Multiple System Atrophy is an infrequent neurodegenerative disorder primarily affecting the autonomic nervous system and movement control. It is characterized by the progressive degeneration of specific brain areas, leading to a wide range of symptoms that affect both motor and non-motor functions. MSA is classified into two main subtypes: MSA with predominant parkinsonism (MSA-P) and MSA with predominant cerebellar ataxia (MSA-C).

In MSA-P, patients experience symptoms similar to Parkinson’s disease, including bradykinesia (slowness of movement), rigidity, and tremors. However, MSA-P presents additional features such as postural instability, autonomic dysfunction (including orthostatic hypotension, urinary incontinence, and constipation), and specific cognitive impairments. On the other hand, MSA-C primarily manifests as ataxia, characterized by uncoordinated movements, gait disturbances, and difficulties with balance and coordination.

Patients with MSA-C may also experience dysarthria (slurred speech) and other autonomic symptoms. The degeneration of cells in specific brain areas, such as the basal ganglia, cerebellum, and brainstem, leads to the characteristic symptoms of MSA. The exact mechanisms behind this degeneration are complex and involve the accumulation of abnormal protein deposits called alpha-synuclein in brain cells.

The epidemiology of Multiple System Atrophy has been studied to understand its prevalence and incidence. Epidemiological research studies have indicated that the incidence rate of MSA is approximately 0.6 cases per 100,000 persons per year, with a prevalence rate of 4-5 cases per 100,000 persons. In Italy alone, an estimated 4,900 prevalent cases have been identified.

The average age of onset is around 54 years, and the median survival ranges from 7 to 9 years. During the study duration in Iceland, 19 instances of MSA were detected (11 females, eight males), resulting in an average yearly occurrence of 0.7 per 100,000 individuals. Ten cases were still living on the day of prevalence, resulting in a prevalence rate of 3.4 per 100,000 individuals. In Japan, the prevalence stands at 13.1 out of every 100,000 individuals. The average yearly incidence is 0.68.

Multiple System Atrophy (MSA) pathophysiology involves the progressive degeneration of some areas of the brain, leading to a wide range of neurological and autonomic dysfunction. The exact cause of MSA is not fully understood, but it is characterized by the accumulation of abnormal protein deposits called alpha-synuclein within brain cells.

The primary affected areas in MSA include the basal ganglia, cerebellum, and brainstem. These regions play critical roles in motor control, coordination, and autonomic function. The accumulation of alpha-synuclein forms characteristic structures called glial cytoplasmic inclusions (GCIs) within the affected brain cells. These GCIs disrupt cellular processes, impairing the normal functioning of neurons and glial cells.

In MSA, there is a loss of cells called oligodendrocytes, which produce myelin, a protective coating around nerve fibers. The loss of oligodendrocytes leads to demyelination, resulting in disrupted communication between neurons. This contributes to the motor and non-motor symptoms observed in MSA.

The degeneration of the autonomic nervous system is a prominent feature of MSA. It affects various functions, such as blood pressure regulation, bladder control, and gastrointestinal motility. The disruption of autonomic pathways in MSA is thought to be caused by the degeneration of neurons in the brainstem, particularly in the areas involved in autonomic control.

The accumulation of alpha-synuclein in MSA is believed to be a critical factor in the pathogenesis of the disease. However, the exact triggers and mechanisms leading to the abnormal accumulation of alpha-synuclein are still under investigation. Genetic factors, environmental influences, and impaired protein clearance pathways are among the factors implicated in the development and progression of MSA.

The etiology, or underlying cause, of Multiple System Atrophy (MSA), still needs to be fully understood.

Genetic Factors: While MSA is generally considered a sporadic disorder with no known family history, there is growing evidence to suggest a genetic component. Mutations in specific genes, such as COQ2 and SYNJ1, have been found in rare familial cases of MSA.

Alpha-Synuclein Accumulation: The hallmark feature of MSA is the abnormal accumulation of alpha-synuclein protein in brain cells. Alpha-synuclein usually is involved in the regulation of neurotransmitter release and synaptic function.

Environmental Factors: Some environmental factors have been suggested to contribute to the development of MSA, although their exact roles are not well-defined. Exposure to certain toxins or chemicals, such as pesticides and industrial solvents, has been proposed as a potential risk factor for MSA.

Protein Handling and Clearance Dysfunction: Impaired protein handling and clearance mechanisms within cells may also play a role in MSA.

Subtype: MSA is classified into two main subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia (MSA-C).

