What could be causing recurrent 15‑minute episodes of bilateral hand and foot paresthesias that awaken a 47‑year‑old woman at night, are worse in the evening, are associated with a cold sensation, have no swelling or color change, and persist despite prior bilateral carpal‑tunnel release?

Recurrent Bilateral Hand and Foot Paresthesias with Failed Carpal Tunnel Surgery

Most Likely Diagnosis: Peripheral Neuropathy with Possible Cardiac Amyloidosis

Given the bilateral hand and foot paresthesias that persist despite carpal tunnel surgery, worsen at night, and are associated with cold sensations, you should strongly consider peripheral neuropathy—and critically, evaluate for cardiac amyloidosis (ATTR), which characteristically presents with unexplained bilateral carpal tunnel syndrome that fails surgical treatment. 1

Key Red Flag: Failed Bilateral Carpal Tunnel Surgery

• Bilateral carpal tunnel syndrome that does not respond to surgical release is a specific red flag for cardiac amyloidosis and should prompt immediate evaluation for this condition 1
• The 2021 ASNC/AHA consensus defines "unexplained bilateral carpal tunnel syndrome" as occurring in the absence of rheumatoid arthritis or known trauma, and this is a major diagnostic criterion for ATTR cardiac amyloidosis 1
• Unexplained peripheral sensorimotor neuropathy (patient-reported paresthesias with no identified cause such as diabetes, alcohol abuse, or toxicity) is another diagnostic criterion for cardiac amyloidosis 1

Immediate Evaluation Required

Essential Workup

• Obtain echocardiography to look for features suggestive of cardiac amyloidosis (increased wall thickness, diastolic dysfunction) 1
• Check serum ferritin level—if <50 ng/mL, this suggests iron deficiency which can cause or worsen peripheral neuropathy and restless legs syndrome 1, 2
• Perform thorough neurological examination looking specifically for:
  • Distal sensory loss in stocking-glove distribution 1
  • Reduced deep tendon reflexes 1
  • Impaired proprioception and vibratory sensation 1
  • Signs of peripheral neuropathy or radiculopathy 1, 3

Laboratory Testing

• Thyroid function tests (hypothyroidism causes carpal tunnel syndrome and peripheral neuropathy) 4
• HbA1c (diabetic neuropathy is the most common cause of peripheral neuropathy in the Western world) 1, 4
• Complete blood count 4
• Serum ferritin 1, 2
• Consider nerve conduction studies if diagnosis remains unclear 4, 5

Critical Differential Diagnoses to Consider

1. Cardiac Amyloidosis (ATTR)

• This is the diagnosis you cannot miss given the failed bilateral carpal tunnel surgery 1
• Additional features to ask about: unexplained heart failure symptoms, orthostatic hypotension, family history of similar symptoms 1
• If echocardiography is suggestive, proceed to 99mTc-PYP/DPD/HMDP nuclear imaging or cardiac MRI 1

2. Restless Legs Syndrome (RLS)

• The nighttime worsening and cold sensation could suggest RLS, but key distinguishing features are:
  • RLS involves an uncomfortable urge to move the legs, not just paresthesias 1, 2, 3
  • RLS symptoms are relieved by movement (walking, stretching) and return when movement stops 1, 2, 3
  • RLS worsens specifically in the evening/night and with rest/inactivity 1, 2
• Up to 90% of RLS patients have periodic limb movements during sleep 2
• Ask specifically: "Do you have an urge to move your legs?" and "Does movement relieve the sensation?" 2, 3

3. Diabetic or Other Peripheral Neuropathy

• Painful diabetic peripheral neuropathy characteristically worsens at night, causing sleep disturbance 1
• Common descriptors include burning pain, electrical shock sensations, tingling, and cold/warm temperature perceptions 1
• Symptoms typically start in feet and progress proximally in stocking-glove distribution 1
• The 15-minute episodic nature is somewhat atypical for standard diabetic neuropathy 1

4. Nocturnal Leg Cramps

• This is less likely given the description, but should be ruled out 2, 3
• Cramps are characterized by painful, involuntary muscle contractions with tightening sensation 2, 3
• Relief comes specifically from stretching the affected muscle, not general movement 3
• No urge to move the legs 2, 3

Common Pitfalls to Avoid

• Do not assume the carpal tunnel surgery failed due to technical issues—bilateral carpal tunnel syndrome that fails surgery is a specific marker for systemic disease, particularly cardiac amyloidosis 1
• Do not confuse RLS with nocturnal cramps or simple paresthesias—the key is asking about the urge to move and whether movement provides relief 2, 3
• Do not assume electrolyte depletion without evidence—this theory is poorly supported for nocturnal symptoms 3
• Do not order polysomnography initially—reserve this for suspected periodic limb movement disorder or RLS when diagnosis is unclear after clinical evaluation 3

Treatment Approach (Pending Diagnosis)

If Cardiac Amyloidosis is Confirmed

• Urgent referral to cardiology for specialized management 1
• Consider genetic testing for hereditary ATTR 1

If RLS is Diagnosed

• Iron supplementation if ferritin <50 ng/mL 2
• First-line pharmacological treatment: gabapentin enacarbil, gabapentin, or pregabalin 2
• Avoid dopaminergic agents as first-line due to augmentation risk 2
• Review and discontinue medications that worsen RLS: tricyclic antidepressants, SSRIs, lithium, dopamine antagonists 1, 6

If Peripheral Neuropathy from Other Causes

• Treat underlying condition (tight glucose control for diabetes, thyroid replacement for hypothyroidism) 4
• Symptomatic relief with gabapentin, pregabalin, or tricyclic antidepressants 1, 4

The failed bilateral carpal tunnel surgery is the critical clue that demands evaluation for cardiac amyloidosis before pursuing other diagnoses. 1