Diabetic Neuro pathy and it's treatment deep dive

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Diabetic Neuropathy: A Deep Dive

Overview

Diabetic neuropathy (DN) is the most common complication of diabetes mellitus and the leading cause of peripheral neuropathy in developed countries. It affects approximately 50% of patients with diabetes over their lifetime. Up to 80% of those who have had diabetes for more than 15 years show some evidence of peripheral nerve damage. Despite extensive research, disease-modifying treatments remain elusive - current management focuses primarily on symptom control and risk reduction.

Classification of Diabetic Neuropathy

Diabetic neuropathy is not a single entity. Multiple distinct syndromes exist, often overlapping:

Type	Key Features
Distal Symmetric Sensorimotor Polyneuropathy (DSPN)	Most common; stocking-glove sensory loss, paresthesias, burning pain starting in toes
Autonomic Neuropathy	Orthostatic hypotension, gastroparesis, sexual dysfunction, anhidrosis, cardiac arrhythmias
Diabetic Radiculoplexus Neuropathy (Amyotrophy / Bruns-Garland syndrome)	Severe asymmetric proximal leg pain, weakness, weight loss; self-limiting but slow recovery
Cranial Mononeuropathies	CN III palsy most common (pupil-sparing); also CN VI, VII
Limb Mononeuropathies	Carpal tunnel (median), ulnar at elbow, peroneal at fibular head
Subclinical Neuropathy	Abnormal nerve conduction studies without clinical symptoms

The Washington Manual classifies them as: (1) subclinical (electrodiagnostic abnormalities only), (2) diffuse symmetric polyneuropathy ± autonomic syndromes, and (3) focal syndromes. - Washington Manual of Medical Therapeutics, p. 906

Epidemiology

Fewer than 10% of patients have clinically evident polyneuropathy at diabetes diagnosis
This rises to 50% after 25 years of disease duration
~15-20% have painful symptoms that significantly impair quality of life
Duration of diabetes is the most important risk factor
Other risk factors: poor glycemic control, retinopathy, nephropathy, metabolic syndrome components (hypertriglyceridemia, BMI, hypertension)
DSPN is responsible for 50-75% of non-traumatic lower extremity amputations - Washington Manual, p. 906

Pathogenesis

The pathogenesis is multifactorial and involves both metabolic and ischemic/vascular mechanisms.

1. Metabolic Pathways (from Hyperglycemia)

Polyol Pathway Activation: Hyperglycemia activates aldose reductase, converting glucose to sorbitol, which accumulates in nerve tissue. This depletes NADPH, reduces glutathione, and increases oxidative stress. Nerve myoinositol depletion occurs through competitive uptake, reducing Na+/K+-ATPase activity.

Advanced Glycosylation End Products (AGEs): AGEs accumulate in nerve tissue, crosslinking structural proteins, activating inflammatory receptors (RAGE), and impairing axonal transport.

Protein Kinase C (PKC) Activation: Excess diacylglycerol from hyperglycemia activates PKC, causing vascular damage and reducing endoneurial blood flow.

Oxidative Stress: Glucose auto-oxidation generates reactive oxygen species (ROS), causing direct axonal and Schwann cell damage. This is the rationale for alpha-lipoic acid trials.

Hexosamine Pathway: Contributes to altered gene expression affecting nerve growth factors.

2. Microvascular / Ischemic Mechanisms

Endoneurial hypoxia is produced by:

Endothelial cell hyperplasia increasing vascular resistance
Reduced nerve blood flow from rheological changes
Once established, capillary damage creates a vicious cycle escalating hypoxia

Hypoxia impairs axonal transport and reduces Na+/K+-ATPase activity, causing axonal atrophy and reduced nerve conduction velocities (NCVs). - Bradley and Daroff's Neurology in Clinical Practice, p. 2689

3. Insulin Deficiency

Insulin has independent neurotrophic effects. Deficiency reduces insulin-like growth factor (IGF) signaling and nerve growth factor (NGF) support, contributing to axonal degeneration independent of glucose levels.

