What are the differential diagnoses and management options for body weakness and lethargy?

Differential Diagnoses for Body Weakness and Lethargy

Immediate Life-Threatening Conditions to Rule Out First

Begin by assessing vital signs, mental status, and perfusion to identify conditions requiring immediate intervention. 1

Critical Metabolic Emergencies

• Diabetic ketoacidosis (DKA) presents with weakness, lethargy, polyuria, polydipsia, abdominal pain, vomiting, and weight loss; check bedside glucose (may read "High"), arterial blood gas showing metabolic acidosis (pH <7.3), elevated anion gap, and urine ketones. 2
• Severe hypoglycemia (glucose <60 mg/dL) causes lethargy, muscle weakness, nausea, irritability, lightheadedness, and sweating; treat immediately with quick-acting glucose followed by sustained carbohydrate source. 3
• Hyponatremia with neurological symptoms requires checking serum sodium and excluding hypothyroidism, adrenal insufficiency, heart failure, and cirrhosis as underlying causes. 4
• D-lactic acidosis should be considered in patients with short bowel syndrome presenting with recurrent episodes of weakness, ataxia, slurred speech, severe lethargy, and metabolic acidosis; diagnosis requires plasma D-lactate level measurement. 5

Cardiovascular Causes

• Orthostatic hypotension characteristically causes dizziness, lightheadedness, weakness, fatigue, lethargy, and visual disturbances that develop upon standing (within 30 seconds to 3 minutes) and are relieved by sitting or lying down; symptoms worsen in morning hours, after meals, heat exposure, and after exertion. 6
• Shock states in children manifest as decreased or altered mental status, prolonged capillary refill >2 seconds, diminished pulses, mottled cool extremities, or decreased urine output <1 mL/kg/h—hypotension is not required for diagnosis. 1

Infectious Etiologies

• Meningococcal disease/bacterial meningitis presents with fever, petechiae, purpura, leg pain, cold extremities, abnormal skin color; in infants and young children, look for poor feeding, irritability, high-pitched cry, full fontanelle, and bulging fontanelle. 1
• Influenza-related encephalopathy can present with lethargy even without prominent fever; in children younger than 2 years, diarrhea and hyperventilation may be the first signs, with lethargy usually being the first neurological manifestation. 1
• Sepsis requires assessment for fever >38°C with complete blood count showing leukocytosis with left shift, blood cultures, and chest radiography. 1

Endocrine and Metabolic Disorders

Hormonal Causes

• Hemochromatosis should be considered when patients complain of fatigue, right upper quadrant abdominal pain, arthralgias (typically of second and third metacarpophalangeal joints), impotence, decreased libido, and symptoms of heart failure or diabetes; weakness and lethargy occur in 19-83% of patients depending on disease stage. 3
• Hypothyroidism must be excluded when evaluating chronic weakness and lethargy, particularly when hyponatremia is present. 4
• Adrenal insufficiency causes weakness, lethargy, and hyponatremia; must be ruled out in the diagnostic workup. 4

Rare Metabolic Conditions

• Insulinoma presents with periodic numbness, prolonged episodes of confusion and lethargy; diagnosis requires fasting insulin level >3 mcIU/mL (usually >6 mcIU/mL), C peptide ≥0.6 ng/mL, and proinsulin ≥5 pmol/L when fasting blood glucose <55 mg/dL. 3
• Glucagonoma manifests with recent-onset diabetes, cachexia, necrolytic erythematous skin rash, and weakness; check blood glucagon and glucose levels. 3
• Glycogen storage disease type I causes hypoglycemia with lethargy, muscle weakness, nausea, and irritability when blood glucose falls below 60 mg/dL; maintain glucose >70 mg/dL with cornstarch supplementation. 3

Neuromuscular Disorders

Organize the differential by anatomical location: brain, spinal cord, nerve roots, peripheral nerves, and neuromuscular junction. 7

Central Nervous System

• Stroke or intracranial hemorrhage requires urgent neuroimaging when weakness is focal or associated with altered mental status. 7
• Encephalopathy from various causes (metabolic, toxic, infectious) presents with altered mental status and lethargy. 1

Peripheral Nervous System

• Guillain-Barré syndrome presents with ascending weakness and areflexia. 7
• Myasthenia gravis causes fatigable weakness worsening with activity. 7
• Peripheral neuropathy from diabetes, toxins, or nutritional deficiencies causes distal weakness and sensory changes. 7

