Small Fiber Neuropathy¶

DIAGNOSIS: Small Fiber Neuropathy (SFN) ICD-10: G62.9 (Polyneuropathy, unspecified); G62.89 (Other specified polyneuropathies); G90.09 (Other idiopathic peripheral autonomic neuropathy) SYNONYMS: SFN; Small fiber sensory neuropathy; Small fiber predominant neuropathy; Pure small fiber neuropathy; Painful small fiber neuropathy; Autonomic small fiber neuropathy; Sensory ganglionopathy (non-length-dependent pattern) SCOPE: Diagnosis and management of small fiber neuropathy presenting with painful sensory and/or autonomic symptoms with normal or near-normal nerve conduction studies. Includes length-dependent and non-length-dependent (ganglionopathy) patterns. Covers etiologic workup for treatable causes, symptomatic pain management, and autonomic symptom treatment.

VERSION: 1.1 CREATED: January 27, 2026 REVISED: January 30, 2026

STATUS: Draft - Pending Review

PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting

KEY CLINICAL FEATURES: - Definition: Neuropathy affecting small myelinated (Aδ) and unmyelinated (C) nerve fibers - Sensory symptoms: Burning pain, allodynia, hyperalgesia, paresthesias, "pins and needles" - Autonomic symptoms: Sudomotor dysfunction (dry skin, hyperhidrosis), orthostatic intolerance, GI dysmotility, urinary symptoms, sicca symptoms - Key diagnostic criterion: Clinical neuropathy with normal or near-normal NCS (which test large fibers only) - Gold standard confirmation: Skin biopsy with reduced intraepidermal nerve fiber density (IENFD)

SECTION A: ACTION ITEMS¶

1. LABORATORY WORKUP¶

1A. Essential/Core Labs¶

Test (CPT)	ED	HOSP	OPD	ICU	Rationale	Target Finding
HbA1c (83036)	-	ROUTINE	ROUTINE	-	Diabetes and prediabetes are most common causes of SFN	<5.7% normal; ≥5.7% prediabetes
Fasting glucose (82947)	STAT	ROUTINE	ROUTINE	-	Current glycemic status; impaired fasting glucose	<100 mg/dL
2-hour oral glucose tolerance test (82951)	-	ROUTINE	ROUTINE	-	Impaired glucose tolerance causes SFN even with normal HbA1c	2-hr glucose <140 mg/dL normal
BMP (80048)	STAT	ROUTINE	ROUTINE	-	Renal function; medication dosing; uremic neuropathy	eGFR >60; normal electrolytes
CBC (85025)	STAT	ROUTINE	ROUTINE	-	Baseline; anemia evaluation	Normal
Vitamin B12 (82607)	-	ROUTINE	ROUTINE	-	B12 deficiency causes SFN; common and treatable	>300 pg/mL (>400 optimal)
TSH (84443)	-	ROUTINE	ROUTINE	-	Hypothyroidism causes neuropathy	0.4-4.0 mIU/L
ESR, CRP (85652/86140)	-	ROUTINE	ROUTINE	-	Inflammatory markers; vasculitis screen	Normal
ANA (86038)	-	ROUTINE	ROUTINE	-	Autoimmune etiology; Sjogren's screen	Negative
Anti-SSA (Ro) and anti-SSB (La) antibodies (86235)	-	ROUTINE	ROUTINE	-	Sjogren syndrome is common cause of SFN (up to 40% of SFN)	Negative
Hepatitis B and C serologies (87340/86803)	-	ROUTINE	ROUTINE	-	HCV-associated neuropathy; cryoglobulinemia	Negative

1B. Extended Workup (Second-line)¶

Test (CPT)	ED	HOSP	OPD	ICU	Rationale	Target Finding
Methylmalonic acid (83921)	-	ROUTINE	ROUTINE	-	More sensitive for B12 deficiency if B12 borderline (200-400)	Normal (<0.4 μmol/L)
Tissue transglutaminase IgA (86364)	-	ROUTINE	ROUTINE	-	Celiac disease causes SFN even without GI symptoms	Negative
Total serum IgA (82784)	-	ROUTINE	ROUTINE	-	IgA deficiency causes false-negative TTG	Normal (not deficient)
SPEP/UPEP with immunofixation (86335/86334)	-	ROUTINE	ROUTINE	-	Paraproteinemia; monoclonal gammopathy	No monoclonal protein
HIV (86701)	-	EXT	ROUTINE	-	HIV-associated sensory neuropathy	Negative
Lipid panel (80061)	-	ROUTINE	ROUTINE	-	Metabolic syndrome associated with SFN	Normal/controlled
Vitamin D (82306)	-	ROUTINE	ROUTINE	-	Deficiency associated with neuropathic pain	>30 ng/mL
Vitamin B1 (84425)	-	ROUTINE	ROUTINE	-	Deficiency causes painful neuropathy	Normal
Vitamin B6 (84207)	-	ROUTINE	ROUTINE	-	Both deficiency and excess cause neuropathy	Normal (neither high nor low)
Copper (82525)	-	ROUTINE	ROUTINE	-	Copper deficiency neuropathy (especially post-bariatric surgery)	Normal (70-140 μg/dL)
Zinc (84630)	-	ROUTINE	ROUTINE	-	Excessive zinc causes copper deficiency	Normal (not elevated)
Salivary gland biopsy (42400)	-	-	ROUTINE	-	Sjogren syndrome if clinical suspicion high and serology negative	Negative for lymphocytic infiltration

