movements.
Extensor plantar responses and hyperreflexia are present in patients with corticospinal dysfunction. 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 corticobasal degeneration (CBD).