4. Inflammatory / Immune Mechanisms

Perivascular inflammation has been found on nerve biopsy in DSPN. Autoimmune mechanisms and inflammatory pathways (TNF-α, IL-6) are increasingly recognized. This is the basis for immune treatments in diabetic amyotrophy (glucocorticoids).

Nerve Pathology

Nerve biopsy reveals: axonal degeneration, endothelial hyperplasia, and occasionally perivascular inflammation. Both axonal and demyelinating features are present in DSPN. - Robbins & Kumar Basic Pathology, p. 459-467

Clinical Presentation

Distal Symmetric Polyneuropathy (DSPN)

Sensory loss: Starts in toes, progresses proximally in a "stocking-glove" pattern
Small fiber symptoms: Burning, tingling, dysesthesias, allodynia (painful to light touch)
Large fiber signs: Loss of vibration, proprioception; balance impairment; falls
Motor involvement: Distal weakness, wasting (in advanced disease)
When severe: Sensory loss can spread to trunk (midline anterior first, then lateral)
Nerve conduction studies show reduced amplitudes and mild-moderate slowing

Autonomic Neuropathy

Cardiovascular: Resting tachycardia, orthostatic hypotension, reduced heart rate variability; associated with increased cardiovascular mortality
GI: Gastroparesis (nausea, vomiting, early satiety, bloating); nocturnal diarrhea alternating with constipation
Genitourinary: Erectile dysfunction, retrograde ejaculation, neurogenic bladder (retention, overflow incontinence)
Sudomotor: Anhidrosis, dry cracked skin; compensatory hyperhidrosis proximally
Ocular: Pupillary abnormalities, reduced dark adaptation

Diabetic Amyotrophy (Bruns-Garland)

Severe pain in low back, hip, thigh - often unilateral at onset
Rapid atrophy and weakness of proximal and distal leg muscles within days to weeks
Often accompanied by severe weight loss
CSF protein elevated, cell count normal; ESR often increased
EMG shows active denervation in proximal and paraspinal muscles; perivascular inflammation on biopsy
Gradual improvement over months to years, but residual deficits common

Diagnosis

ADA 2026 Screening Recommendations

Per the ADA 2026 Standards of Care:

Type 2 DM: Screen for DPN at time of diagnosis, then annually
Type 1 DM: Screen starting 5 years after diagnosis, then annually
Minimum annual assessment: 10-g monofilament (to identify feet at risk for ulceration), PLUS either temperature/pinprick sensation (small fiber) OR 128-Hz tuning fork (large fiber vibration sense)
Autonomic neuropathy screening at same intervals: ask about orthostatic dizziness, syncope, early satiety, erectile dysfunction, sweating changes, dry cracked skin

Clinical Assessment Tools

Test	What It Assesses
10-g Semmes-Weinstein monofilament	Protective sensation loss (large fiber)
128-Hz tuning fork	Vibration sense (large fiber)
Pinprick / temperature	Small fiber function
Nerve conduction studies (NCS)	Axonal vs. demyelinating features, severity
Quantitative sudomotor axon reflex test (QSART)	Autonomic sudomotor function
Tilt-table / orthostatic BP	Cardiovascular autonomic function
Corneal confocal microscopy	Emerging: small fiber density, early detection

Important: Diabetic neuropathy is a diagnosis of exclusion. Non-diabetic causes of neuropathy (B12 deficiency, hypothyroidism, CIDP, paraproteinemia, vasculitis, toxic/drug-induced) must be excluded, especially in atypical presentations. - ADA 2026 Standards

Treatment

1. Pathogenetic / Disease-Modifying Approaches

Glycemic Control (Most Important)