1C. Rare/Specialized (Refractory or Atypical)¶

Test (CPT)	ED	HOSP	OPD	ICU	Rationale	Target Finding
Alpha-galactosidase A enzyme activity (82657)	-	-	ROUTINE	-	Fabry disease screening (X-linked; consider in males and females)	Normal enzyme activity
GLA gene sequencing (81405)	-	-	EXT	-	Confirm Fabry disease if enzyme low or high clinical suspicion	No pathogenic variants
TTR gene sequencing (81404)	-	-	ROUTINE	-	Hereditary transthyretin amyloidosis; early SFN with autonomic symptoms	No pathogenic variants
Fat pad or skin biopsy, Congo red (88313)	-	-	ROUTINE	-	Amyloidosis if suspected (autonomic features, cardiomyopathy, CTS)	No amyloid deposits
Serum free light chains (83883)	-	ROUTINE	ROUTINE	-	AL amyloidosis screen	Normal kappa:lambda ratio
Anti-FGFR3 antibodies (86235)	-	-	EXT	-	Autoimmune SFN (especially ganglionopathy pattern)	Negative
Anti-TS-HDS antibodies (86235)	-	-	EXT	-	Autoimmune SFN marker	Negative
Sarcoidosis workup: ACE, chest imaging (82164)	-	ROUTINE	ROUTINE	-	Sarcoid neuropathy	Normal ACE; no hilar adenopathy
Paraneoplastic antibody panel (86255)	-	ROUTINE	ROUTINE	-	Paraneoplastic sensory ganglionopathy (anti-Hu) if rapid onset	Negative
Cryoglobulins (86157)	-	-	EXT	-	Cryoglobulinemic neuropathy (especially with HCV)	Negative
Schirmer test (68760)	-	-	ROUTINE	-	Objective dry eye for Sjogren diagnosis	Normal (>5mm in 5 min)
SCN9A, SCN10A, SCN11A gene testing (81479)	-	-	EXT	-	Sodium channelopathies causing inherited SFN (erythromelalgia)	No pathogenic variants

2. DIAGNOSTIC IMAGING & STUDIES¶

2A. Essential/First-line¶

Study (CPT)	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Nerve conduction studies (95907-95909)	-	ROUTINE	ROUTINE	-	At initial evaluation	Normal or near-normal (SFN spares large fibers)	None
Skin biopsy, 3mm punch at distal leg and thigh (88305/88342)	-	-	ROUTINE	-	After NCS shows normal large fiber function	Reduced IENFD below normative threshold for age/sex/site	Bleeding diathesis; anticoagulation (relative)

2B. Extended¶

Study (CPT)	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
Quantitative sudomotor axon reflex test, QSART (95923)	-	-	ROUTINE	-	Autonomic symptoms; suspected sudomotor dysfunction	Normal sweat volumes at all sites	None
Sudoscan (95923)	-	-	ROUTINE	-	Screening for sudomotor dysfunction; non-invasive	Normal electrochemical skin conductance hands and feet	None
Autonomic reflex screen (95924)	-	EXT	ROUTINE	-	Comprehensive autonomic evaluation; orthostatic symptoms	Normal cardiovagal, adrenergic, and sudomotor function	None
Tilt table test (95924)	-	EXT	ROUTINE	-	Orthostatic intolerance; POTS evaluation	No excessive HR rise; no orthostatic hypotension	None
Quantitative sensory testing, QST (95924)	-	-	EXT	-	Thermal threshold testing; research and specialized centers	Normal thermal detection thresholds	None
Thermoregulatory sweat test (95924)	-	-	EXT	-	Global sudomotor evaluation if QSART equivocal	Normal sweat distribution	Cardiac instability
Corneal confocal microscopy (92132)	-	-	EXT	-	Non-invasive small fiber assessment; research tool	Normal corneal nerve fiber density and length	None

2C. Rare/Specialized¶

Study (CPT)	ED	HOSP	OPD	ICU	Timing	Target Finding	Contraindications
EMG (95886)	-	ROUTINE	ROUTINE	-	If large fiber involvement suspected; atypical features	Normal (SFN spares motor and large sensory fibers)	Anticoagulation (relative)
MRI spine, cervical/thoracic (72141/72146)	-	ROUTINE	ROUTINE	-	Ganglionopathy pattern; non-length-dependent SFN	Normal dorsal root ganglia; no dorsal column signal	MRI contraindications
MRI neurography (72197)	-	-	EXT	-	Research; visualize small nerves	No nerve enlargement or signal abnormality	MRI contraindications
PET-CT (78816)	-	EXT	EXT	-	Sarcoidosis or malignancy suspected; paraneoplastic evaluation	No abnormal uptake	Pregnancy
Echocardiogram (93306)	-	ROUTINE	ROUTINE	-	Amyloidosis suspected (cardiomyopathy screening)	No infiltrative cardiomyopathy features	None
Cardiac MRI (75561)	-	EXT	EXT	-	Cardiac amyloidosis evaluation if echo abnormal	No amyloid infiltration	MRI contraindications; devices

3. TREATMENT¶

3A. Acute/Emergent¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
IV fluids	IV	Acute orthostatic hypotension with symptoms	500-1000 mL :: IV :: bolus :: 500-1000 mL NS bolus for symptomatic orthostatic hypotension; avoid in heart failure	Heart failure; volume overload	Volume status; BP response	STAT	STAT	-	STAT
Pain crisis management	IV/PO	Severe acute neuropathic pain flare not responding to outpatient regimen	Multimodal :: IV/PO :: PRN :: IV lidocaine infusion (1-3 mg/kg/hr) if refractory; avoid chronic opioids	Lidocaine: cardiac conduction abnormality	Pain scores; cardiac monitoring for lidocaine	URGENT	URGENT	-	URGENT
Glucose management	Various	Acute presentation with new diabetes diagnosis	Per protocol :: Various :: per protocol :: Initiate diabetes management; hypoglycemia causes SFN flare	Per specific agent	Glucose	STAT	STAT	-	STAT

3B. Symptomatic Treatments (Neuropathic Pain - First-line)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Duloxetine	PO	First-line for neuropathic pain; also treats depression/anxiety common in SFN	30 mg :: PO :: daily :: Start 30 mg daily x 1 week; increase to 60 mg daily; max 120 mg/day	MAOIs; uncontrolled narrow-angle glaucoma; severe renal impairment (CrCl <30)	Hepatic function; BP; suicidal ideation	-	ROUTINE	ROUTINE	-
Pregabalin	PO	First-line for neuropathic pain; FDA-approved for postherpetic neuralgia and DPN	50 mg :: PO :: TID :: Start 50 mg TID or 75 mg BID; titrate q3-7d; max 300 mg/day; reduce if CrCl <60	Angioedema to pregabalin/gabapentin	Dizziness, somnolence, weight gain, peripheral edema	-	ROUTINE	ROUTINE	-
Gabapentin	PO	First-line; less expensive alternative to pregabalin	300 mg :: PO :: qHS :: Start 300 mg qHS; titrate by 300 mg q3-7d; target 1800-3600 mg/day divided TID; reduce if CrCl <60	Severe renal impairment (dose adjust required)	Sedation, dizziness, ataxia, edema	-	ROUTINE	ROUTINE	-
Amitriptyline	PO	TCA for neuropathic pain; helps insomnia; inexpensive	10 mg :: PO :: qHS :: Start 10-25 mg qHS; titrate by 10-25 mg q1-2wk; typical 25-75 mg qHS; max 150 mg	Cardiac conduction disease; recent MI; urinary retention; narrow-angle glaucoma; elderly (high anticholinergic burden)	ECG if age >40 or cardiac history; anticholinergic side effects	-	ROUTINE	ROUTINE	-
Nortriptyline	PO	TCA with less sedation and anticholinergic effects than amitriptyline	10 mg :: PO :: qHS :: Start 10-25 mg qHS; titrate by 10-25 mg q1-2wk; typical 25-75 mg qHS	Cardiac conduction disease; recent MI; urinary retention; narrow-angle glaucoma	ECG if dose >100 mg/day or cardiac risk factors	-	ROUTINE	ROUTINE	-
Venlafaxine XR	PO	SNRI alternative to duloxetine	37.5 mg :: PO :: daily :: Start 37.5 mg daily; increase by 37.5-75 mg q1wk; target 150-225 mg daily	MAOIs; uncontrolled hypertension	BP at higher doses; discontinuation syndrome if stopped abruptly	-	ROUTINE	ROUTINE	-

