2d:I[856015,["/_next/static/immutable/chunks/1xzisbplk9czp.js","/_next/static/immutable/chunks/3j2i1faptc_-9.js","/_next/static/immutable/chunks/0fma7nlq6immz.js","/_next/static/immutable/chunks/08tq8rmv423j5.js","/_next/static/immutable/chunks/1chr5wkk3j58k.js","/_next/static/immutable/chunks/37kmmh_zm4dov.js","/_next/static/immutable/chunks/311zvdjfxff-f.js","/_next/static/immutable/chunks/1a_hqhrsle_n_.js"],"default"] 2e:T6392,

Summary Table

Category	Details
Risk Factors	Long-standing diabetes (especially poorly controlled), Type 2 > Type 1 for prevalence, smoking, hypertension, dyslipidemia, obesity, chronic kidney disease
Etiology	Chronic hyperglycemia causing metabolic and microvascular injury to peripheral nerves via the polyol pathway, advanced glycation end products, and oxidative stress
Patient Presentation	Bilateral "burning," "tingling," or "numbness" in feet progressing proximally in a symmetric stocking-glove distribution; painless foot ulcers; unsteady gait in the dark
Classic Physical Exam	Decreased sensation to monofilament and vibration (128 Hz tuning fork) at the great toe; absent ankle reflexes with preserved knee reflexes; dry skin and hair loss on distal lower extremities; Charcot joint deformity in advanced cases
Key Diagnostic Results	Clinical diagnosis in the appropriate setting; nerve conduction studies show reduced amplitude (axonal) and mildly reduced velocity; HbA1c elevated; normal B12 and TSH (to exclude mimics)
Management	Tight glycemic control (foundation); symptomatic pain relief with pregabalin, duloxetine, or gabapentin as first-line agents; comprehensive foot care program
Keywords	"Stocking-glove distribution," "burning feet," "painless ulcer," "loss of vibration sense," "absent ankle jerk," "length-dependent neuropathy," "monofilament testing"

1. Pathophysiology

Diabetic neuropathy is the most common complication of diabetes and the most frequent cause of peripheral neuropathy worldwide. The underlying damage is driven by sustained hyperglycemia acting through several interconnected metabolic pathways.

The polyol (sorbitol) pathway is the most heavily tested mechanism. When intracellular glucose is elevated, the enzyme aldose reductase converts excess glucose into sorbitol, which cannot cross cell membranes efficiently. Sorbitol accumulates within Schwann cells and neurons, drawing water in by osmotic force and causing cellular swelling and dysfunction. Sorbitol is then slowly oxidized to fructose, depleting NADPH in the process. Because NADPH is required to regenerate glutathione (the cell's primary antioxidant), its depletion leaves the nerve vulnerable to oxidative stress.

Simultaneously, chronic hyperglycemia promotes the non-enzymatic glycosylation of structural proteins, forming advanced glycation end products (AGEs). AGEs bind to receptors on endothelial cells and macrophages, triggering inflammatory cascades and thickening the basement membrane of the vasa nervorum (the tiny blood vessels supplying peripheral nerves). This microvascular ischemia compounds the direct metabolic injury, starving the nerve of oxygen and nutrients.

The result is a length-dependent axonal degeneration: the longest nerve fibers are affected first because they are furthest from the cell body and most metabolically vulnerable. This is why symptoms begin at the toes and feet and gradually ascend. Small unmyelinated C fibers (carrying pain and temperature) are damaged early, producing burning pain and dysesthesias. As the disease progresses, large myelinated fibers (carrying vibration and proprioception) are lost, resulting in numbness, gait imbalance, and loss of protective sensation. The "stocking-glove" pattern directly reflects this length-dependent process: once symptoms reach the mid-calf, the fingertips begin to be involved because those are the next-longest fibers.

Autonomic nerve fibers are also susceptible, leading to a parallel syndrome of cardiovascular (resting tachycardia, orthostatic hypotension), gastrointestinal (gastroparesis), genitourinary (erectile dysfunction, neurogenic bladder), and sudomotor (anhidrosis) dysfunction.