Age at Onset: The age at which MSA symptoms first appear can influence the disease course. Generally, an earlier onset of symptoms is associated with a more rapid progression of MSA.

Motor Symptoms: The severity and progression of motor symptoms, such as parkinsonism or ataxia, can provide insights into the prognosis. Rapid progression of motor symptoms and early development of severe disability are generally associated with a worse prognosis.

Autonomic Dysfunction: Autonomic dysfunction, including orthostatic hypotension, urinary dysfunction, and cardiovascular complications, is a common feature of MSA.

Cognitive Impairment: Cognitive impairment can occur in MSA, although it is generally less severe compared to other neurodegenerative disorders like Parkinson’s disease with dementia or dementia with Lewy bodies.

Response to Treatment: MSA is a challenging condition with no cure. However, some symptomatic treatments can help manage certain aspects of the disease, such as motor symptoms or autonomic dysfunction.

Clinical history

The clinical presentation of Multiple System Atrophy can vary, but it generally involves a combination of motor and non-motor symptoms.

Age group:

The age group affected by MSA is typically between 40 and 60 years, although it can also occur in younger or older individuals.

Physical examination

During a physical examination of a person suspected to have Multiple System Atrophy (MSA), healthcare professionals will assess various aspects of motor function, autonomic function, and other relevant findings.

Motor Function Assessment:

• Evaluation of gait and balance: look for signs of instability, shuffling gait, unsteadiness, or difficulty initiating or stopping movements.
• Measure muscle tone and rigidity: check for increased muscle tone, stiffness, or resistance to passive movement.
• Examination of coordination and fine motor skills: finger tapping or rapid alternating movements.
• Assessment of muscle strength: manual resistance or testing against gravity.

Autonomic Function Assessment:

• Measurement of blood pressure
• Evaluation of heart rate and rhythm
• Examination of pupillary function
• Assessment of sweating

Neurological Examination:

• Evaluation of reflexes: knee jerk reflex and ankle reflex, to assess the function of the peripheral nervous system.
• Examination of sensation: touch, pain, and temperature may be assessed in different body areas.
• Assessment of coordination: finger-to-nose or heel-to-shin.

Other Findings:

• Examination of speech and swallowing
• Evaluation of eye movements
• Observation of facial expression

Associated Comorbidity or Activity:

No specific comorbidities or activities are strongly associated with the development of MSA. However, certain risk factors, such as a history of exposure to toxins or environmental factors, may be present in some cases. It is worth noting that MSA is considered a sporadic disorder, meaning it typically occurs without a clear family history.

Acuity of Presentation:

The onset of MSA is usually insidious, with symptoms gradually worsening over time. However, the rate of disease progression can vary among individuals, and some may experience a more rapid decline in function.

• Motor Symptoms: Motor symptoms in MSA can resemble those seen in Parkinson’s disease, although they tend to progress more rapidly. These symptoms may include bradykinesia, rigidity, tremors, and postural instability. Gait disturbances are common, characterized by a shuffling gait, difficulty initiating movements, and frequent falls.
• Non-Motor Symptoms: Non-motor symptoms are a prominent feature of MSA and can significantly impact a person’s quality of life. These symptoms can involve various bodily systems, including the autonomic nervous system. Common non-motor symptoms include orthostatic hypotension, urinary dysfunction, constipation, and sexual dysfunction.

Treatment paradigm

The treatment paradigm for Multiple System Atrophy (MSA) focuses primarily on managing symptoms and providing supportive care, as there is currently no cure for the condition. The treatment approach aims to address both motor and non-motor symptoms and improve the overall quality of life for individuals with MSA.

Motor Symptoms: Medications commonly used in Parkinson’s disease, such as levodopa, may be prescribed to manage parkinsonism-like symptoms in MSA. However, the response to levodopa is often limited and may decline over time. Other medications, such as dopamine agonists or monoamine oxidase-B inhibitors, may be considered alternative or adjunctive treatments. Physical therapy and exercise programs can help improve mobility, balance, and muscle strength.

Non-Motor Symptoms: The management of non-motor symptoms in MSA is equally essential. For autonomic dysfunction, lifestyle modifications (e.g., maintaining hydration, avoiding triggers) and medications to address specific symptoms like orthostatic hypotension (e.g., fludrocortisone, midodrine) or urinary dysfunction (e.g., anticholinergic medications) may be employed.

