Neurodegenerative Disorders

Clinical Presentation

• Multiple System Atrophy (MSA) is a progressive neurodegenerative disorder that involves abnormal accumulation of alpha-synuclein in oligodendroglia, presenting with various motor and non-motor symptoms beyond the classic triad of parkinsonism, cerebellar ataxia, and autonomic dysfunction, according to the American College of Radiology 1
• MSA can cause both restless legs syndrome and anxiety as part of its constellation of symptoms, and can be subdivided into three clinical subtypes: MSA-P (Predominant parkinsonian features), MSA-C (Predominant cerebellar symptoms), and MSA-A (Predominant autonomic dysfunction, also known as Shy-Drager syndrome) 1
• The mean disease duration of MSA is approximately 6 years from onset 1

Diagnostic Evaluation

• The presence of RLS or anxiety symptoms in a patient with suspected MSA should prompt comprehensive evaluation for other characteristic features of MSA, including autonomic dysfunction, parkinsonism, and cerebellar signs, as recommended by the American College of Radiology 1
• Urine albumin-to-creatinine ratio (ACR) is recommended as part of the testing for patients with suspected kidney disease, including those with sleep disorders like Restless Legs Syndrome (RLS), as stated by the European Urology guidelines and the American College of Physicians 2, 3
• ACR helps classify chronic kidney disease (CKD) stages and assess progression risk, with even low levels of albuminuria associated with increased cardiovascular and kidney disease risk, according to the American Diabetes Association, with a moderate level of evidence 3, 4
• Normal ACR is defined as <30 mg/g creatinine, moderately increased as 30-299 mg/g creatinine, and severely increased as >300 mg/g creatinine, based on guidelines from the American Diabetes Association 4

Restless Legs Syndrome (RLS) Diagnosis

• RLS is characterized by an urge to move the legs accompanied by uncomfortable sensations, symptoms that begin or worsen during periods of rest, relief with movement, and worsening of symptoms in the evening or night, according to the American Geriatrics Society and the National Comprehensive Cancer Network 5, 6, 7
• The International Restless Legs Syndrome Study Group established four essential diagnostic criteria for RLS, including an urge to move the legs, symptoms beginning or worsening during periods of rest or inactivity, symptoms being partially or totally relieved by movement, and symptoms occurring only in the evening/night or being worse during these times, as recommended by the American Academy of Sleep Medicine 8
• Diagnostic tools, such as the RLS Diagnostic Index (RLS-DI), the Cambridge-Hopkins Diagnostic Questionnaire (CH-RLSq), and the Hening Telephone Diagnostic Interview (HTDI), are available to aid in diagnosis, with the RLS-DI having excellent diagnostic attributes with sensitivity of 93% and specificity of 98.9%, according to the American Academy of Sleep Medicine 8

Differential Diagnosis

• Peripheral neuropathies typically have sensory symptoms that are constant rather than circadian, whereas RLS symptoms are worse at night, as noted by the American Geriatrics Society 5
• Vascular disease/intermittent claudication is characterized by pain triggered by exercise, not rest, unlike RLS, which is triggered by rest or inactivity 5
• Nocturnal leg cramps are characterized by sudden, painful muscle contractions, distinct from RLS symptoms, as described by the American Geriatrics Society 5
• Neuroleptic-induced akathisia is not typically worse at night and involves generalized restlessness, unlike RLS, which is worse at night and involves leg-specific symptoms 5
• Positional discomfort is relieved by changing position rather than continued movement, whereas RLS symptoms are relieved by movement, as noted by the American Geriatrics Society 5
• Arthritis pain is typically related to specific joints and movements, unlike RLS symptoms, which are more generalized and worse at night, as described by the American Geriatrics Society 5

Laboratory Evaluation

• Ferritin level is a priority in laboratory evaluation, with values less than 50 ng/mL consistent with a diagnosis of RLS and suggesting the need for iron supplementation, as recommended by the American Geriatrics Society 5
• Additional testing, including complete blood count, basic metabolic panel, liver function tests, thyroid function tests, HbA1c, and urine albumin:creatinine ratio, should be considered to rule out secondary causes, as suggested by the European Urology guidelines and the American Geriatrics Society 2, 5

Non-Pharmacological Management

• Moderate exercise, smoking cessation, alcohol avoidance, caffeine reduction or elimination, and discontinuation of potentially exacerbating medications are recommended before or alongside pharmacological treatment, as suggested by the American Geriatrics Society 5
• Non-pharmacological approaches, including regular aerobic and resistance exercise, are recommended for RLS management, according to the American Geriatrics Society and the American Academy of Sleep Medicine 5, 9
• Proper hydration throughout the day can help prevent leg cramps, as recommended by the European Society of Cardiology 10
• Sleeping with the head of the bed elevated (10°) is suggested to maintain better fluid distribution, as per the European Society of Cardiology guidelines 10
• Compression stockings or abdominal binders may be considered if venous pooling is suspected in elderly patients, according to the European Society of Cardiology 10

Pharmacological Management

• Alpha-2-delta ligands (pregabalin or gabapentin) are recommended as first-line pharmacologic therapy for moderate to severe RLS due to their effectiveness and lower risk of augmentation compared to dopamine agonists, as recommended by the American Academy of Sleep Medicine 9
• Dopamine agonists, such as ropinirole, pramipexole, or rotigotine patch, should be used for short-term management only due to the risk of augmentation, with starting doses of 0.25 mg orally 1-3 hours before bedtime for ropinirole and 0.125 mg orally 2-3 hours before bedtime for pramipexole, as recommended by the American Geriatrics Society and the American Academy of Sleep Medicine 5, 9
• Opioids may be considered for severe cases of RLS that fail to respond to first and second-line treatments, with caution due to risk of central sleep apnea and respiratory depression, as recommended by the American Geriatrics Society, the American Academy of Sleep Medicine, and other guidelines 5, 9, 11
• The following treatment options are recommended for specific patient populations:

Monitoring and Follow-up

• Regular monitoring for medication side effects is essential, particularly for patients on dopamine agonists, who are at risk of augmentation, as recommended by the American Academy of Sleep Medicine and the American Geriatrics Society 9, 5
• Regular follow-up is necessary to assess symptom control and adjust treatment as needed, typically with minimal dose increases over time, as recommended by the American Academy of Sleep Medicine 9
• Geriatric patients should be started with lower doses and titrated slowly, and monitored for orthostatic hypotension, especially with dopamine agonists, and augmentation, characterized by earlier symptom onset, increased symptom intensity, and spread of symptoms to other body parts, as recommended by the American Geriatrics Society 5
• Prolonged use of dopamine agonists should be limited due to high risk of augmentation, and iron deficiency should not be overlooked, with ferritin levels checked and supplemented when <50 ng/mL, as recommended by the American Geriatrics Society 5