2. Classification and Clinical Manifestation

Type	Subtype	Clinical Features	Key Exam Findings
Distal Symmetric Polyneuropathy (DSPN)	Most common (~75% of cases)	Bilateral numbness, tingling, burning pain in feet progressing proximally; worse at night	Reduced monofilament and vibratory sense distally; absent ankle reflexes; stocking-glove sensory loss
Autonomic Neuropathy	Cardiovascular	Resting tachycardia, exercise intolerance, orthostatic hypotension, painless myocardial ischemia	Heart rate that fails to vary with deep breathing (loss of R-R variability); orthostatic drop in systolic BP greater than 20 mmHg
	Gastrointestinal	Early satiety, nausea, bloating, erratic glucose control (gastroparesis); diarrhea alternating with constipation	Succussion splash; gastric scintigraphy showing delayed emptying
	Genitourinary	Erectile dysfunction, retrograde ejaculation, overflow incontinence from neurogenic bladder	Elevated post-void residual on bladder scan
	Sudomotor	Anhidrosis in feet (dry, cracked skin predisposing to ulcers); compensatory hyperhidrosis in upper body	Dry distal skin; calluses and fissures
Diabetic Mononeuropathy	Cranial nerve III palsy	Acute onset ptosis, "down and out" eye with pupil-sparing (distinguishes from aneurysmal compression)	Eye deviated inferolaterally; normal pupillary response to light
Diabetic Mononeuropathy	Median, ulnar, peroneal nerve	Carpal tunnel syndrome (median); wrist or foot drop (ulnar/peroneal)	Focal motor and sensory deficits in a single nerve territory
Diabetic Amyotrophy (Lumbosacral Radiculoplexus Neuropathy)	Proximal motor neuropathy	Acute/subacute severe pain in thigh and hip followed by weakness and atrophy of proximal leg muscles; often asymmetric; weight loss	Quadriceps weakness and wasting; reduced knee jerk; can be mistaken for L3-L4 radiculopathy
Diabetic Radiculopathy	Thoracic or truncal	Band-like pain across thorax or abdomen; can mimic cardiac, pulmonary, or abdominal pathology	Dermatomal sensory loss on trunk; normal abdominal imaging

3. Diagnostic Workup

Test	Role	Expected Finding
10-g Semmes-Weinstein Monofilament	Best initial screening test	Inability to detect filament at plantar surface of great toe or metatarsal heads
128 Hz Tuning Fork	Screening for large-fiber involvement	Reduced or absent vibratory sense at the great toe
Ankle Reflex Testing	Part of bedside neuro exam	Absent ankle jerk (often the earliest reflex lost)
HbA1c	Assesses glycemic control and supports diabetes as the cause	Typically elevated (though neuropathy can occur even with borderline control)
Serum B12, TSH, SPEP	Exclusion of mimics	Should be normal; abnormality points to an alternative or coexisting cause
Nerve Conduction Studies / EMG	Most accurate confirmatory test (when diagnosis is uncertain)	Reduced sensory nerve action potential amplitudes (axonal pattern); mildly reduced conduction velocity; EMG shows denervation in distal muscles
Skin Biopsy with Intraepidermal Nerve Fiber Density (IENFD)	Gold standard for small-fiber neuropathy	Reduced IENFD at the distal leg

Diabetic neuropathy is fundamentally a clinical diagnosis. In a patient with established diabetes, a symmetric stocking-glove pattern of sensory loss, and an abnormal monofilament or tuning fork exam, no further testing is needed to confirm the diagnosis. This is the scenario most commonly tested on exams: recognize the pattern and move straight to management.

However, the exam will also test your ability to exclude other causes of neuropathy, especially when the presentation is atypical. Red flags that should prompt further investigation include: predominantly motor symptoms, rapid onset, marked asymmetry, onset within five years of a Type 1 diabetes diagnosis, or progression despite adequate glycemic control. In these situations, order serum B12 (to rule out deficiency, which also causes a length-dependent neuropathy), TSH (hypothyroid neuropathy), and serum protein electrophoresis (SPEP) (to screen for paraproteinemia and amyloidosis).

Nerve conduction studies (NCS) and electromyography (EMG) are reserved for cases where the diagnosis is genuinely unclear or the pattern does not fit diabetic neuropathy. NCS will reveal an axonal pattern (reduced amplitudes with relatively preserved conduction velocity), which distinguishes it from demyelinating conditions like Guillain-Barre syndrome or CIDP, where conduction velocity is prominently reduced.

For patients presenting with isolated burning pain and normal NCS (suggesting small-fiber neuropathy), a skin punch biopsy measuring intraepidermal nerve fiber density is the gold standard. This is a growing testing point as small-fiber neuropathy becomes better recognized.

Autonomic neuropathy is confirmed with cardiovascular autonomic reflex tests: heart rate variability during deep breathing, the Valsalva ratio, and orthostatic blood pressure measurements. Gastric scintigraphy (the four-hour solid-meal study) is the standard for confirming gastroparesis.

