Possible Etiologies of Progressive Bilateral Lower Extremity Weakness and Heart Failure with Reduced Ejection Fraction
Primary Consideration: Cardiac Amyloidosis
Cardiac amyloidosis is the most critical diagnosis to exclude in any patient presenting with both progressive symmetric lower extremity weakness and heart failure with reduced ejection fraction, because it represents a treatable systemic infiltrative disease that affects both cardiac and peripheral nervous systems. 1
Why Amyloidosis Should Be First on Your Differential
Cardiac amyloidosis typically begins as restrictive cardiomyopathy with mildly depressed left ventricular systolic dysfunction and can progress to severe systolic dysfunction in advanced stages, matching the HFrEF presentation. 1
Amyloid deposits occur in multiple organs including the heart, kidney, liver, and nervous system, explaining the dual cardiac and neurologic manifestations. 1
Peripheral neuropathy is a cardinal extracardiac manifestation of AL (light-chain) amyloidosis, presenting as progressive symmetric weakness that can mimic other neuromuscular disorders. 1
Carpal tunnel syndrome is another common neurologic manifestation that may precede or accompany the lower extremity weakness. 1
Median survival in AL amyloidosis is approximately 13 months but decreases drastically to 4 months with the onset of heart failure symptoms, making early diagnosis life-saving. 1
Diagnostic Approach for Amyloidosis
Obtain serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) immediately to screen for monoclonal proteins characteristic of AL amyloidosis. 1
Perform transthoracic echocardiography looking for increased wall thickness, left atrial enlargement, and the classic "sparkling" granular appearance of the myocardium. 1
Cardiac magnetic resonance imaging with late gadolinium enhancement shows a characteristic diffuse subendocardial or transmural pattern that is highly specific for cardiac amyloidosis. 1
Endomyocardial biopsy with Congo red staining remains the gold standard when non-invasive testing is equivocal. 1
Secondary Considerations: Other Systemic Diseases Affecting Heart and Peripheral Nerves
Cardiac Sarcoidosis
Cardiac sarcoidosis can cause dilated cardiomyopathy with reduced ejection fraction through granulomatous infiltration of the myocardium. 1
Neurosarcoidosis affects peripheral nerves in approximately 5% of sarcoid patients, potentially causing symmetric polyneuropathy. 1
Diagnosis requires cardiac MRI showing patchy mid-wall or epicardial late gadolinium enhancement in a non-coronary distribution, plus evidence of systemic sarcoidosis. 1
PET-CT with FDG uptake can identify active cardiac inflammation and guide biopsy sites. 1
Autoimmune/Inflammatory Cardiomyopathy
Myocarditis can progress to dilated cardiomyopathy with systolic dysfunction, particularly when associated with systemic autoimmune diseases. 1
Systemic lupus erythematosus, rheumatoid arthritis, and polyarteritis nodosa can cause both cardiomyopathy and peripheral neuropathy through vasculitic mechanisms. 1
Check inflammatory markers (ESR, CRP), autoimmune serologies (ANA, RF, ANCA), and consider endomyocardial biopsy when clinical suspicion is high. 1
Endocrine and Metabolic Cardiomyopathies
Thyroid dysfunction (both hypo- and hyperthyroidism) can cause heart failure with reduced ejection fraction and is often accompanied by proximal muscle weakness. 1
Diabetes mellitus causes both diabetic cardiomyopathy and symmetric distal polyneuropathy, though the neuropathy typically affects sensation before motor function. 1
Hemochromatosis causes restrictive-dilated cardiomyopathy and can produce peripheral neuropathy through iron deposition. 1
Measure thyroid-stimulating hormone, hemoglobin A1c, and consider iron studies (ferritin, transferrin saturation) in the initial workup. 1
Tertiary Considerations: Genetic and Toxic Cardiomyopathies with Neuromuscular Involvement
Genetic Cardiomyopathies
Lamin A/C mutation dilated cardiomyopathy presents with progressive conduction disease, arrhythmias, and skeletal muscle weakness in a characteristic pattern. 1
Neuromuscular disorders including Duchenne/Becker muscular dystrophy, myotonic dystrophy, and Friedreich ataxia cause both cardiomyopathy and progressive limb weakness. 1
Approximately one-third to one-half of dilated cardiomyopathy cases have a familial/genetic cause, making family history critical. 1
Genetic testing and family screening should be pursued when no other etiology is identified. 1
Cardiotoxic Agents
Anthracyclines (doxorubicin) cause dose-dependent left ventricular dysfunction (7-26% at 550 mg/m²) and can produce peripheral neuropathy. 1
Cyclophosphamide, trastuzumab, and tyrosine kinase inhibitors all cause cardiotoxicity with varying rates of left ventricular dysfunction. 1
Alcohol causes both dilated cardiomyopathy and alcoholic polyneuropathy with symmetric distal-to-proximal progression. 1
Obtain a detailed medication history including chemotherapy, immunotherapy, and substance use. 1
Critical Diagnostic Algorithm
Step 1: Exclude Ischemic Cardiomyopathy
Coronary artery disease is the underlying cause of heart failure in approximately two-thirds of patients with left ventricular systolic dysfunction, but it does not explain the bilateral lower extremity weakness. 1
Perform stress testing or coronary angiography to exclude significant coronary disease as the primary cardiac etiology. 1
Step 2: Screen for Infiltrative Disease
Order SPEP, UPEP, serum free light chains, and cardiac biomarkers (troponin, BNP/NT-proBNP) immediately. 1
Obtain transthoracic echocardiography with specific attention to wall thickness, left atrial size, and myocardial texture. 1
Proceed to cardiac MRI with late gadolinium enhancement when echocardiography suggests infiltrative disease or when the diagnosis remains uncertain. 1
Step 3: Evaluate Peripheral Nervous System
Perform electromyography (EMG) and nerve conduction studies to characterize the pattern of weakness (axonal vs. demyelinating, motor vs. sensory). 1
Check creatine kinase to distinguish myopathy from neuropathy. 1
Consider nerve or muscle biopsy when systemic amyloidosis or vasculitis is suspected. 1
Step 4: Assess for Systemic Disease
Measure TSH, hemoglobin A1c, inflammatory markers (ESR, CRP), and autoimmune serologies (ANA, RF, ANCA). 1
Obtain chest CT to evaluate for sarcoidosis or malignancy. 1
Check vitamin B12, folate, and heavy metal screening if other causes are excluded. 1
Common Pitfalls to Avoid
Do not attribute the lower extremity weakness solely to deconditioning from heart failure without excluding systemic infiltrative diseases, as this delays diagnosis of treatable conditions like amyloidosis. 1
Do not assume the two presentations are unrelated; the coexistence of cardiomyopathy and peripheral neuropathy strongly suggests a systemic process. 1
Do not rely on echocardiography alone to exclude cardiac amyloidosis; cardiac MRI with late gadolinium enhancement is far more sensitive for tissue characterization. 1
Do not delay endomyocardial biopsy when non-invasive testing is equivocal and clinical suspicion for infiltrative disease remains high, as early diagnosis of amyloidosis dramatically alters prognosis. 1
Do not forget to screen for reversible causes including thyroid dysfunction, alcohol use, and cardiotoxic medications, as these may be treatable. 1