3C. Second-line/Refractory (Neuropathic Pain)¶

Treatment	Route	Indication	Dosing	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Capsaicin 8% patch (Qutenza)	Topical	Localized neuropathic pain; add-on therapy	1 patch :: Topical :: q3mo :: Applied by trained healthcare provider; pre-treat with topical anesthetic; may repeat q3mo	Application to face/mucous membranes; broken skin	Pain/burning during application; transient BP increase	-	-	ROUTINE	-
Lidocaine 5% patch	Topical	Localized pain; adjunctive therapy; allodynia	1-3 patches :: Topical :: daily :: Apply to most painful area; up to 3 patches for 12h on/12h off	Allergy to local anesthetics; damaged skin	Skin irritation	-	ROUTINE	ROUTINE	-
Lamotrigine	PO	Sodium channel blocker; some evidence in SFN	25 mg :: PO :: daily :: Start 25 mg daily x 2wk; then 50 mg daily x 2wk; increase by 50 mg q2wk; max 400 mg/day	SJS/TEN history; valproate use (reduce dose by 50%)	RASH (especially first 8 weeks) - stop immediately if rash	-	ROUTINE	ROUTINE	-
Lacosamide	PO	Sodium channel blocker; well-tolerated	50 mg :: PO :: BID :: Start 50 mg BID; increase by 50 mg/day weekly; max 400 mg/day	Second or third degree AV block (without pacemaker)	ECG for PR prolongation; dizziness	-	ROUTINE	ROUTINE	-
Carbamazepine	PO	Sodium channel blocker; limited evidence for SFN specifically	100 mg :: PO :: BID :: Start 100 mg BID; titrate by 200 mg/wk; max 1200 mg/day	AV block; bone marrow suppression; HLA-B*1502 in Asian patients (SJS risk)	CBC, LFTs, sodium; drug interactions (CYP3A4 inducer)	-	ROUTINE	ROUTINE	-
Mexiletine	PO	Sodium channel blocker; especially if SCN9A mutation suspected	150 mg :: PO :: TID :: Start 150 mg TID; titrate by 150 mg q3d; max 1200 mg/day; take with food	Cardiomyopathy; second/third degree AV block	ECG; arrhythmia monitoring	-	EXT	ROUTINE	-
Desipramine	PO	TCA with minimal anticholinergic effects	25 mg :: PO :: qHS :: Start 25 mg qHS; titrate by 25 mg q1-2wk; target 50-100 mg	Same as other TCAs	ECG; drug levels available if needed	-	ROUTINE	ROUTINE	-
Tramadol	PO	Moderate pain; opioid-like with serotonergic properties	50 mg :: PO :: q6h PRN :: Start 50 mg q6h PRN; max 400 mg/day; reduce if renal/hepatic impairment	Seizure disorder; concurrent MAOIs/SSRIs (serotonin syndrome risk)	Seizures, serotonin syndrome, constipation	-	ROUTINE	ROUTINE	-
Tapentadol ER	PO	Refractory pain; mu-opioid agonist with norepinephrine reuptake inhibition	50 mg :: PO :: BID :: Start 50 mg BID; titrate by 50 mg BID q3d; max 500 mg/day	Severe respiratory depression; MAOIs; paralytic ileus	Respiratory status, constipation, sedation	-	EXT	ROUTINE	-
Combination therapy	Various	Inadequate response to monotherapy	Per regimen :: Various :: per regimen :: Gabapentinoid + SNRI; TCA + gabapentinoid; use lower doses of each	Per individual agents	Additive side effects; falls in elderly	-	ROUTINE	ROUTINE	-
Low-dose naltrexone (LDN)	PO	Emerging evidence for neuropathic pain; anti-inflammatory	1.5 mg :: PO :: qHS :: Start 1.5 mg qHS; increase by 1.5 mg q2wk; max 4.5 mg; compounded	Current opioid use; hepatic impairment	Vivid dreams, insomnia (take in AM if occurs)	-	-	EXT	-
Spinal cord stimulation	Implant	Refractory SFN pain; failed multiple medications	Per protocol :: Implant :: per protocol :: Trial stimulation before permanent implant; high-frequency or burst stimulation preferred	Infection; coagulopathy; psychiatric instability	Device function; pain relief	-	-	EXT	-

3D. Autonomic Symptom Management¶

Treatment	Route	Indication	Dosing	Pre-Treatment Requirements	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Fludrocortisone	PO	Orthostatic hypotension; volume expansion	0.1 mg :: PO :: daily :: Start 0.1 mg daily; may increase to 0.2 mg daily; max 0.3 mg	Check potassium; assess volume status	Heart failure; hypertension; hypokalemia	Weight, BP supine and standing, potassium, edema	-	ROUTINE	ROUTINE	-
Midodrine	PO	Orthostatic hypotension; alpha-1 agonist vasoconstrictor	2.5 mg :: PO :: TID :: Start 2.5 mg TID (with meals); titrate to 5-10 mg TID; last dose 4h before bed	None specific	Severe cardiac disease; urinary retention; supine hypertension	Supine BP (check for supine hypertension); avoid at bedtime	-	ROUTINE	ROUTINE	-
Droxidopa (Northera)	PO	Neurogenic orthostatic hypotension; FDA-approved for autonomic failure	100 mg :: PO :: TID :: Start 100 mg TID; titrate by 100 mg/day q24-48h; max 600 mg TID	None specific	Supine hypertension (severe)	Supine BP; avoid lying flat for 2h after dose	-	ROUTINE	ROUTINE	-
Pyridostigmine	PO	Orthostatic hypotension; enhances ganglionic transmission	30 mg :: PO :: TID :: Start 30 mg TID; may increase to 60 mg TID; modest BP effect but no supine hypertension	None specific	Mechanical GI/GU obstruction; bradyarrhythmia	Cholinergic effects (diarrhea, salivation)	-	ROUTINE	ROUTINE	-
Compression stockings	External	Orthostatic hypotension; venous pooling	30-40 mmHg :: External :: daily :: Waist-high preferred over knee-high; put on before rising; 30-40 mmHg compression	Peripheral arterial disease (ABI <0.5)	None absolute if ABI >0.5	Skin integrity; ABI if arterial disease suspected	-	ROUTINE	ROUTINE	-
Oxybutynin	PO	Bladder urgency/frequency	5 mg :: PO :: BID :: Start 5 mg BID or 10 mg XL daily; max 30 mg/day	None specific	Urinary retention; uncontrolled narrow-angle glaucoma; GI obstruction	Anticholinergic effects; cognition in elderly	-	ROUTINE	ROUTINE	-
Solifenacin	PO	Bladder urgency; better tolerated anticholinergic	5 mg :: PO :: daily :: Start 5 mg daily; may increase to 10 mg daily	None specific	Same as oxybutynin; severe hepatic impairment	Anticholinergic effects	-	ROUTINE	ROUTINE	-
Mirabegron	PO	Bladder urgency; beta-3 agonist (non-anticholinergic)	25 mg :: PO :: daily :: Start 25 mg daily; may increase to 50 mg daily	None specific	Uncontrolled hypertension; severe hepatic impairment	BP; urinary retention	-	ROUTINE	ROUTINE	-
Metoclopramide	PO	Gastroparesis; prokinetic	5 mg :: PO :: AC :: 5-10 mg 30 min before meals and at bedtime; limit to <12 weeks	None specific	Tardive dyskinesia (limit duration); GI obstruction; Parkinson disease	Tardive dyskinesia; extrapyramidal symptoms	-	ROUTINE	ROUTINE	-
Domperidone	PO	Gastroparesis; prokinetic with less CNS effects	10 mg :: PO :: TID :: 10 mg TID before meals; not FDA-approved (requires IND or international pharmacy)	ECG baseline for QT	QT prolongation; ventricular arrhythmia	ECG for QT; arrhythmia	-	-	EXT	-
Erythromycin	PO	Gastroparesis; motilin receptor agonist	250 mg :: PO :: TID :: 250 mg PO TID before meals; short-term use due to tachyphylaxis	ECG baseline for QT	QT prolongation; drug interactions	ECG; GI upset; tachyphylaxis limits long-term use	-	ROUTINE	ROUTINE	-
Sildenafil	PO	Erectile dysfunction in autonomic SFN	25 mg :: PO :: PRN :: Start 25-50 mg 1h before activity; max 100 mg; avoid with nitrates	Cardiovascular assessment	Nitrate use; severe cardiovascular disease	Cardiovascular status; vision changes	-	-	ROUTINE	-

3E. Disease-Modifying / Etiology-Targeted Therapies¶

Treatment	Route	Indication	Dosing	Pre-Treatment Requirements	Contraindications	Monitoring	ED	HOSP	OPD	ICU
Glycemic control optimization	Various	Diabetes/prediabetes-associated SFN	Per guidelines :: Various :: per protocol :: Lifestyle first for prediabetes; HbA1c <7% target; tighter control slows progression	Diabetes education	Hypoglycemia risk	HbA1c q3-6mo; glucose monitoring	-	ROUTINE	ROUTINE	-
IVIG	IV	Autoimmune SFN (Sjogren-associated; anti-FGFR3+; idiopathic with evidence of inflammation)	2 g/kg :: IV :: divided over 2-5 days monthly :: 2 g/kg divided over 2-5 days monthly; limited evidence; consider trial	Check IgA level (IgA-deficient patients need IgA-depleted product)	IgA deficiency (use IgA-depleted); renal impairment; hypercoagulable state	Renal function; thrombotic risk; headache	-	ROUTINE	ROUTINE	-
Enzyme replacement therapy — Fabry disease	IV	Fabry disease-associated SFN	1 mg/kg :: IV :: q2wk :: Agalsidase beta (Fabrazyme) 1 mg/kg IV q2wk; lifelong therapy; infusion reactions common early	Genetic confirmation of Fabry disease	None absolute	Infusion reactions; anti-drug antibodies	-	ROUTINE	ROUTINE	-
Tafamidis (Vyndamax/Vyndaqel)	PO	Hereditary and wild-type TTR amyloidosis with polyneuropathy	80 mg :: PO :: daily :: 80 mg (Vyndamax) or 61 mg (Vyndaqel) PO daily; TTR stabilizer	Genetic confirmation of TTR amyloidosis	None	Cardiac function; neuropathy progression	-	-	ROUTINE	-
Inotersen/Patisiran	SC/IV	Hereditary TTR amyloidosis with polyneuropathy	Per protocol :: SC/IV :: per protocol :: Inotersen 284 mg SC weekly; Patisiran 0.3 mg/kg IV q3wk	TTR gene mutation confirmed; specialist management	Thrombocytopenia (inotersen); infusion reactions	Platelets (inotersen); hepatic function	-	-	EXT	-
Gluten-free diet	Diet	Celiac disease-associated SFN	Strict gluten-free :: Diet :: daily :: Lifelong strict gluten-free diet; dietitian referral; neuropathy may stabilize/improve	Celiac confirmation (biopsy or serology)	None	TTG-IgA levels; symptom response	-	-	ROUTINE	-
B12 supplementation	PO/IM	B12 deficiency-associated SFN	1000 mcg :: PO :: daily :: 1000-2000 mcg PO daily; or 1000 mcg IM weekly x 4, then monthly if poor absorption	Confirmed B12 deficiency	None	B12 and MMA levels q3-6mo until stable	-	ROUTINE	ROUTINE	-
Immunosuppression (Sjogren's)	Various	Sjogren's-associated SFN with systemic disease activity	Per rheumatology :: Various :: per protocol :: Hydroxychloroquine, methotrexate, rituximab; coordinate with rheumatology	Rheumatology co-management	Per specific agent	Per specific agent	-	ROUTINE	ROUTINE	-
Alpha-lipoic acid	PO	Antioxidant; some evidence in painful neuropathy; European guidelines	600 mg :: PO :: daily :: 600 mg PO daily; may take 3-6 months for effect; limited evidence	None	GI upset	May enhance hypoglycemia in diabetics	-	-	ROUTINE	-