Type 1 DM: The DCCT demonstrated intensive insulin therapy reduces the development of neuropathy by 64% over 5 years vs. conventional therapy. The benefit persisted at 8-year follow-up (DCCT/EDIC), underscoring the "metabolic memory" concept.
Type 2 DM: Evidence is less compelling. The ACCORD trial (targeting HbA1c <6%) found reduced new neuropathy in the intensive group but was stopped early due to a 22% relative increase in all-cause mortality. The ADVANCE trial showed no significant effect on neuropathy.
Once neuropathy is established, existing damage is largely irreversible - glycemic control is most effective as prevention
Avoid hypoglycemia unawareness; also avoid neurotoxins (alcohol, smoking)

Lifestyle Modifications

Exercise and diet have demonstrated efficacy in DSPN in type 2 DM
Weight loss and metabolic surgery show positive effects on DPN
Treat hypertension and dyslipidemia (high triglycerides have the strongest relationship to neuropathy risk in T2DM per ADA 2026)

Vitamin B12

Metformin reduces intestinal B12 absorption in T2DM - check and replace if deficient (sublingual or parenteral in pernicious anemia)
Pernicious anemia is more common in T1DM (autoimmune polyendocrine association)

Alpha-Lipoic Acid (ALA)

Two large multicenter RCTs (ALADIN and SYDNEY trials) showed benefit of IV and oral ALA in reducing neuropathic symptoms and nerve deficits
Dosing studied: 600 mg IV or 600 mg PO three times daily
Mechanism: antioxidant, reduces oxidative stress
Not FDA-approved for this indication but used widely in Europe

Agents Studied but Disappointing

Aldose reductase inhibitors: Modest changes in NCV but no convincing clinical improvement; some proved toxic
Myoinositol supplementation: Conflicting trial results
NGF (nerve growth factor): Failed Phase III trials
VEGF gene therapy, C-peptide: Promising in animal models; human trials ongoing

2. Symptomatic Treatment of Painful DSPN

No single agent is universally effective. ~20% of patients with chronic painful diabetic neuropathy improve without treatment (spontaneous resolution). Direct head-to-head comparisons between agents are lacking - switching drug class if no response or intolerable side effects is standard.

First-Line Agents

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Duloxetine (Cymbalta): FDA-approved for diabetic peripheral neuropathy. Typical dosing 60-120 mg/day. Inhibits reuptake of serotonin and norepinephrine in descending pain-modulating pathways. Most evidence-backed first-line agent.
Venlafaxine: Evidence for efficacy; not FDA-labeled for this indication. Also consider desvenlafaxine.

Gabapentinoids

Pregabalin (Lyrica): FDA-approved for diabetic peripheral neuropathy. Dosing 150-300 mg/day in divided doses. Binds voltage-gated calcium channel alpha-2-delta subunit, reducing neuronal excitability. Also anxiolytic benefit helps with sleep.
Gabapentin: Widely used off-label; dosing 900-3600 mg/day in divided doses. Less bioavailable than pregabalin. Main side effects: sedation, dizziness, peripheral edema.

Tricyclic Antidepressants (TCAs)

Amitriptyline: Typical dosing 10-150 mg at bedtime. Effective for neuropathic pain; also improves sleep. Anticholinergic side effects (dry mouth, urinary retention, constipation) limit use, especially in elderly.
Caution in cardiac disease (QTc prolongation), glaucoma, prostatic hypertrophy.

Second-Line / Additional Options

Sodium Channel Blockers

Carbamazepine: 100-400 mg twice daily; monitor for blood dyscrasias (CBC at baseline)
Lamotrigine, oxcarbazepine: Some evidence in neuropathic pain

Topical Agents

Capsaicin patch (8% - Qutenza): FDA-approved; works by depleting substance P from nociceptors. Applied in clinic; lasts ~3 months per application. Burning/stinging on application is a major limiting factor.
Topical capsaicin 0.075% cream: Less effective than the high-concentration patch; can be tried
Lidocaine patches: Limited evidence specifically for DN

Tapentadol (Nucynta ER): FDA-approved for painful diabetic peripheral neuropathy. Dual mechanism: mu-opioid agonist + norepinephrine reuptake inhibitor. Modest efficacy with addiction risk - less preferred.