4. Management and Treatment

Category	Agent / Intervention	Details
Foundation	Glycemic control	Target HbA1c per guidelines (generally less than 7%); prevents progression and may partially reverse early neuropathy
First-Line Pain Agents	Pregabalin	Start 75 mg twice daily, titrate to 150-300 mg twice daily (max 600 mg/day); FDA-approved for diabetic neuropathic pain; requires dose adjustment in renal impairment
	Duloxetine	Start 30 mg daily for one week, then 60 mg daily (max 120 mg/day); SNRI; avoid in severe hepatic impairment or with concurrent MAOIs
	Gabapentin	Start 300 mg at bedtime, titrate to 300-1200 mg three times daily; dose adjust for renal function; less evidence than pregabalin but widely used
Second-Line	Tricyclic antidepressants (amitriptyline, nortriptyline)	Start 10-25 mg at bedtime, titrate to 75-150 mg; effective but limited by anticholinergic side effects (dry mouth, urinary retention, sedation, orthostatic hypotension); avoid in elderly and patients with cardiac conduction disease
Second-Line	Venlafaxine	150-225 mg/day; alternative SNRI
Topical	Capsaicin 8% patch	Applied in clinic for 30-60 minutes; depletes substance P from C fibers; useful for localized pain
Topical	Lidocaine 5% patch	Applied to the most painful area; safe adjunct with minimal systemic absorption
Autonomic Neuropathy	Gastroparesis: Metoclopramide	5-10 mg before meals (max 12 weeks due to tardive dyskinesia risk); dietary modifications (small, frequent, low-fat, low-fiber meals)
	Orthostatic hypotension: Midodrine or Fludrocortisone	Midodrine 2.5-10 mg three times daily (avoid in supine hypertension); Fludrocortisone 0.1-0.2 mg daily
	Neurogenic bladder	Timed voiding, intermittent catheterization if post-void residual is elevated
Foot Care	Multidisciplinary foot program	Daily foot inspection, proper footwear, podiatric referral, annual monofilament screening

The single most important intervention tested on licensing exams is glycemic control. Tight glucose management (HbA1c below 7%) has been shown in landmark trials to reduce the incidence and progression of diabetic neuropathy. In Type 1 diabetes, the benefit is robust. In Type 2 diabetes, the evidence for reversal is weaker, but glycemic control remains the cornerstone because no other intervention addresses the underlying cause.

For symptomatic neuropathic pain, pregabalin and duloxetine carry the strongest evidence and are the most commonly tested first-line choices. A vignette presenting a diabetic patient with burning foot pain and asking for the "next best step in management" after glycemic optimization is almost always pointing toward one of these two agents. The choice between them is guided by comorbidities: duloxetine is preferred in a patient with coexisting depression or anxiety; pregabalin is preferred when the patient has concurrent generalized anxiety or insomnia (it causes somnolence). In renal impairment, pregabalin and gabapentin both require dose reduction.

Tricyclic antidepressants are effective but carry a higher side-effect burden. They are contraindicated in patients with cardiac arrhythmias or recent myocardial infarction due to their pro-arrhythmic and anticholinergic effects. This is a frequent exam distractor: a vignette may describe an elderly diabetic with neuropathic pain and a prolonged QT interval, where amitriptyline would be the wrong answer.

Opioids are explicitly discouraged for chronic diabetic neuropathic pain and should not be selected as a correct answer on the exam except in refractory, supervised, short-term contexts. Tramadol and tapentadol may appear as later-line options.

