Timothy C. Hain, MD Page last modified: August 22, 2015
Multiple system atrophy is a rare neurological disorder characterized by a combination of Parkinsonism, cerebellar and pyramidal signs, and autonomic dysfunction. The term "Multiple System Atrophy" is synonymous with striatonigral degeneration (SND) when Parkinsonism predominates, olivopontocerebellar atrophy (OPCA) when cerebellar signs predominate, and Shy-Drager syndrome when autonomic failure is dominant. The incidence (new case per 100,000 person years) for ages 50 to 99 years is 3.0 (Bower et al, 1997), or about half as frequent as it's close relative, progressive supranuclear palsy (PSP). The mean age of onset is 54. In our medical practice in Chicago, which focuses on dizziness and ataxia, as of 2015, we saw only 8 patients with MSA out of a total of 14000 unique patients.
Although exceedingly rare, MSA has been studied very extensively -- as of 2015, Pubmed contained more than 1500 articles with "multiple system atrophy" in the title alone. This amount of papers published concerning MSA hugely exceeds that done on immensely more common conditions (such as cervical vertigo).
The Parkinsonism of MSA is generally an akinetic rigid syndrome, similar to that of PSP. Rest tremor may occur but is not a predominant feature. Postural instability is common. Parkinsonism is generally the most common initial sign and eventually develops in about 90% of all patients.
The cerebellar signs inlude finger-to-nose or heel-shin dysmetria, gait ataxia, intention tremor and nystagmus. Cerebellar signs are the first feature on only about 5% of patients. Cerebellar signs are observed in 50% of cases (Ben-Shlomo et al, 1997). Sporadic OPCA evolves into MSA in roughly 25% of cases within 5 years.
Autonomic dysfunction includes impotence (the most common male sign), postural hypotension with syncope, urinary incontinence and retention, and fecal incontinence. Cold and violaceous fingers is sometimes seen, thought to be related to impaired peripheral neurovascular control (Klein et al, 1997).
Sleep disturbance is common, affecting about 1/4 (Moreno-Lopez et al, 2011). There is disturbance both of rapid eye movement (REM) sleep as well as sleep apnea. Both are caused by central disease.(Gilman et al. 2003; Gilman et al. 2003)
Disease progression in MSA is quicker than in Parkinsonism but similar or slightly slower to that of PSP (Bower, 1997). Almost 80% of patients are disabled within 5 years of onset of the motor symptoms, and only 20% survive past 12 years. The mean survival is roughly 6 years.
|Figure 1: Synuclein positive neural and glial inclusions in MSA (Image courtesy of Dr. Dennis Dickson, Mayo Clinic, Jacksonville FL, USA).|
There is neuronal loss and gliosis in the inferior olives, pons, cerebellum, substantia nigra, locus ceruleus, striatum and the intermediolateral column of the spinal cord. Typical but not specific to MSA are argyrophilic inclusions containing accumulations of tubules. Alpha-synuclein has recently been shown to be accumulated in glial cytoplasmic incusions (see figure 1).
Wenning and others (2008) suggested that MSA is essentially a disease of the oligodendroglia. The component of the inclusions, Alpha synuclein is also a component of Lewy bodies in sporadic Parkinsonism, dementia with Lewy bodies, and a rare variant of Alzheimer's disease with abundant Lewy bodies (Tu and others, 1998). This is in distinction to the "tau" rich inclusion bodies found in most types of Alzheimer's disease and PSP. In MSA there may be several stages -- alpha-synuclein accumulates in the oligodendroglial cells, then there is failure of mitochondrial function as well as loss of trophic factor support. Then the oligodendroglia degenerate, followed by microglia and astroglial activation. alpha-synuclein misfolds in MSA. Some investigators suggest that the misfolded proteins propogate in a way similar to prion proteins such are seen in the transmissable dementias such as JC disease. (Brundin et al, 2010).
Depletion of catecholamine neurons in the rostral ventrolateral medulla is a consistant finding in patients with MSA and autonomic failure. (Bennaroch et al, 1998).
|Figure 2: "hot cross bun" sign seen in pons on T2 MRI. (c) Timothy C. Hain, M.D.|
A consensus conference on the diagnosis of multiple system atrophy set out diagnostic criteria (Gilman et al, 1999). MSA includes four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction. The diagnosis of possible MSA requires one criterion plus two features from separate other domains. The diagnosis of probable MSA requires the criterion for autonomic failure/urinary dysfunction plus poorly levodopa responsive Parkinsonism or cerebellar ataxia. The diagnosis of definite MSA requires pathological confirmation
The so-called "hot cross bun sign" is said to be specific for but not pathognomonic for MSA (Burk et al, 2001). Figure 2 shows the sign in one of our patients felt to have MSA. A hot cross bun sign is also seen in some of the spinocerebellar atrophies.
So far, there are no biomarkers for MSA. Potential ones include alpha-synuclein imaging and MRI morphometry.
The most difficult diagnosis is between Parkinsons disease and levodopa-responsive striato-niagral degeneration-type MSA. PSP is generally confirmed by eye-movement abnormalities. In early stages, Cortico-basal-ganglionic degeneration may be impossible to distinguish from MSA but as more cortical signs develop in later stages, the disorders may be possible to separate. We have encountered a patient with what we thought was CBGD, that turned out to have Jacob Creutzfeldt (a prion disease). The rapid progression in this patient was probably the key.
According to Goldstein and others (2000), orthostatic hypotension that occurs in Parkinsonism is due to cardiac sympathetic denervation, while in MSA, it caused by central regulatory disturbances. According to Kraft and others (2002), T2 MRI distinguishes MSA from Parkinsonism by the finding of low-intensity areas, attributed to iron deposition, on T2 gradiant echo.
A case of valproic acid toxicity has been described mimicking MSA (Shill and Fife, 2000).
MSA patients either do not respond or respond poorly to levodopa. Doses of 1 to 1.5 gram per day must be used before unresponsiveness is declared, but generally only about 1/3 of patients respond.
Autonomic failure can be treated with salt supplements, florinef, and mitodrine. Mitodrine might work in the orthostatic hypotension of MSA as opposed to that of Parkinsonism, as in MSA the post-ganglionic sympathetics are retained (Goldstein et al, 2002).
It has been suggested that MSA patients may benefit from replacement of central norepinephrine or epinephrine with precursors such as dihidroxyphenylserine (Benarroch et al, 1998).
There is no effective treatment for the cerebellar disturbance.
Many patients with MSA develop sleep-disordered breathing with stridor, due to bilateral vocal fold paresis. For this reason, patients with MSA should get a sleep study. Treatment of the sleep disorder may include continuous positive airway pressure (CPAP) or tracheostomy. (Blumin JH, Berke GS, 2002)
Most individuals with MSAand their caregivers attempt to make realistic plans anticipating a slow neurological decline. Patients and caregivers should establish early on their wishes regarding invasive supportive care -- intubation, feeding tubes -- as these issues are almost certain to come up in the course of the disease. As little is understood about MSA, efforts to encourage research into its diagnosis, mechanism and treatment seem highly worthwhile.
Patients with MSA should consider donating their brains for autopsy examination at the time of death. In this way, a cure for this condition may eventually be found. This involves signing consent forms prior to death, and informing both one's relatives and doctors of ones desire to do this. The CurePSP society , or "Foundation for PSP, CBD and Related Brain Diseases, is presently coordinating this effort along with the Mayo Clinic (Jacksonville)