Multiple system atrophy

1 Clinic

• MSA is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, Bradykinesia, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia.
• MSA is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum.
• Autonomic dysfunction is common
• Vocal cord palsy is important
• MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine medications used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor.
• MSA is distinct from multisystem proteinopathy, a more common muscle-wasting syndrome.

2 Signs / Symptoms

• Autonomic dysfunction
  • Orthostatic hypotension
  • Impotence
  • Loss of sweating
  • Dry mouth
  • Urinary retention
  • Incontinence
• Parkinsonism
  • Muscle rigidity
  • Tremor
  • Brady kinesia
• Cerebellar ataxia (Poor coordination/unsteady walking, double vision)

Entities / Miasms
Rigidity
Tremor
Brady kinesia
Cerebellar Ataxia
Impotence
Urine Retention

3 Related disease

• A variant with combined features of MSA and dementia with Lewy bodies may also exist
• There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.
• RBD parasomnia

4 Initial presentation

• The most common first sign of MSA is the appearance of an "akinetic-rigid syndrome" (Resembling Parkinson's disease) found in 62% at first presentation.
• Other common signs at onset include Cerebellar ataxia (22% at first presentation), followed by genito-urinary symptoms (9%): both men and women often experience urgency, frequency, incomplete bladder emptying, or an inability to pass urine (retention).
• About 1 in 5 MSA patients experience a fall in their first year of disease.
• For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity.

5 Progression[edit]

As the disease progresses one of three groups of symptoms predominates. These are:^{[citation needed]}

1. Parkinsonism - slow, stiff movement, writing becomes small and spidery
2. Cerebellar dysfunction - difficulty coordinating movement and balance
3. Autonomic nervous system dysfunction - impaired automatic body functions, including one, some, or all of the following:

• Postural or orthostatic hypotension, resulting in dizziness or fainting upon standing up
• urinary incontinence or urinary retention
• impotence
• constipation
• vocal cord paralysis
• dry mouth and skin
• trouble regulating body temperature due to sweating deficiency in all parts of the body
• loud snoring, abnormal breathing or inspiratory stridor during sleep
• other sleep disorders including sleep apnea, REM behavior disorder
• double vision
• muscle twitches
• Cognitive impairment

6 Genetics[edit]

One study found a correlation between the deletion of genes in a specific genetic region and the development of MSA in a group of Japanese patients. The region in question includes the SHC2 gene which, in mice and rats, appears to have some function in the nervous system. The authors of this study hypothesized that there may be a link between the deletion of the SHC2 and the development of MSA.

A follow-up study was unable to replicate this finding in American MSA patients. The authors of the U.S. study concluded that "Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds."^{[clarification needed]}

Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS; a disease with a diagnostic overlap with MSA. The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause.

7 Pathophysiology[edit]

Multiple system atrophy can be explained as cell loss and gliosis or a proliferation of astrocytes in damaged areas of the central nervous system. This damage forms a scar which is then termed a glial scar. The presence of inclusion bodies known as Papp–Lantos bodies, in the movement, balance, and autonomic-control centres of the brain are the defining histopathologic hallmark of MSA.

The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is alpha-synuclein. Mutations in this substance may play a role in the disease. The conformation of the alpha-synuclein is different from that of alpha-synuclein in Lewy bodies. The disease probably starts with an oligodendrogliopathy.

Tau proteins have been found in some glial cytoplasmic inclusion bodies.

8 Diagnosis[edit]

8.1 Clinical[edit]

Clinical diagnostic criteria were defined in 1998 and updated in 2007. Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.

8.2 Radiologic[edit]

Both MRI and CT scanning may show a decrease in the size of the cerebellum and pons in those with cerebellar features (MSA-C). The putamen is hypointense on T2-weighted MRI and may show an increased deposition of iron in the Parkinsonian (MSA-P) form. In MSA-C, a "hot cross bun" sign is sometimes found; it reflects atrophy of the pontocerebellar tracts that give T2 hyper intense signal intensity in the atrophic pons.

MRI changes are not required to diagnose the disease as these features are often absent, especially early in the course of the disease. Additionally, the changes can be quite subtle and are usually missed by examiners who are not experienced with MSA.^{[citation needed]}

8.3 Pathologic[edit]

Pathological diagnosis can only be made at autopsy by finding abundant GCIs on histological specimens of the central nervous system.

Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations, MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons. MSA also differs from other synucleinopathies in its regional pathological presentation, with α-synuclein positive inclusions detected predominantly in the striatum, midbrain, pons, medulla and cerebellum, rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases. However, recent studies using novel, monoclonal antibodies specific for C-terminally truncated α-synuclein (αSynΔC) have now shown that neuronal α-synuclein pathology is more abundant than previously thought. One group revealed robust α-synuclein pathology in the pontine nuclei and medullary inferior olivary nucleus upon histological analysis of neurological tissue from MSA patients. Histopathological investigation on six cases of pathologically confirmed MSA, using antibodies directed at a variety of α-synuclein epitopes, revealed substantial variation in α-synuclein protein deposition across both cases and brain regions within cases, providing evidence for 'strains' of aggregated conformers that may differentially promote pathological prion-like spread.

In 2020, researchers at The University of Texas Health Science Center at Houston concluded that protein misfolding cyclic amplification could be used to distinguish between two progressive neurodegenerative diseases, Parkinson’s disease and multiple system atrophy, being the first process to give an objective diagnosis of Multiple System Atrophy instead of just a differential diagnosis.

8.4 Classification[edit]

MSA is one of several neurodegenerative diseases known as synucleinopathies: they have in common an abnormal accumulation of alpha-synuclein protein in various parts of the brain. Other synucleinopathies include Parkinson's disease, the Lewy body dementias, and other more rare conditions.

8.4.1 Old terminology[edit]

Historically, many terms were used to refer to this disorder, based on the predominant systems presented. These terms were discontinued by consensus in 1996 and replaced with MSA and its subtypes, but awareness of these older terms and their definitions is helpful to understanding the relevant literature prior to 1996. These include striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy–Drager syndrome. A table describing the characteristics and modern names of these conditions follows: