Many Faces, Same Disease – A patient primer from the University of Florida Center for Movement Disorders & Neurorestoration
What is MSA?
MSA, or Multiple System Atrophy, is a form of parkinsonism with many features that overlap with those of classic Parkinson disease and make it confusing to diagnose clinically. In fact, early symptoms may appear just like Parkinson disease (PD) and standard treatments, such as carbidopa/levodopa (Sinemet), can initially be helpful only to wane later in effectiveness as the disease progresses. As the disorder’s name alludes, MSA is a multisystem neurodegenerative disease that is characterized by a combination of symptoms including parkinsonism, cerebellar and pyramidal tract signs, and autonomic dysfunction. Parkinsonism is a descriptive term and includes tremor (usually resting), stiffness or rigidity, bradykinesia (slowed movements), and postural and gait instability. Cerebellar signs in contrast refer to problems with coordination and may include tremor with activity, past pointing (when reaching for objects), slurred speech, and an unstable “drunk-like” gait. Autonomic problems are non-motor features that involve failure of the automatic nervous system which controls things like heart rate, blood pressure, bowel, bladder and sexual functions. These are things you don’t often think about and are “automatically” controlled by the brain. In MSA people develop problems with this system and may present with lightheadedness/dizziness (related to changes in position, such as standing, and referred to as orthostatic hypotension), fainting spells, urinary retention or urgency (even incontinence), erectile dysfunction in men, constipation, and abnormal heat/cold intolerance and problems with sweat production. Additional features that are closely linked to MSA (and other parkinsonian syndromes) include REM sleep behavior disorder—characterized by yelling or thrashing about during dream sleep—periodic limb movements or restless legs, and respiratory stridor (harsh, strangled breathing). Importantly, it is possible for these other symptoms to precede motor symptoms by months to years.
What are the “faces” of MSA?
Given the multitude of features in MSA, clinical presentation is varied resulting in many “faces” of the disease. Since its first description in the 1960s the disease has been given different names—Shy-Drager syndrome, striatonigral degeneration (SND), and olivopontocerebellar atrophy (OPCA)—depending on the predominant presenting symptoms. However, it was later discovered that each of these syndromes shared a similar pathology characterized by the presence of abnormal protein deposits in the brain, called glial cytoplasmic inclusions or GCI’s. These inclusions are similar to “Lewy bodies” seen in PD, but unlike PD they are not found in neurons but rather in supporting glial cells. In the brain these glial cells are important for making myelin, a substance that “insulates” nerve fibers. The finding of this common pathological feature regardless of the clinical presentation (or “face” of the disease) led to the terminology used today, multiple system atrophy or MSA. Two clinical variants are generally still distinguished by clinicians based on the predominant presenting symptoms: parkinsonism (MSA-P, also known as Shy Drager or SND) or cerebellar ataxia (MSA-C, or OPCA). Both variants include autonomic dysfunction and as the disease progresses the features of these variants increasingly overlap.
Who does MSA affect?
MSA affects men and women equally and median age of onset is about 58 years-old. Although not as prevalent as PD, MSA affects about 4 per 100,000 individuals. In North America and Europe the parkinsonian variant of MSA (MSA-P) predominates, whereas the cerebellar variant (MSA-C) is more frequent in Asian populations. Disease progression unfortunately is usually more rapid than in PD and reflects a more widespread neurodegeneration in the brain. The combination of autonomic and motor symptoms, particularly if early in onset, can be fraught with more complications and shorter survival. Therefore early disease identification is critical. Referral to a movement disorders neurologist is recommended for proper diagnosis and symptom management.
How is MSA diagnosed?
Although the diagnosis of MSA is primarily based on clinical criteria (possible vs. probable disease; definitive diagnosis is made only at autopsy), several diagnostic studies may be helpful to support the diagnosis or to rule out other disease. So far there is no one blood test to identify MSA from other parkinsonian syndromes. Biomarkers such as alpha-synuclein, a protein abundantly found in Lewy body disorders, are being explored but remain controversial. The ability to distinguish MSA from PD and other parkinsonian syndromes is key and further study is still needed to increase the sensitivity and specificity of any blood or CSF (spinal fluid) test. On the other hand, brain imaging such as MRI is frequently used and can be helpful, particularly in cases that present with “atypical” parkinsonian features as in MSA. Brain MRI is often performed to evaluate for other potential causes of parkinsonism like stroke, inflammation, or hydrocephalus (“fluid on the brain”). In MSA a brain MRI can show atrophy or degeneration of specific brain region that are characteristic—including brainstem (pons, olivary nuclei), cerebellum, and basal ganglia—and lend support to the diagnosis. These classic signs are not always seen though, so repeat imaging may be needed as the disease progresses and if concern regarding diagnosis remains.
Newer imaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) are actively being explored, including major efforts here at the University of Florida. Functional MRI has the ability to look at brain activity based on changes in regional blood flow, whereas DTI is used to examine changes in brain connectivity by measuring water diffusion along nerve fiber tracts in the brain. Research here at UF by Dr. Vaillancourt and colleagues has demonstrated promising findings using these imaging techniques that may one day help distinguish MSA from classic PD and other forms of parkinsonism. Another imaging technique of note is the DaTscan™ (125I-iofluane SPECT), recently approved by the FDA, which measures the integrity of the dopamine system in the brain. Although touted as able to diagnose PD, it is not specific for PD and is typically abnormal in MSA patients (and other parkinsonian syndromes). Thus, while a DaTscan™ is not specific, it may also be helpful in supporting the diagnosis of MSA.
Testing for “non-motor” symptoms in MSA can also be useful. Patients that describe sleep disturbance including restlessness, jerking, dream-enactment (yelling, flailing), breathing issues (snoring and apnea), or just plain insomnia and excessive daytime fatigue should ask their physician to order a sleep study, or polysomnography. Restless leg syndrome (RLS), periodic limb movements of sleep (PLMS), and REM-sleep behavior disorder (RBD) can all be treated and improve sleep quality. If stridor or sleep apnea is identified, then the use of a machine that provides continuous positive airway pressure, or CPAP, may be indicated. Evaluation of autonomic symptoms can also be done, but may require specialized equipment and expertise. Simple lying, sitting, standing blood pressure check can be used to diagnose orthostatic hypotension. More detailed examination may include tilt-table testing that monitors changes in heart rate and BP with gradual incline. To measure sweat response, a variety of tests can be performed that stimulate or gently heat a portion of skin and assess sweat output—a part of the sympathetic or “flight/fight” response. Gastrointestinal motility can also be tested. If one experiences early satiety, or feeling of fullness or nausea after eating just small portions, a gastric emptying study may be in order. Urinary symptoms such as frequency, urgency, and incontinence should be evaluated by a urologist. Measurement of post-void residual (urine) and urodynamic testing are some of the things that may be done and helpful to determine cause of problems.
How is MSA treated?
Treatment of MSA remains largely supportive. About 30-60% of patients respond to typical Parkinson’s medications such as carbidopa/levodopa (Sinemet), and dose trial of up to 1 gram/day of levodopa for a few months is recommended. Benefit seen early in disease often fades though, or becomes fraught with complications. Two major complications include exacerbation of orthostatic symptoms (lightheadedness, dizziness, or fainting on standing) and dyskinesias, or abnormal involuntary movements that often involve the jaw or face. These symptoms can result in limiting the dose of medication tolerated, and thus also the effectiveness of drug treatment. More advanced motor symptoms, such as muscle spasm or fixed postures (dystonia), can be treated with “muscle relaxants” and sometimes by injection of botulinum toxin (i.e., Botox). Deep brain stimulation (DBS), however, is generally not recommended as poor outcomes have been reported. Physical and occupational therapies for gait and balance, range of motion and mobility, and help with activities of daily living are critical and require staff familiar with Parkinsonian patient needs. For those with progressive speech and swallowing issues therapy with a specialist is also highly recommended and includes regular swallow testing. Prevention of falls and aspiration (pneumonia) are major goals as these frequently lead to worsening disability and even death.
Although there is often focus on motor symptoms, the non-motor symptoms of MSA can also be just as disabling. Orthostatic symptoms, dizziness and even fainting, can become very limiting and lead to the wheelchair or recliner-bound patient. Treatment initially begins with “conservative” therapies including increased fluid intake, salt in diet (considering of course any concomitant heart disease), and wearing pressure stockings or binder. If these are not enough, drug treatment may be necessary. Options include “blood volume increasers” (fludrocortisone) or “pressor agents” (e.g., midodrine). Both increase BP thereby reducing episodes of low BP, but the later can also cause excessive high BP usually when lying down. Careful monitoring of BP is needed, avoiding ups and downs, and a happy medium found for each individual. Urinary and bowel symptoms likewise can be treated with select agents depending on the issue. Sleep disturbance can also be successfully treated depending on cause.
As a multisystem disorder Multiple System Atrophy has many “faces” and results in varied symptoms that require an interdisciplinary approach. Patient care begins with proper diagnosis and then focused, and even specialized, treatment of the various symptoms of MSA.
Please feel free to contact me, Dr. Nikolaus McFarland, University of Florida Center for Movement Disorders and Neurorestoration http://mdc.mbi.ufl.edu, firstname.lastname@example.org for further information.
Learn more about the University of Florida Progressive Supranuclear Palsy & Atypical Parkinsonism Clinic which sees MSA patients …