What could be causing tingling in both lower legs and feet in a patient with a history of taking fluoxetine (Selective Serotonin Reuptake Inhibitor), escitalopram (Selective Serotonin Reuptake Inhibitor), divalproex (Valproate), buspirone (Anxiolytic), and dextroamphetamine-amphetamine (Central Nervous System Stimulant) for 4 months, who has been off these medications for 3 months?

Differential Diagnosis: Peripheral Neuropathy Following Psychotropic Medication Use

The tingling in both lower legs and feet is most likely drug-induced peripheral neuropathy or restless legs syndrome (RLS), with SSRIs (fluoxetine and escitalopram) being the primary suspects, though amphetamine-related peripheral vasculopathy and valproate-induced neuropathy must also be considered.

Primary Considerations

SSRI-Induced Restless Legs Syndrome

• SSRIs are well-documented causes of RLS, which presents with distressing sensations deep inside the limbs, typically occurring at rest, with an irresistible urge to move that provides temporary relief 1
• Both escitalopram and fluoxetine can induce or exacerbate RLS symptoms, with onset typically occurring within the initial days of treatment 1, 2
• In prospective studies, 9% of patients developed RLS as a side effect of second-generation antidepressants, with rates varying from 5-10% for SSRIs like fluoxetine, paroxetine, citalopram, sertraline, and escitalopram 2
• RLS symptoms can persist after medication discontinuation, though they typically improve within days to weeks of stopping the offending agent 1

Amphetamine-Related Peripheral Vasculopathy

• Dextroamphetamine-amphetamine is associated with peripheral vasculopathy, including Raynaud's phenomenon, which can cause numbness, pain, and sensory changes in extremities 3
• Signs include fingers or toes feeling numb, cool, or painful, with potential color changes from pale to blue to red 3
• Peripheral vasculopathy effects were observed at therapeutic dosages in all age groups throughout the course of treatment 3
• In a case series of 16 patients on amphetamine analogues, 62.5% presented with vasospastic symptoms involving upper, lower, or both extremities, with symptoms persisting even after medication discontinuation in many cases 4

Valproate-Induced Neuropathy

• Divalproex (valproate) can cause peripheral neuropathy, though this is less commonly reported than with other anticonvulsants
• The mechanism may involve nutritional deficiencies or direct neurotoxic effects

Critical Diagnostic Approach

Immediate Assessment Required

• Evaluate for peripheral arterial disease (PAD): assess lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and venous filling time 5
• Perform comprehensive neurological assessment: 10-g monofilament testing or Ipswich touch test with at least one additional assessment (pinprick, temperature, or vibration) 5
• Assess for digital ischemia: look for color changes, temperature differences, or tissue breakdown that would indicate severe peripheral vasculopathy 3
• Characterize the symptoms: determine if symptoms are worse at rest/night (suggesting RLS) versus constant (suggesting neuropathy or vasculopathy)

Distinguish Between RLS and Peripheral Neuropathy

• RLS presents with an irresistible urge to move the limbs that provides temporary relief, most pronounced in evening or at night 1, 6
• Peripheral neuropathy typically presents with numbness and tingling without the characteristic urge to move or circadian pattern 5
• Peripheral vasculopathy may present with pain, coolness, and color changes in addition to sensory symptoms 3, 4

Management Strategy

If RLS is Suspected

• Symptoms typically improve within 2 days to 1 week after discontinuation of the offending SSRI 1
• Consider duloxetine for neuropathic pain, numbness, and tingling if symptoms persist and neuropathy is confirmed 5
• Physical activity may help both RLS and neuropathy symptoms 5

If Peripheral Vasculopathy is Suspected

• Urgent rheumatology referral is appropriate for patients who develop signs or symptoms of peripheral vasculopathy 3
• Underlying rheumatologic disorders were found in 25% of patients with amphetamine-related vascular manifestations and were associated with more severe presentations 4
• Monitor for digital ulceration or soft tissue breakdown, which can occur as sequelae of peripheral vasculopathy 3

If Peripheral Neuropathy is Confirmed

• Assess for contributing factors: diabetes, vitamin deficiencies (especially B12), thyroid dysfunction, renal disease 5
• Offer duloxetine as first-line pharmacologic treatment for neuropathic symptoms 5
• Recommend physical activity as a non-pharmacologic intervention 5

Important Caveats

Timing Considerations

• The 3-month interval since medication discontinuation makes ongoing drug effects less likely but does not exclude them, as some patients experience prolonged symptoms 1, 4
• Drug-induced RLS typically occurs during initial days of treatment but can persist after discontinuation 2

Multiple Drug Exposure

• The patient's sequential exposure to multiple serotonergic agents (fluoxetine, escitalopram, buspirone) increases cumulative risk for serotonergic-related adverse effects 5
• Combination of amphetamine with SSRIs increases risk of serotonin syndrome, though the patient's symptoms don't suggest this acute emergency 3

Red Flags Requiring Urgent Evaluation

• Unexplained wounds appearing on fingers or toes would indicate severe peripheral vasculopathy requiring immediate intervention 3
• Progressive weakness, severe pain, or tissue loss would necessitate urgent vascular surgery consultation 4
• Bilateral symptoms with rapid progression could indicate an alternative systemic etiology requiring comprehensive workup