Continuing Education Activity

Shy Drager syndrome refers to a progressive neuromuscular disorder that affects the nervous system. It falls on the multiple system atrophy spectrum of disease. This activity outlines the evaluation and management of Shy Drager syndrome and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of Shy Drager syndrome.
• Describe the evaluation of Shy Drager syndrome.
• Review the management available for Shy Drager syndrome.
• Summarize the importance of communication and coordination amongst the interprofessional team to enhance the care of patients with Shy Drager syndrome.

Introduction

Shy Drager syndrome was originally classified in 1960 as a neurological disorder that resulted in orthostatic hypotension of unknown etiology.[1] Since then, its naming convention and the understanding of its etiology have undergone several revisions. In a 1998 consensus statement, the term "Shy Drager syndrome" was formally taken out of use and placed under the categorization of "multiple system atrophy" (MSA).[2] Multiple system atrophy has been further categorized into MSA-P and MSA-C, depending on whether parkinsonian or cerebellar features predominate, respectively.[3] As indicated in its name, the anatomical hallmark of MSA is atrophy. Specifically, the cerebellum, pons, and putamen are the primary areas of brain involvement. MSA-P and MSA-C differ in the amount of involvement in each of these areas of the brain. In the spinal column, both MSA-P and MSA-C include the intermediolateral area of the spinal cord in addition to Onuf's nucleus and the vagal nucleus.[4]

Etiology

The exact cause of multiple system atrophy and its subtypes is unknown. However, there are several hypotheses that have been heavily researched and proposed. The vast majority of proposed disease mechanisms encompass the accumulation of intracellular alpha-synuclein. More recently, mitochondrial dysfunction and inflammation have been suggested in its pathogenesis.[4] Alpha-synuclein has been shown to accumulate intracellularly in other nervous system disorders, such are Parkinson's, but alpha-synuclein build-up seems to occur in oligodendrocytes in MSA primarily.[5]

Further studies are ongoing and suggest that the excess alpha-synuclein is either a result of genetic overexpression in oligodendrocytes of affected patients or a result of increased uptake from the surrounding extracellular environment.[4] Patients with MSA demonstrate mutations in the COQ2 gene, which encodes for the production of Coenzyme Q10 (CoQ10). CoQ10 is a component of the respiratory chain in mitochondria involved in ATP production. Brain tissue gathered from autopsies of patients with MSA show a significant decrease in CoQ10, but this was only seen in the cerebellum, suggesting that CoQ10 deficiency may predominate the cerebellar form of MSA.[6] Finally, the role of inflammation has largely been elucidated in brain tissue, demonstrating increased microglial activation.[7]

Epidemiology

The number of new cases of multiple system atrophy overall has been approximated between 0.6 to 0.7 per 100,000 people each year. Each subtype demonstrates a region-specific pattern. MSA-C is largely concentrated in Japan, while MSA-P tends to dominate new cases of MSA in Western countries. The clinical onset of MSA becomes apparently most often in the sixth decade of life.[4]

History and Physical

Motor dysfunction, dysautonomia, and sleep disorders form the backbone of the history and physical exam findings present in patients with MSA. Parkinsonism features are predominated in MSA-P and are characterized by physical exam findings that include postural instability, tremor, rigidity, and bradykinesia.[8] Dysautonomia occurs in both MSA-P and MSA-C in the form of urinary dysfunction, anhydrosis, and orthostatic hypotension.[5] Disturbances in sleep include sleep apnea, stridor, and ataxic breathing, which also occur with MSA.[9]

Evaluation

The gold standard diagnosis of multiple system atrophy can only be carried out post mortem. It is based on the intracellular build-up of alpha-synuclein and accompanying neurodegenerative changes in the accompanying brain structures. The MSA diagnosis used in practice is, therefore, pieced together based on its clinical features. Formal diagnosis requires the presence of adult-onset (over age 30) parkinsonian or cerebellar ataxia, the presence of autonomic failure in the urinary or cardiovascular system, and one additional supporting feature of MSA.[3]

MSA and Parkinson's disease parallel many of the same clinical symptoms but differ in their response to levodopa. A poor response to levodopa is found in MSA, while patients with Parkinson's respond well to levodopa. This distinction is useful clinically to separate the conditions and is often used as a supporting feature in MSA diagnosis.[3] No imaging studies are diagnostic by themselves, but some magnetic resonance imaging (MRI) findings can be used as supporting features in MSA diagnosis. These include neurodegeneration seen on MRI of the pons, putamen, or middle cerebellar peduncle.[10]

