Multiple system atrophy

Multiple system atrophy (MSA) is a rare

A prion of the alpha-synuclein protein within affected neurons may cause MSA.^[2] About 55% of MSA cases occur in men, with those affected first showing symptoms at the age of 50–60 years.^[3] MSA often presents with some of the same symptoms as Parkinson's disease. However, those with MSA generally show little response to the dopamine agonists used to treat Parkinson's disease and only about 9% of MSA patients with tremor exhibit a true parkinsonian pill-rolling tremor.^[4]

MSA is distinct from multisystem proteinopathy, a more common muscle-wasting syndrome. MSA is also different from multiple organ dysfunction syndrome, sometimes referred to as multiple organ failure, and from multiple organ system failures, an often-fatal complication of septic shock and other severe illnesses or injuries.

Signs and symptoms

MSA is characterized by the following: Autonomic and at least one Motor (clinically established MSA criteria 2022)^[5][6]

• autonomic dysfunction
  : Post-void urinary residual volume ≥100 mL (usually by ultrasound); Unexplained urinary urge incontinence; or Neurogenic orthostatic hypotension (≥20/10 mmHg blood pressure drop) within 3 minutes (usually by head‐up tilt)
• muscle rigidity +/ tremor
  and slow movement: MSA-P)
• cerebellar ataxia (Poor coordination/unsteady walking: MSA-C)

A variant with combined features of MSA and dementia with Lewy bodies may also exist.^{[unreliable medical source?][7]} There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.^[8]

Initial presentation

The most common first sign of MSA is the appearance of an "akinetic-rigid syndrome" (i.e. slowness of initiation of movement resembling Parkinson's disease) found in 62% at first presentation. Other common signs at onset include problems with balance (cerebellar ataxia) found in 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.^[9]

For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity.^[10]

Progression

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^[11][12]
2. Cerebellar dysfunction - difficulty coordinating movement and balance^[13]
3. Autonomic nervous system dysfunction - impaired automatic body functions, including one, some, or all of the following:^[14]

• postural or
  fainting upon standing up^[15]
• urinary incontinence or urinary retention^[16][17][18]
• impotence^[19]
• constipation^[20]
• vocal cord
  paralysis
• dry mouth
  and skin
• trouble regulating
  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^[21]
• double vision^[22]
• muscle twitches^[22]
• Cognitive impairment[23]

Genetics

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.^[24]

A follow-up study was unable to replicate this finding in American MSA patients.^[25] The authors of the 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.^[26][27] The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause.^[26]

Pathophysiology

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.^[28] 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.^[29]

The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is

Clinical diagnostic criteria were defined in 1998[35] and updated in 2007^[36] and in 2022.^[37] Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.^[38][39][40]

Radiologic

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]}

Pathologic

Pathological diagnosis can only be made at autopsy by finding abundant GCIs on histological specimens of the central nervous system.^[41]

Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations,^[42] MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons.^[43] 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,^[44][45] rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases.^[45] 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.^[46][47] 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.^[46] 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.^[48]

In 2020, researchers at

The current terminology and diagnostic criteria for the disease were established at a 2007 conference of experts and set forth in a position paper.[36] This Second Consensus Statement defines two categories of MSA, based on the predominant symptoms of the disease at the time of evaluation. These are:

• MSA with predominant parkinsonism (MSA-P) - defined as MSA where extrapyramidal features predominate. It is sometimes termed striatonigral degeneration, a parkinsonian variant.^{[citation needed]}
• MSA with cerebellar features (MSA-C) - defined as MSA in which cerebellar ataxia predominates. It is sometimes termed sporadic olivopontocerebellar atrophy.^{[citation needed]}

Management

Supervision

Ongoing care from a

The drug riluzole is ineffective in treating MSA or PSP.^[9]

Rehabilitation

Management by rehabilitation professionals including

Early intervention of swallowing difficulties is particularly useful to allow for discussion around tube feeding further in the disease progression.^[citation needed] At some point in the progression of the disease, fluid and food modification may be implemented.^{[citation needed]}

Avoidance of postural hypotension

One particularly serious problem, the

Social workers and occupational therapists can also help with coping with disability through the provision of equipment and home adaptations, services for caregivers and access to healthcare services, both for the person with MSA as well as family caregivers.^[citation needed]

Prognosis

The average lifespan after the onset of symptoms in patients with MSA is 6–10 years.^[3] Approximately 60% of patients require a wheelchair within five years of onset of the motor symptoms, and few patients survive beyond 12 years.^[3] The disease progresses without remission at a variable rate. Those who present at an older age, those with parkinsonian features, and those with severe autonomic dysfunction have a poorer prognosis.^[3] Those with predominantly cerebellar features and those who display autonomic dysfunction later have a better prognosis.^[3]

Causes of death

The most common causes of death are sudden death and death caused by infections, which include urinary catheterization infections, feeding tube infections, and aspiration pneumonia. Some deaths are caused by cachexia, also known as wasting syndrome.^[60]

Epidemiology

Multiple system atrophy is estimated to affect approximately 5 per 100,000 people. At autopsy, many patients diagnosed during life with Parkinson's disease are found actually to have MSA, suggesting that the actual incidence of MSA is higher than that estimate.^[3] While some suggest that MSA affects slightly more men than women (1.3:1), others suggest that the two sexes are equally likely to be affected.^[3][5][28] The condition most commonly presents in persons aged 50–60.^[3]

Research

Mesenchymal

• Nikolai Andrianov was a Soviet/Russian gymnast who held the record for men for the most Olympic medals at 15 (7 gold medals, 5 silver medals, 3 bronze medals) until Michael Phelps surpassed him at the 2008 Beijing Summer Olympics.^[62]
• Todd J. Campbell (1956–2021), United States district judge and counsel to former Vice President Al Gore.^[63]
• Singer and songwriter Johnny Cash wrote in his autobiography that he was diagnosed with Shy–Drager in 1997.^[64]
• American-Israeli basketball player^[65]
• United States district judge of the United States District Court for the District of Maryland.^[66]
• Kenneth More British actor, originally diagnosed with Parkinson's disease.
• Chef Kerry Simon died from complications of MSA.^[67]
• David Colin Sherrington FRS (1945-2014), noted polymer chemist, who was diagnosed in 2012 and died from pneumonia two years later.

References