4. OTHER RECOMMENDATIONS¶

4A. Referrals & Consults¶

Recommendation	ED	HOSP	OPD	ICU
Neuromuscular specialist for skin biopsy interpretation and complex SFN management	-	ROUTINE	ROUTINE	-
Rheumatology if Sjogren's, lupus, or other connective tissue disease suspected	-	ROUTINE	ROUTINE	-
Endocrinology if diabetes/prediabetes for glycemic optimization and metabolic management	-	ROUTINE	ROUTINE	-
Genetics counselor if hereditary etiology suspected (Fabry, TTR amyloidosis, SCN9A channelopathies)	-	-	ROUTINE	-
Gastroenterology for celiac confirmation, gastroparesis management, or liver biopsy if amyloid suspected	-	ROUTINE	ROUTINE	-
Cardiology if TTR amyloidosis suspected or autonomic symptoms with cardiac involvement	-	ROUTINE	ROUTINE	-
Pain management for refractory neuropathic pain and interventional options (spinal cord stimulation)	-	-	ROUTINE	-
Physical therapy for balance training, strengthening, and fall prevention	-	ROUTINE	ROUTINE	-
Autonomic disorders specialist if complex autonomic symptoms (POTS, orthostatic hypotension)	-	-	ROUTINE	-
Psychiatry/psychology for chronic pain coping and comorbid depression/anxiety management	-	-	ROUTINE	-
Hematology/oncology if amyloidosis confirmed for staging and treatment	-	ROUTINE	ROUTINE	-

4B. Patient Instructions¶

Recommendation	ED	HOSP	OPD
Report any new weakness, gait difficulty, or falls as these may indicate progression to large fiber involvement	STAT	STAT	ROUTINE
Monitor for signs of infection in feet (redness, warmth, drainage) if sensation is impaired	-	ROUTINE	ROUTINE
Keep a pain diary to track triggers, severity, and medication response	-	ROUTINE	ROUTINE
Rise slowly from sitting or lying to prevent falls from orthostatic hypotension	STAT	ROUTINE	ROUTINE
Increase salt and fluid intake (2-3L/day, 6-10g sodium) if orthostatic hypotension present (unless contraindicated)	-	ROUTINE	ROUTINE
Wear compression stockings before rising in the morning if orthostatic hypotension diagnosed	-	ROUTINE	ROUTINE
Take all prescribed pain medications as directed; do not stop gabapentinoids or SNRIs abruptly	-	ROUTINE	ROUTINE
Avoid excessive heat exposure which can worsen symptoms; stay hydrated in warm weather	-	ROUTINE	ROUTINE
Return if severe headache, vision changes, or syncope develop (may indicate medication side effects or disease progression)	STAT	STAT	ROUTINE

4C. Lifestyle & Prevention¶

Recommendation	ED	HOSP	OPD
Strict glycemic control (HbA1c <7% or <5.7% if prediabetes) to prevent progression; lifestyle modifications first	-	ROUTINE	ROUTINE
Alcohol cessation as alcohol independently causes and worsens small fiber neuropathy	-	ROUTINE	ROUTINE
Smoking cessation as smoking impairs nerve regeneration and worsens outcomes	-	ROUTINE	ROUTINE
Regular low-impact exercise (swimming, stationary bike, walking) to improve pain and maintain function	-	ROUTINE	ROUTINE
Healthy diet (Mediterranean or DASH) to optimize metabolic health and reduce inflammation	-	ROUTINE	ROUTINE
Weight management as metabolic syndrome is associated with SFN	-	ROUTINE	ROUTINE
Sleep hygiene to improve sleep quality; chronic pain worsens with poor sleep	-	ROUTINE	ROUTINE
Stress reduction techniques (mindfulness, meditation) as stress can amplify pain perception	-	ROUTINE	ROUTINE
Fall prevention with home safety evaluation given proprioceptive deficits and orthostatic hypotension	-	ROUTINE	ROUTINE
Avoid B6 (pyridoxine) supplementation above RDA (1.3-2 mg/day) as excess causes neuropathy	-	ROUTINE	ROUTINE