Cardiac and Pulmonary Causes

Cardiac Conditions

• Cardiomyopathy in Pompe disease or hemochromatosis causes weakness, lethargy, and symptoms of heart failure; obtain echocardiogram and 24-hour ambulatory ECG to monitor for life-threatening arrhythmias. 3
• Heart failure is a common cause of weakness, lethargy, and hyponatremia; assess for volume overload and reduced ejection fraction. 4

Respiratory Insufficiency

• Progressive respiratory insufficiency from neuromuscular disease causes chronic CO2 retention, hypoxemia, daytime fatigue, and lethargy; may develop first during sleep before manifesting while awake. 3
• Sleep-disordered breathing with diaphragmatic weakness causes daytime lethargy and weakness; vital capacity decreases >10% from upright to supine position indicate diaphragmatic weakness. 3

Gastrointestinal and Nutritional Causes

• Superior mesenteric artery syndrome presents with constipation, colicky abdominal pain, lethargy, weakness, and body aches; CT shows dilated esophagus, stomach, and duodenum with short aortomesenteric distance. 8
• Malabsorption syndromes and nutritional deficiencies cause chronic weakness and lethargy. 3
• Cirrhosis with hepatic encephalopathy causes lethargy, weakness, and hyponatremia. 4

Oncologic and Treatment-Related Causes

Cancer-Related Fatigue

• Cancer-related fatigue (CRF) is characterized by persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning; assess cardiorespiratory fitness as it is a strong predictor of fatigue level. 3
• Cytokine release syndrome in patients receiving CAR T-cell therapy manifests with lethargy and requires immediate recognition. 1

Neuroendocrine Tumors

• VIPoma causes characteristic watery diarrhea, weakness, and lethargy; test for VIP and electrolytes, obtain multiphase CT or MRI. 3

Iatrogenic Causes

• SGLT-2 inhibitor use with ketogenic diet can precipitate severe DKA presenting with weakness, lethargy, and altered mental status even in non-insulin dependent type 2 diabetes. 9
• Overtreatment of hypoglycemia in glycogen storage disease leads to hyperinsulinemia, insulin resistance, and worsening lactic acidosis. 3

Diagnostic Approach Algorithm

Step 1: Immediate Assessment

• Check vital signs, capillary refill, mental status, and bedside glucose. 1, 2
• If glucose <60 mg/dL or reads "High," treat immediately. 3, 2
• If signs of shock present (altered mental status, prolonged capillary refill >2 seconds, diminished pulses), establish IV access within 90 seconds or proceed to intraosseous access; administer normal saline 20 mL/kg bolus rapidly. 1

Step 2: Essential Laboratory Workup

• Complete blood count with differential (assess for infection, anemia). 1
• Comprehensive metabolic panel including electrolytes, glucose, renal function, liver function. 1, 2
• Arterial blood gas if acidosis suspected. 2
• Thyroid-stimulating hormone and cortisol to exclude hypothyroidism and adrenal insufficiency. 4
• Urinalysis for ketones and glucose. 2

Step 3: Targeted Testing Based on Clinical Presentation

• If orthostatic symptoms: Measure blood pressure supine and after standing 1-3 minutes. 6
• If cardiac symptoms: Echocardiogram, ECG, 24-hour ambulatory monitoring. 3
• If suspected hemochromatosis: Transferrin saturation and ferritin levels; consider genetic testing for C282Y homozygosity. 3
• If suspected neuroendocrine tumor: Measure specific hormones (insulin, C-peptide, proinsulin, glucagon, VIP) with imaging (CT/MRI, EUS, somatostatin scintigraphy). 3
• If neurological localization: Neuroimaging, EMG/NCS, lumbar puncture as indicated. 7

Step 4: Age-Specific Considerations

• Infants <60 days: Assess for Brief Resolved Unexplained Events with cyanosis, pallor, absent/decreased breathing, altered tone, and lethargy. 1
• Children: Consider influenza complications, meningococcal disease, and dehydration; administer parenteral antibiotics immediately if meningococcal disease suspected without delaying for investigations. 1

Critical Pitfalls to Avoid

• Do not assume hypotension is required for shock diagnosis—altered mental status with poor perfusion is sufficient. 1
• Do not use octreotide or lanreotide in insulinoma patients without positive somatostatin scintigraphy, as they can suppress counterregulatory hormones and precipitously worsen hypoglycemia with fatal complications. 3
• Do not correct severe chronic hyponatremia faster than 10 mmol/L/day to prevent osmotic demyelination syndrome. 4
• Do not overlook SGLT-2 inhibitor-induced DKA in patients on ketogenic diets, as it can occur even in non-insulin dependent diabetes. 9
• Do not miss D-lactic acidosis in short bowel syndrome patients—standard lactate assays may not detect D-lactate; specific D-lactate level measurement is required. 5