Constipation can be managed through dietary changes, increased fluid intake, and medications such as laxatives or stool softeners. Speech and swallowing difficulties may require speech therapy and modifications to diet consistency. Addressing sleep disturbances, anxiety, and depression may involve a combination of pharmacological interventions and behavioral strategies.

Supportive Care: MSA is a progressive condition, and supportive care is essential to address the evolving needs of individuals with the disease. Regular follow-ups with healthcare professionals, including neurologists and other specialists, can help monitor symptoms, adjust medications, and provide guidance on managing specific challenges. Palliative care and multidisciplinary approaches, including social support, physical and occupational therapy, and psychological counseling, can be crucial in optimizing comfort, function, and emotional well-being.

Neurology

Physical Medicine and Rehabilitation

Modifying the environment can significantly contribute to the well-being and safety of individuals with Multiple System Atrophy (MSA), considering their unique needs and challenges.  

• Fall Prevention: MSA can cause gait instability and increased fall risk. Ensure the environment is free of tripping hazards, such as loose rugs or cluttered pathways.  
• Accessibility and Mobility: Arrange furniture and belongings to create clear pathways, allowing for ease of movement and wheelchair or walker accessibility if needed.  
• Communication Assistance: MSA can affect speech and swallowing. To facilitate communication, ensure a quiet environment when engaging in conversations.  
• Comfort and Temperature Regulation: MSA can impact the body’s ability to regulate temperature. Ensure the living environment is comfortable and well-ventilated.  
• Supportive Equipment: Depending on the specific needs of the individual, consider providing assistive equipment such as mobility aids (e.g., walkers, canes), raised toilet seats, shower chairs, or specialized eating utensils to enhance independence and safety. 

Neurology

Physical Medicine and Rehabilitation

The primary function of levodopa in individuals with suspected MSA is investigative; an inadequate or short-lived reaction to levodopa treatment is typically noted in patients with MSA and can aid in distinguishing the parkinsonian form of MSA (MSA-P) from idiopathic Parkinson’s disease.

Nevertheless, certain patients with clinically likely MSA exhibit improved outcomes with levodopa therapy compared to those without it, and some also experience fluctuations in motor function and involuntary movements (dyskinesia). 

In individuals with progressed illness who have displayed a positive response to oral levodopa, levodopa-carbidopa intestinal gel (LCIG) is an alternative aided by a device. This option can potentially enhance overall functional scores and enable the cessation of oral antiparkinsonian medications in certain patients. 

Neurology

Physical Medicine and Rehabilitation

Currently, no efficacious drugs are available to address the ataxia and abnormalities in gait that are predominantly observed in the cerebellar variant of MSA. Physical therapy is crucial in preventing falls, minimizing contractures, and preserving mobility for as long as feasible. Therapists are instrumental in assessing patients’ specific needs and assisting with using walkers and wheelchairs once the individual becomes nonambulatory. 

The administration of botulinum toxin injections can be beneficial in relieving symptoms of focal dystonias, such as cervical dystonia (abnormal neck muscle contractions) and blepharospasm (involuntary eyelid closure), which may occur in MSA. However, caution is recommended when performing injections on MSA patients with cervical dystonia due to the potential risk of exacerbating underlying dysphagia (difficulty swallowing) frequently associated with the disease. 

Referring patients to speech therapy at an early stage of the disease facilitates an objective assessment of the progression of dysphagia (difficulty swallowing). The necessity for percutaneous gastrostomy tube placement should be evaluated through videofluoroscopic swallow evaluation and barium swallow studies. These diagnostic procedures provide valuable insights into the swallowing function and help determine whether a feeding tube is required. 

Neurology

Physical Medicine and Rehabilitation

Lifestyle Modifications: 

• Increasing fluid intake: Ensuring adequate hydration by drinking plenty of fluids, especially water, can help maintain blood volume and improve blood pressure stability. 
• Dietary changes: Consuming smaller, frequent meals that are lower in carbohydrates and higher in salt content can help increase blood pressure. 
• Avoiding triggers: Identifying and avoiding factors that worsen orthostatic hypotension, such as prolonged standing, hot environments, or alcohol consumption, can be helpful. 

Physical Maneuvers and Compression Garments: 

• Leg exercises: Regular leg exercises, such as flexing and extending the calf muscles while sitting or lying down, can enhance venous return and improve blood pressure control. 
• Compression garments: Wearing compression stockings or abdominal binders can help improve blood flow and maintain blood pressure. 