SECTION B: REFERENCE¶

5. DIFFERENTIAL DIAGNOSIS¶

Alternative Diagnosis	Key Distinguishing Features	Tests to Differentiate
Diabetic polyneuropathy (large fiber)	NCS abnormal; mixed sensorimotor findings; more numbness than pain	EMG/NCS shows axonal polyneuropathy
Fibromyalgia	Widespread pain; tender points; normal skin biopsy; chronic fatigue	ACR criteria; normal IENFD on skin biopsy
Complex regional pain syndrome (CRPS)	Regional rather than length-dependent; swelling, color changes, dystrophy	Budapest criteria; regional distribution
Erythromelalgia	Intermittent burning with redness and warmth; triggered by heat; may have SCN9A mutation	Clinical pattern; genetic testing if suspected
Central sensitization syndromes	Normal peripheral testing; pain out of proportion to objective findings	QST pattern; skin biopsy normal
Psychogenic/functional sensory symptoms	Non-anatomical distribution; inconsistent findings; psychiatric comorbidity	Careful neurological exam; normal objective testing
Vitamin B12 deficiency	May have subacute combined degeneration; cognitive changes; macrocytic anemia	B12, MMA levels; MRI spine
Lyme disease	Endemic area; prior tick bite; rash history; may have radiculopathy	Lyme serology (ELISA + Western blot)
Hereditary sensory neuropathy (HSAN)	Family history; anhidrosis; painless injuries; mutilating features	Genetic testing (HSAN genes)
Burning mouth syndrome	Isolated to oral mucosa; taste changes; dry mouth	Location-specific; oral exam
Restless legs syndrome	Urge to move legs; worse at rest/night; relief with movement	Clinical criteria; may coexist with SFN
Vasculitic neuropathy	Asymmetric; mononeuritis multiplex pattern; systemic symptoms; rapid onset	Nerve biopsy; inflammatory markers; angiography
Paraneoplastic sensory ganglionopathy	Subacute onset; asymmetric; non-length-dependent; cancer history/risk	Anti-Hu antibodies; CT chest/abdomen/pelvis

6. MONITORING PARAMETERS¶

Parameter	Frequency	Target/Threshold	Action if Abnormal	ED	HOSP	OPD	ICU
Pain scores (NRS, VAS, BPI)	Each visit	50%+ reduction or functional improvement	Adjust medications; consider combination or referral	-	ROUTINE	ROUTINE	-
HbA1c (if diabetes/prediabetes)	Every 3-6 months	<7% (or <5.7% if prediabetes)	Intensify glycemic management	-	ROUTINE	ROUTINE	-
Orthostatic vitals (lying, sitting, standing)	Each visit if autonomic symptoms	SBP drop <20 mmHg; no symptoms	Adjust autonomic medications; hydration; compression	STAT	ROUTINE	ROUTINE	-
Repeat skin biopsy (IENFD)	Every 1-2 years if monitoring disease course	Stable or improved IENFD	Intensify etiology treatment if declining	-	-	ROUTINE	-
Autonomic symptoms inventory	Each visit	Stable or improved	Adjust autonomic treatments; workup new symptoms	-	ROUTINE	ROUTINE	-
ECG	Baseline if on TCAs or sodium channel blockers; periodically	Normal PR, QRS, QTc intervals	Dose reduction or discontinuation if prolonged intervals	-	ROUTINE	ROUTINE	-
Renal function (eGFR)	Every 6-12 months	eGFR >60 or stable	Adjust medication doses; nephrology referral	-	ROUTINE	ROUTINE	-
Potassium (if on fludrocortisone)	Monthly initially, then every 3-6 months	3.5-5.0 mEq/L	Supplement potassium; reduce fludrocortisone dose	-	ROUTINE	ROUTINE	-
Weight and edema	Each visit	Stable weight; no edema	Adjust pregabalin/gabapentin or autonomic meds	-	ROUTINE	ROUTINE	-
Depression screen (PHQ-9)	Every 6-12 months	<5 (no depression)	Mental health referral; consider duloxetine/venlafaxine	-	ROUTINE	ROUTINE	-
Falls assessment	Each visit	No falls	PT referral; home safety; reduce sedating medications	-	ROUTINE	ROUTINE	-

7. DISPOSITION CRITERIA¶

Disposition	Criteria
Discharge home	Symptoms stable; pain controlled; autonomic symptoms not causing hemodynamic instability; follow-up arranged
Admit to floor	Severe uncontrolled pain requiring IV medications; syncope from orthostatic hypotension; new diagnosis requiring urgent workup (suspected amyloidosis with cardiac involvement)
Admit to ICU	Hemodynamically unstable from autonomic dysfunction; severe symptomatic bradycardia or hypotension
Outpatient follow-up	Every 3-6 months for medication optimization; annually for etiology reassessment if initially idiopathic

8. EVIDENCE & REFERENCES¶

Recommendation	Evidence Level	Source
Skin biopsy (IENFD) as diagnostic standard for SFN	Class II, Level B	Lauria et al. European Journal of Neurology 2010
QSART for sudomotor function assessment in SFN	Class II, Level B	Low et al. Muscle & Nerve 1983
Impaired glucose tolerance as cause of SFN	Class II, Level B	Singleton et al. Neurology 2001
Sjogren syndrome associated with SFN	Class II, Level B	Chai et al. Annals of Neurology 2005
Duloxetine for neuropathic pain	Class I, Level A	Lunn et al. Cochrane 2014
Gabapentin for neuropathic pain	Class I, Level A	Wiffen et al. Cochrane 2017
Pregabalin for neuropathic pain	Class I, Level A	Derry et al. Cochrane 2019
TCAs for neuropathic pain	Class II, Level B	Moore et al. Cochrane 2015
Fludrocortisone for orthostatic hypotension	Class II, Level C	Freeman et al. Neurology 2018 Consensus Statement
Midodrine for orthostatic hypotension	Class I, Level A	Wright et al. Am Heart J 1998
Droxidopa for neurogenic orthostatic hypotension	Class I, Level A	Biaggioni et al. Neurology 2015
IVIG for autoimmune SFN	Class III, Level C	Liu et al. J Periph Nerv Syst 2014
Fabry disease as cause of SFN	Class II, Level B	Biegstraaten et al. Orphanet J Rare Dis 2012
TTR amyloidosis neuropathy treatment	Class I, Level A	Adams et al. NEJM 2018 (Patisiran trial)
Sodium channelopathies (SCN9A) in SFN	Class II, Level B	Faber et al. Ann Neurol 2012

