Timothy C. Hain, MD Page last modified: December 1, 2019
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 2016, Pubmed contained more than 1600 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). This fondness for study of a rare disease is likely due to the dramatic nature of symptoms and poor prognosis. No gene has been found to be correlated with MSA, in spite of a vigorous attempt (Sailer et al, 2016).
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 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). Persons diagnosed with sporadic OPCA (Olivopontocerebellar degeneration) evolve 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). Of course sleep disturbance is common in people without MSA as well. There is disturbance both of rapid eye movement (REM) sleep as well as sleep apnea. Of course, sleep apnea is also common in the general population. Both the REM sleep disturbance and sleep apnea 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 (silver loving) 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). This hypothesis has been gaining considerable ground in recent years. It seems likely that tau spontaneously mutates into a pathologic form that recruits other tau and causes disease. In other words, rather than being transmitted through "mad cow" nervous tissue, these disorders may, be spontaneous mutations that take 20 years to spread within one's nervous system.
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; 2008).
MSA includes four domains as well as some add-on imaging findings.
There are three levels of certainty: Possible, probable and definate. The diagnosis of possible MSA and probable MSA basically involves having more of these features. We don't think it is all that important how many findings it takes to allocate to possible/probable as these are mainly judgement calls and subject to "fudging". Rather, we think the main goal should be to identify people in whom MSA is worth considering, and following them to see if they are progressing.
The diagnosis of definite MSA requires pathological confirmation (i.e. widespread alpha-synuclein inclusion in glial cytoplasm in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures). This definition means that there are essentially no persons living with "definate" MSA.
So far, there are no biomarkers for MSA. Potential ones include alpha-synuclein imaging and MRI morphometry. Ramli et al (2015) discussed use of MRI to differentiate MSA from Parkinsonism. 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. The sensitivity for MSA is about 36% (Ramli et al, 2015). DAT Spect is not a reliable method to differentiate MSA from PD. 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. In spite of this assertion, in general it is thought that MRI is not specific for MSA.
Kaufmann et al (2017) suggested that the sense of smell as quantified by the UPSIT score, differentiated MSA from DLB and Parkinsonism. The small number of MSA patients they studied had UPSIT scores in the 30's, while the small number of PD and DLB patients that they studied were about 10-25. So in other words, if your sense of smell is normal, this is a point for MSA. The same authors observed that supine NE was somewhat higher in MSA patients than most DLB and all PAF patients. These observations need confirmation as they are based on too few patients.
The most difficult differential 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.
Kim et al (2015) proided approximately 30 different conditions that might be confused with MSA -- basically all of neurology. The most common mimickers are:
- Corticoganglionic degeneration
- Hereditory forms of OPCA (olivopontocerebellar atrophy) -- the cerebellar atrophies (a huge group).
- Dementia with Lewy bodies (DLB)
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.
A case of valproic acid toxicity has been described mimicking MSA (Shill and Fife, 2000). This is certainly not a common mimicker.
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)
Patients with MSA have lower levels (on average) of a vitamin called CoQ10 (Mitsui et al, 2016). There are also many papers suggesting associations of MSA with mutations in the COQ2 gene (e.g. Multiple-System Atrophy Research, 2013). As CoQ is harmless, it seems prudent to us to supplement with CoQ should you have MSA.
Most individuals with MSA and 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)