Medications: 

• Fludrocortisone: Fludrocortisone is a synthetic corticosteroid that helps retain salt and water, thereby increasing blood volume and improving blood pressure. It is commonly prescribed for the treatment of orthostatic hypotension in MSA. 
• Midodrine: Midodrine is an alpha-1 adrenergic agonist that helps constrict blood vessels and elevate blood pressure. It is often used to manage orthostatic hypotension by improving vasoconstriction. 
• Pyridostigmine: Pyridostigmine is an acetylcholinesterase inhibitor that increases the availability of acetylcholine, a neurotransmitter involved in blood pressure regulation. It can be used to enhance postural blood pressure control. 

Neurology

Physical Medicine and Rehabilitation

Dietary Modifications: 

• Smaller, more frequent meals: Consuming smaller meals throughout the day instead of large, heavy meals can help prevent a significant drop in BP after eating. 
• Hydration: Ensuring adequate fluid intake before, during, and after meals can help maintain blood volume and stabilize blood pressure. Drinking water or other non-alcoholic beverages with meals is recommended. 

• Avoidance of trigger foods: Certain foods and beverages, such as high-carbohydrate meals or drinks with high sugar, can contribute to postprandial hypotension.  

Mealtime Strategies: 

• Slow and controlled eating: Encouraging slow, mindful eating and taking time to chew food thoroughly can help promote better digestion and minimize the postprandial drop in blood pressure. 
• Positioning: Sitting upright or slightly reclined during meals can help improve blood pressure control. Avoiding lying down immediately after eating is also advisable. 
• Use of abdominal binders or compression garments: Wearing compression garments or abdominal binders during mealtime may assist in maintaining blood pressure by improving venous return. 

Medications: 

• Midodrine: Midodrine is an alpha-1 adrenergic agonist that helps constrict blood vessels and raise blood pressure. In MSA, it is often prescribed to address orthostatic hypotension, including PPH. Midodrine increases peripheral vascular resistance, improving blood pressure control during and after meals. 
• Pyridostigmine: Pyridostigmine is an acetylcholinesterase inhibitor that increases the availability of acetylcholine, a neurotransmitter involved in blood pressure regulation. By enhancing cholinergic activity, pyridostigmine can help improve blood pressure control during and after meals in individuals with MSA and PPH. 

Neurology

When addressing overactive bladder, the initial approach for individuals with MSA is comparable to that of the general population. This approach involves educating patients about lifestyle modifications, such as reducing the intake of diuretic substances like caffeine and alcohol and avoiding fluid consumption before bedtime. Additionally, prompted or timed bladder emptying techniques and behavioral therapies, like pelvic floor muscle training, are implemented to manage symptoms. 

In patients with persistent bothersome symptoms of overactive bladder, adjunctive medications should be considered. The primary pharmacological treatments, offered as first-line therapies, include beta-3 adrenergic agonists (such as mirabegron and vibegron) and antimuscarinic drugs. To minimize the potential for side effects, initiating medications at low doses and gradually increasing the dosage as needed is advisable. 

Mirabegron: Mirabegron, in particular, appears to have a more favorable adverse event profile in individuals with MSA, and it does not typically induce cognitive side effects. Recent evidence suggests that mirabegron is effective and well-tolerated in patients with Parkinson’s disease as well. 

Antimuscarinic agents: These agents with minimal central nervous system penetration, such as darifenacin, solifenacin, and trospium, are typically preferred due to their lower likelihood of causing neurocognitive side effects. Solifenacin, in particular, has been specifically examined in patients with Parkinson’s disease. It is advisable to avoid older medications like oxybutynin and tolterodine, if possible, in individuals with MSA, as they carry a higher risk of causing confusion and exacerbating constipation. 

Alpha-adrenergic blockers: tamsulosin and silodosin, should be used with great caution, if at all, for urinary symptoms in individuals with MSA. These medications can potentially worsen orthostatic hypotension, a common symptom of MSA characterized by a drop in blood pressure upon standing. 

In cases of bladder atony, intermittent self-catheterization is recommended when there is retention or a residual urine volume exceeding 100 mL. As the severity of bladder dysfunction advances, a permanent transcutaneous suprapubic catheter may become necessary to manage urinary drainage. 

Psychiatry/Mental Health

Depression frequently manifests in patients with MSA and often necessitates psychiatric intervention involving counseling for the patient and their family. In certain instances, antidepressant medication may be warranted as a treatment approach. 