For gastroparesis, the tested drug is metoclopramide, a dopamine antagonist and prokinetic. The critical pearl is the risk of tardive dyskinesia with prolonged use, which limits the recommended duration to 12 weeks. If a vignette mentions a diabetic patient on metoclopramide who develops involuntary facial movements, the answer is to discontinue the drug.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
B12 Deficiency Neuropathy	Also produces a symmetric stocking-glove neuropathy with loss of vibration and proprioception	Check serum B12 and methylmalonic acid; B12 deficiency causes subacute combined degeneration with upper motor neuron signs (positive Babinski, spasticity) alongside the peripheral neuropathy; diabetes does not produce UMN signs
Alcoholic Neuropathy	Length-dependent sensory-predominant neuropathy; burning feet; similar demographics	History of heavy alcohol use; often accompanied by nutritional deficiencies (thiamine, folate); may have cerebellar signs (ataxia, nystagmus) beyond what diabetes causes
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)	Progressive weakness and sensory loss in extremities; can coexist with diabetes	CIDP is demyelinating (markedly reduced conduction velocity on NCS); presents with prominent proximal and distal weakness (not just distal); areflexia is diffuse; elevated CSF protein; responds to IVIG or steroids
Hypothyroid Neuropathy	Distal sensory neuropathy; paresthesias	Elevated TSH; other features of hypothyroidism (fatigue, weight gain, delayed relaxation of ankle reflex); neuropathy resolves with thyroid replacement
Charcot-Marie-Tooth Disease (CMT)	Distal weakness and sensory loss; high arches (pes cavus); "inverted champagne bottle" legs	CMT is hereditary; onset in childhood or adolescence; family history; pes cavus and hammer toes are prominent; NCS shows either demyelinating or axonal pattern depending on subtype
Amyloid Neuropathy	Painful small-fiber neuropathy; autonomic dysfunction	Often has concurrent cardiomyopathy or nephrotic-range proteinuria; SPEP/UPEP abnormal; tissue biopsy shows apple-green birefringence with Congo red stain
Guillain-Barre Syndrome (GBS)	Ascending weakness and areflexia	GBS is acute (days to weeks) and predominantly motor; preceded by infection; CSF shows albuminocytologic dissociation; diabetic neuropathy is chronic and sensory-predominant

6. Traps and High-Yield Pearls

The most common way students lose points on diabetic neuropathy questions is by failing to recognize atypical presentations that point away from simple DSPN. A vignette describing asymmetric proximal leg weakness and thigh pain in a diabetic patient is not "regular diabetic neuropathy." That is diabetic amyotrophy, and selecting "distal symmetric polyneuropathy" would be incorrect. Similarly, an acute CN III palsy with a spared pupil in a diabetic patient should immediately signal diabetic mononeuropathy, not a posterior communicating artery aneurysm (which causes CN III palsy with a fixed, dilated pupil because the parasympathetic fibers run on the outside of the nerve and are compressed first by the aneurysm).

Another classic trap involves the workup. When the vignette gives you a straightforward diabetic patient with symmetric stocking-glove numbness, the answer is almost never "order nerve conduction studies." The diagnosis is clinical. But when the vignette introduces a red flag (rapid progression, asymmetry, motor predominance, or very early onset in a young Type 1 patient), you must recognize that further workup is warranted. The exam is testing whether you can distinguish "classic presentation, treat it" from "atypical presentation, investigate further."

On the treatment side, the most heavily tested trap involves amitriptyline in the elderly or in patients with cardiac disease. A vignette pairing neuropathic pain with urinary retention, constipation, or a cardiac conduction abnormality is begging you to avoid the TCA and choose pregabalin or duloxetine instead. Watch for the combination of diabetes, neuropathy, and a prolonged QTc on ECG: that patient should receive duloxetine or pregabalin, not amitriptyline.

Finally, remember that foot care is a cornerstone of management that gets tested indirectly. A diabetic patient with neuropathy who presents with a painless ulcer on the plantar surface of the foot is the classic setup for a question about loss of protective sensation. The patient did not feel the injury because of the neuropathy. The "most important next step" in preventing recurrence is monofilament-based screening and a structured foot care program, not simply adding another pain medication.

The core competency being tested across all diabetic neuropathy questions is your ability to connect the pathophysiology (length-dependent axonal damage from hyperglycemia) to the clinical pattern (distal-to-proximal, sensory-first, symmetric), and then to apply the correct diagnostic and treatment sequence based on whether the case is classic or atypical.

1e:["$","$L2d",null,{"article":{"id":"5b297b44-cb86-4403-8a42-dcf52689bcd1","title":"Neuropati Diabetikum","content":"$2e","category":"Neurologi","created_at":"2026-07-09T07:18:45.257127+00:00","status":"published","subcategory":null},"questionCount":0,"sections":[{"id":"section-pathophysiology","num":"01","title":"Pathophysiology"},{"id":"section-classification-and-clinical-manifestation","num":"02","title":"Classification and Clinical Manifestation"},{"id":"section-diagnostic-workup","num":"03","title":"Diagnostic Workup"},{"id":"section-management-and-treatment","num":"04","title":"Management and Treatment"},{"id":"section-differential-diagnosis-and-distractors","num":"05","title":"Differential Diagnosis and Distractors"},{"id":"section-traps-and-high-yield-pearls","num":"06","title":"Traps and High-Yield Pearls"}],"hasSummaryTable":true}]