CHANGE LOG¶

v1.1 (January 30, 2026) - Standardized lab tables: reordered columns to Test (CPT) | ED | HOSP | OPD | ICU | Rationale | Target Finding - Added CPT codes to all lab tests (1A: 11 rows, 1B: 12 rows, 1C: 12 rows) - Standardized imaging tables: reordered columns to Study (CPT) | ED | HOSP | OPD | ICU | Timing | Target Finding | Contraindications - Added CPT codes to all imaging studies (2A: 2 rows, 2B: 7 rows, 2C: 6 rows) - Fixed structured dosing first fields across all treatment sections (3A-3E): starting dose only in first field - Renamed CLINICAL SYNONYMS to SYNONYMS - Added VERSION/CREATED/REVISED header block - Moved SYNONYMS before SCOPE in header

v1.0 (January 27, 2026) - Initial template creation - Comprehensive etiologic workup (diabetes, Sjogren's, amyloidosis, Fabry, celiac) - Diagnostic approach with skin biopsy and autonomic testing - Neuropathic pain treatment with structured dosing format - Autonomic symptom management section - Disease-modifying therapies for treatable causes - Differentiation of length-dependent vs non-length-dependent patterns

APPENDIX A: SFN Diagnostic Criteria¶

Clinical Features Suggesting SFN¶

Symptom Category	Examples
Positive sensory symptoms	Burning pain; electric shock sensations; tingling; allodynia; hyperalgesia
Negative sensory symptoms	Numbness; thermal hypoesthesia (can't feel hot/cold)
Autonomic symptoms	Dry eyes/mouth; sweating abnormalities; orthostatic intolerance; GI dysmotility; urinary dysfunction; erectile dysfunction
Distribution	Length-dependent (feet > hands) OR non-length-dependent (patchy, proximal, asymmetric)

Diagnostic Certainty Levels¶

Level	Criteria
Possible SFN	Clinical symptoms and signs compatible with SFN
Probable SFN	Clinical features + abnormal QST thermal thresholds OR abnormal QSART
Definite SFN	Clinical features + reduced IENFD on skin biopsy below age/sex/site normative values

Length-Dependent vs Non-Length-Dependent (Ganglionopathy) Pattern¶

Feature	Length-Dependent	Non-Length-Dependent
Distribution	Distal > proximal; symmetric; feet before hands	Patchy; asymmetric; proximal involvement; face/trunk
Common causes	Diabetes; metabolic; toxic; idiopathic	Sjogren's; paraneoplastic; autoimmune; amyloidosis
Prognosis	Often slowly progressive	May be more aggressive; depends on etiology
Workup focus	Metabolic causes	Autoimmune and systemic causes

APPENDIX B: Skin Biopsy Interpretation¶

Procedure¶

Sites: Distal leg (10 cm above lateral malleolus) and proximal thigh (20 cm below iliac spine)
Technique: 3mm punch biopsy; send to laboratory with PGP9.5 immunostaining capability
Processing: Fix in PLP or Zamboni's fixative; immunostain for PGP9.5

Interpretation¶

Result	Interpretation
IENFD below 5th percentile for age/sex/site	Diagnostic of SFN
IENFD at lower range of normal (5th-10th percentile)	Borderline; correlate clinically
Distal/proximal IENFD ratio >2:1	Length-dependent pattern
Both sites equally reduced	Consider ganglionopathy or diffuse process
Sweat gland nerve fiber density reduced	Supports autonomic involvement

Normative Values (Approximate - Use Laboratory-Specific Norms)¶

Site	Typical 5th Percentile Values
Distal leg (age 20-40)	~8-9 fibers/mm
Distal leg (age 60-80)	~4-5 fibers/mm
Proximal thigh	Generally higher than distal leg

APPENDIX C: Autonomic Testing Interpretation¶

QSART (Quantitative Sudomotor Axon Reflex Test)¶

Pattern	Interpretation
Reduced sweat volume at distal sites (foot) with normal proximal	Length-dependent autonomic SFN
Globally reduced sweat volumes	Diffuse autonomic involvement
Normal QSART	Does not exclude SFN (may have sensory-predominant)

Autonomic Reflex Screen Components¶

Test	What It Measures	Abnormality in SFN
QSART	Postganglionic sudomotor function	Reduced sweat volumes
Heart rate variability	Cardiovagal function	Reduced HRV to deep breathing
Valsalva maneuver	Cardiovagal and adrenergic function	Abnormal BP/HR response
Tilt table test	Adrenergic function; orthostatic tolerance	Orthostatic hypotension or POTS

POTS (Postural Orthostatic Tachycardia Syndrome) Criteria¶

HR increase ≥30 bpm (or ≥40 bpm if age 12-19) within 10 minutes of standing
Absence of orthostatic hypotension (SBP drop <20 mmHg)
Symptoms of orthostatic intolerance
Duration ≥6 months