Treatment / Management

As of now, no cure for multiple system atrophy exists. The combination of symptom management and emerging research of novel therapies can give affected patients hope for the future. Symptomatic management is targeted at the predominant features of how MSA or its subtypes manifest.[11] Parkinsonism is treated with a variety of agents, including monoamine oxidase inhibitors and levodopa. For cerebellar ataxia, cholinergic agents have been used. Urinary and fecal incontinence have been treated with trospium chloride or vasopressin analogs, laxatives, or straight catheterization.

Midodrine and fludrocortisone have been used to treat orthostatic hypotension with physical therapy as a supplement for additional motor symptoms.[11] Novel therapies in the pipeline include agents that block alpha-synuclein accumulation or uptake into oligodendrocytes. Selective serotonin reuptake inhibitors (SSRIs), including sertraline and paroxetine, have recently shown promise. In vitro studies demonstrate that sertraline blockages the alpha-synuclein uptake and aggregation in oligodendrocytes. In 2006, a clinical trial of the SSRI paroxetine demonstrated a statistically significant improvement in motor function amongst patients with MSA.[12]

Mesenchymal stem cells (MSCs) have also been explored in the treatment of MSA. A 2019 phase I/II clinical trial utilized intrathecal implantation of MSCs in 24 patients with MSA at quantities varying from 10-200 million. Derived from adipose tissue, MSCs use demonstrated a statistically significant decreased rate of disease progression.[13] Studies aiming at modulating inflammation and microglial activation are underway as well.

The myeloperoxidase (MPO) inhibitor verdiperstat was shown to decrease microglial activation and neuronal rescue in a mouse model of MSA. A phase 3 placebo-controlled human trial on the efficacy of verdiperstat in improving the quality of life for patients with MSA is currently underway.[14]

Differential Diagnosis

Multiple system atrophy can present with either cerebellar or parkinsonian dominant features. In addition to Parkinson's disease itself, the differential diagnosis for MSA includes neurological disease affecting the cerebellum, including Friedreich ataxia and other spinocerebellar ataxias.[5] Further disease considerations should incorporate progressive supranuclear palsy, fragile X–associated tremor ataxia syndrome, and dementia with Lewy bodies.[5]

Prognosis

The prognosis for patients diagnosed with multiple system atrophy is poor, with an average life expectancy of 6 to 10 years after initial diagnosis.[4] The older the patient is at the time of diagnosis, the worse the long-term survival. Other characteristics have been associated with increased mortality after diagnosis, including frequent falls, female gender, and the presence of severe autonomic symptoms.[15]

Complications

The complications of multiple system atrophy are a direct result of an impaired neurological system. Disruptions in sleep due to sleep apnea are frequently reported due to sleep apnea and stridor.[16] Encephalopathy is a traumatic sequela of repeated falls due to poor balance or orthostatic hypotension.[17] Significant speech and breathing difficulties can arise as vocal cord paralysis progresses in MSA.[18] Finally, aspiration pneumonia can occur from increased swallowing abnormalities in patients with MSA.[19]

Deterrence and Patient Education

The pathology of MSA mimics many other neurological diseases. It is therefore integral that a thorough history and physical exam should be performed to rule out other similar diseases. In addition, the role of early levodopa as both a diagnostic and a partially therapeutic agent should be strongly encouraged. This would both help elucidate underlying disease pathology faster and result in expedited treatment of either disease. Furthermore, due to the limited life expectancy and treatments available following diagnosis, end-of-life planning in addition to therapy, expectations should be incorporated into every treatment plan.[5]

Enhancing Healthcare Team Outcomes

MSA presents patients with a myriad of unique challenges in activities of daily living. It is, therefore, critical that an interprofessional team work together to coordinate care in an effort to decrease the burden of treatment. Many studies have demonstrated a patient benefit in the use of technology to improve health care coordination amongst providers. [Level 1][20] Equally important is to ensure patient education and a continued role in their own health. The use of patient portals has allowed patients to easily access their medical records. Encouraging patient portal use has the potential to improve healthcare outcomes of patients with MSA by increasing patient-provider collaboration, decreasing the frequency of unnoticed medical inaccuracies, and increasing patient compliance. [Level 1][21]