What are the possible causes and initial work‑up for generalized whole‑body tingling (paresthesia)?

Whole-Body Tingling: Differential Diagnosis and Initial Work-Up

Generalized whole-body tingling (paresthesia) most commonly indicates a systemic metabolic, toxic, or inflammatory polyneuropathy rather than a structural lesion, and your initial work-up should focus on a targeted three-test laboratory panel (glucose/HbA1c, vitamin B12 with metabolites, and serum protein immunofixation) combined with a focused neurologic examination to distinguish length-dependent polyneuropathy from atypical patterns that require urgent imaging. 1

Critical First Step: Pattern Recognition on Clinical Examination

Determine whether the tingling follows a length-dependent, symmetric "stocking-glove" distribution or presents in an atypical pattern:

• Length-dependent symmetric pattern (distal legs/feet first, later progressing to fingertips) strongly suggests polyneuropathy and does NOT require immediate imaging 1
• Non-length-dependent patterns (simultaneous onset in all limbs, asymmetric distribution, or rapid progression over days to weeks) raise concern for Guillain-Barré syndrome, multifocal mononeuropathy, or CNS pathology and warrant urgent evaluation 2, 1

Perform a focused bedside examination:

• Test vibration sense with a 128-Hz tuning fork at the great toes and ankles (most sensitive for large-fiber dysfunction) 1
• Assess ankle reflexes (reduced or absent in polyneuropathy) 2, 1
• Document gait stability (wide-based, unsteady gait indicates proprioceptive loss from large-fiber involvement) 1
• Check for orthostatic hypotension (≥20 mmHg systolic or ≥10 mmHg diastolic drop suggests autonomic involvement) 1

High-Yield Laboratory Screening Panel (Order for ALL Patients)

These three tests provide the highest diagnostic yield and should be obtained immediately: 1

1. Fasting glucose/HbA1c – Diabetes and pre-diabetes (impaired glucose tolerance) are the leading causes of polyneuropathy in developed countries; if fasting glucose is normal but clinical suspicion remains high (especially with prominent pain), order a glucose tolerance test 1

2. Serum vitamin B12 with metabolites (methylmalonic acid ± homocysteine) – Metabolite testing increases sensitivity for true B12 deficiency that standard B12 levels may miss 1

3. Serum protein immunofixation electrophoresis – Preferred over standard SPEP for detecting monoclonal gammopathies that can underlie unexplained polyneuropathy 1

Additional targeted screening based on clinical context:

• TSH – Hypothyroidism is a reversible metabolic cause 1
• HIV serology – Distal symmetric sensory neuropathy occurs in approximately 57% of HIV-infected individuals 1
• Hepatitis B/C and Lyme serology – When epidemiologic exposure is relevant 1
• Comprehensive metabolic panel – To assess for chronic kidney disease and uremic neuropathy 1

When to Order Electrodiagnostic (Nerve Conduction) Studies

Do NOT order nerve conduction studies if the patient has:

• Classic distal symmetric sensory loss in a stocking distribution 1
• Reduced ankle reflexes 1
• Known risk factors (diabetes, B12 deficiency) 1
• Symmetric, length-dependent progression 1

DO order nerve conduction studies when:

• Symptoms are asymmetric in distribution 1
• Disease progresses rapidly over weeks to months (raises concern for Guillain-Barré syndrome) 2, 1
• Predominant motor weakness or distal muscle atrophy is present 1
• Diagnostic uncertainty persists after initial clinical and laboratory evaluation 1

Critical timing consideration: If Guillain-Barré syndrome is suspected, do NOT perform electrodiagnostic studies within the first week of symptom onset, as studies are normal in 30-34% of patients even with active demyelinating disease; repeat testing 2-3 weeks later is essential if initial studies are normal but clinical suspicion remains high 1

When Imaging IS Required

Order urgent MRI brain/spine with contrast if ANY of the following are present:

• Focal neurologic deficits beyond typical distal symmetric sensory loss (e.g., localized weakness, cranial nerve involvement) 1
• Headache that awakens the patient from sleep, worsens with Valsalva maneuvers, or shows rapid increase in frequency 1
• Rapid progression suggesting Guillain-Barré syndrome (patients typically reach maximum disability within 2 weeks) 2
• Asymmetric presentation suggesting mononeuritis multiplex, vasculitic neuropathy, or radiculopathy 1