Laryngeal stridor, a high-pitched sound during breathing, commonly occurs during sleep in individuals with MSA. However, in advanced cases, symptoms may also manifest during the daytime. Sleep dysfunction, a significant contributor to mortality in MSA, requires thorough evaluation to understand its implications and potential interventions. 

Patients experiencing symptomatic stridor should be referred to specialists in otolaryngology and sleep medicine for an overnight polysomnography evaluation.

Usually, initial symptomatic treatment involves nocturnal continuous positive airway pressure (CPAP). However, when central sleep apnea coexists, adaptive servo-ventilation (ASV) may be employed as an alternative to CPAP. 

Neurology

Melatonin and clonazepam are medications commonly used in the management of Rapid Eye Movement sleep behavior disorder (RBD), which can occur in Multiple System Atrophy (MSA).  

Melatonin: It is a hormone that naturally produced by the pineal gland that helps in the regulation of the sleep-wake cycle. It is effective in diminishing the frequency and severity of RBD episodes. Melatonin supplementation can help promote a more regular sleep pattern and inhibit the muscle activity associated with RBD during REM sleep. 

Clonazepam: Clonazepam is a benzodiazepine medication that can effectively manage RBD symptoms. It acts as a central nervous system depressant, reducing muscle activity during REM sleep and preventing the physical acting out of dreams associated with RBD. 

Neurology

There are currently no specific procedures or interventions that can cure/halt the progression of the disease. MSA is primarily managed through symptomatic treatment and supportive care measures. However, specific procedures may be considered part of the overall management approach. These procedures aim to alleviate specific symptoms or improve quality of life.  

• Deep Brain Stimulation (DBS): In some cases of MSA with predominant parkinsonism (MSA-P), deep brain stimulation may be a treatment option for managing motor symptoms such as tremors, rigidity, and bradykinesia. DBS involves the implantation of electrodes into specific brain regions, typically the subthalamic nucleus (STN) or globus pallidus internus (GPi), which are then connected to a neurostimulator device. The device delivers electrical impulses to modulate abnormal brain activity and help alleviate motor symptoms.  
• Bladder Procedures: MSA can lead to urinary dysfunction, including urgency, frequency, and incontinence. In some cases, specific procedures may be performed to manage bladder symptoms. For example, intermittent self-catheterization or indwelling urinary catheters may be used to help with bladder emptying. Surgical interventions such as bladder augmentation (enlargement) or placement of an artificial urinary sphincter may be considered in severe cases of urinary incontinence or to improve bladder function. 

• Percutaneous Endoscopic Gastrostomy (PEG): In individuals with severe swallowing difficulties (dysphagia), a percutaneous endoscopic gastrostomy tube (PEG tube) may be inserted into the stomach through a small incision in the abdominal wall. The PEG tube allows for direct feeding and administration of medications when oral intake becomes challenging or unsafe due to dysphagia. 

Neurology

Managing Multiple System Atrophy (MSA) typically involves a phased approach encompassing different aspects of care throughout the disease course. While there is no cure for MSA, the goal of management is to optimize symptom control, enhance quality of life, and provide comprehensive support to individuals with MSA and their caregivers. 

Early Phase: In the early phase of MSA, the focus is establishing an accurate diagnosis and initiating symptomatic treatment. This involves a thorough evaluation by a neurologist or movement disorder specialist to differentiate MSA from other conditions and assess the specific symptoms and their impact on daily life.

Treatment strategies may include medications for motor symptoms (e.g., levodopa, dopamine agonists) and non-motor symptoms (e.g., orthostatic hypotension, urinary dysfunction). Lifestyle modifications and supportive therapies such as physical and occupational therapy are often initiated to address mobility, balance, and activities of daily living. During this phase, educating the individual and their caregivers about the disease, providing emotional support, and connecting them to appropriate resources and support networks are crucial. 

Advanced Phase: As MSA progresses, the management focus shifts towards comprehensive supportive care and symptom management. Palliative care approaches are essential to address the evolving needs and challenges of the individual with MSA. This phase involves ongoing monitoring and adjustment of medications to optimize symptom control while minimizing side effects.

Multidisciplinary care teams, including neurologists, palliative care specialists, physical and occupational therapists, speech therapists, and social workers, work collaboratively to provide personalized care and support. Attention is given to comfort, managing complications such as respiratory problems or infections, and ensuring the individual’s emotional and psychosocial well-being.

Supportive interventions may include respiratory support, mobility aids, adaptive devices for communication and daily activities, and counseling or psychological support for the individual and their caregivers.