Do NOT order imaging for:

• Bilateral, symmetric, length-dependent tingling without focal deficits 1
• Classic polyneuropathy presentation with known risk factors 1

Specific Diagnostic Considerations

Small-Fiber Neuropathy

Recognize that conventional nerve conduction studies will be NORMAL because they do not assess unmyelinated C-fibers: 1

• Presents with burning pain, tingling, and prominent autonomic symptoms (orthostatic hypotension, gastrointestinal dysmotility, urinary retention, erectile dysfunction) 1
• Requires skin biopsy measuring intra-epidermal nerve-fiber density for diagnosis 1
• Affects 79.6-91.4% of peripheral nerve fibers but is not detected by standard electrodiagnostic testing 1

Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)

Key distinguishing features: 2

• Rapidly progressive bilateral weakness of legs and/or arms (maximum disability typically within 2 weeks) 2
• Distal paresthesias or sensory loss accompanied or followed by weakness 2
• Reflexes decreased or absent at presentation, almost always absent at nadir 2
• Dysautonomia common (blood pressure/heart rate instability, pupillary dysfunction, bowel/bladder dysfunction) 2
• Pain frequently reported (muscular, radicular, or neuropathic) 2

Atypical presentations in young children (<6 years): Poorly localized pain, refusal to bear weight, irritability, meningism, or unsteady gait 2

"Sural Sparing" pattern on nerve conduction studies: Normal sural sensory nerve action potential with abnormal or absent median and ulnar sensory nerve action potentials is highly characteristic 1

Drug-Induced Peripheral Neuropathy

Common culprits to review in medication history: 3, 4, 5

• Chemotherapeutic agents (vinca alkaloids, platinum compounds, taxanes, bortezomib, thalidomide) 3, 4, 5
• Antimicrobials (metronidazole, fluoroquinolones, isoniazid, nitrofurantoin) 4, 5
• Cardiovascular drugs (statins, amiodarone) 4
• Anticonvulsants (phenytoin) 4, 5
• Immune checkpoint inhibitors (emerging cause) 1

Drug-induced peripheral neuropathy is almost always due to dose-dependent primary axonal degeneration; the drug should be stopped when neuropathy develops, and reversal depends on severity, intensity/duration of treatment, and existence of causative cofactors, but prognosis is generally good. 3

Common Pitfalls to Avoid

• Do NOT assume neuropathy in a diabetic patient is automatically diabetic neuropathy – Diabetic neuropathy is a diagnosis of exclusion; other causes (B12 deficiency, hypothyroidism, monoclonal gammopathy) must be evaluated 1

• Do NOT order routine serial nerve conduction studies for stable neuropathy – Serial neurologic examinations are preferred; repeated electrodiagnostic testing is only warranted when there is uncertainty about new or worsening neurological processes 1

• Do NOT dismiss whole-body tingling as anxiety without objective examination – While anxiety can amplify perception of paresthesias 6, failure to identify treatable causes (B12 deficiency, hypothyroidism, Guillain-Barré syndrome) can result in permanent neurologic damage 2, 1

• Do NOT confuse tactile tingling with pulsatile tinnitus – Whole-body tingling is a somatosensory symptom requiring metabolic/neurologic work-up, not vascular imaging 7

• Do NOT overlook hereditary neuropathies in younger patients – Obtain comprehensive family history; genetic testing for CMT1A (PMP22 duplication) yields diagnostic results in 54-80% of patients with clinically probable demyelinating CMT 1

Referral to Neurology

Refer immediately when:

• Atypical features are present (asymmetric distribution, rapid progression, predominant motor weakness) 1
• Guillain-Barré syndrome is suspected (requires intravenous immunoglobulin 0.4 g/kg daily for 5 days or plasma exchange 200-250 ml/kg for 5 sessions) 2
• Nerve biopsy is needed (when vasculitis or amyloidosis is suspected) 1
• Genetic counseling and testing are indicated (suspected hereditary neuropathy) 1
• Diagnostic uncertainty persists after initial work-up 1