What to Avoid

Traditional opioids: The AAN guideline on painful diabetic neuropathy (reaffirmed February 2025) explicitly states opioids should NOT be used for painful diabetic neuropathy given modest efficacy and significant addiction risk.

3. Treatment of Autonomic Neuropathy

Orthostatic Hypotension

Non-pharmacologic (first-line):

Adequate salt intake; avoid dehydration and diuretics
Compression stockings (lower extremity); abdominal binders
Physical activity; postural maneuvers (gradual rising, leg crossing)
Elevate head of bed

Pharmacologic:

Midodrine (alpha-1 agonist): FDA-approved; first-line agent
Droxidopa (Northera): FDA-approved norepinephrine prodrug
Fludrocortisone: 0.1-0.3 mg/day; mineralocorticoid for volume expansion; watch for supine hypertension

Resting tachycardia: beta-blockers with caution (risk of masking hypoglycemia)

Gastroparesis

Small, frequent meals (6-8/day); soft, low-fat, low-fiber
Metoclopramide 10-20 mg before meals (prokinetic); limit to <12 weeks due to tardive dyskinesia risk
Erythromycin 125-500 mg QID (motilin receptor agonist): short-term use only
Domperidone: Used in many countries (not FDA-approved in US); fewer CNS side effects than metoclopramide
Parenteral nutrition for refractory cases

Diabetic Cystopathy

Bethanechol 10 mg three times daily (cholinergic agonist for detrusor contraction)
Intermittent self-catheterization for urinary retention
Treat UTIs aggressively due to residual urine

Erectile Dysfunction

PDE5 inhibitors (sildenafil, tadalafil) as first-line
Vacuum erection devices, intracavernosal prostaglandin injection, penile prosthesis

Diabetic Diarrhea

Tetracycline or metronidazole (if bacterial overgrowth component)
Loperamide, cholestyramine, clonidine (last resort - may worsen orthostasis)

4. Treatment of Diabetic Amyotrophy

Primarily supportive; gradual spontaneous improvement in most
Glucocorticoids used in acute phase with severe pain (IV methylprednisolone or oral prednisone) - no RCT evidence but observational benefit
IVIg has been tried in immunotherapy-responsive cases
Physical therapy critical for rehabilitation

5. Foot Care and Prevention of Complications

Per ADA 2026 and Goldman-Cecil:

Annual foot examination: musculoskeletal deformities, skin changes, pulses, sensory testing
Daily self-inspection of feet; avoid walking barefoot
Protective footwear; avoid sandals outdoors; thermal injuries (no heating pads)
Callus formation, deformities, or sensory loss → referral to podiatrist
Ulcers: aggressive debridement, systemic antibiotics for infection, pressure offloading (total contact cast), revascularization if PAD present
Toe systolic BP <30 mmHg suggests PAD and inability to heal → vascular evaluation
Charcot arthropathy: immobilization, offloading

Emerging and Future Directions (2025)

Per Yang et al., Signal Transduction and Targeted Therapy (2025) [PMID: 40274830]:

Corneal confocal microscopy: Non-invasive imaging of small nerve fiber density - validated early biomarker for detection and monitoring
Biomarker-based diagnostics: Serum neurofilament light chain, skin punch biopsy intraepidermal nerve fiber density
Neuroprotective agents: PARP inhibitors, SIRT1 activators, GLP-1 receptor agonists (emerging evidence for neuroprotection beyond glycemic control)
GLP-1 RAs and DPP-4 inhibitors: Growing evidence for direct neuroprotective effects independent of glucose lowering
Gene therapy / stem cell therapy: VEGF gene transfer, mesenchymal stem cell approaches in early trials
Anti-inflammatory strategies: Targeting TNF-α, IL-6 pathways
Mitochondria-targeted antioxidants: MitoQ and similar compounds under investigation

Summary: Treatment Algorithm for Painful DSPN

Optimize glycemic control + lifestyle modification + B12 check
            ↓
First-line: Duloxetine (60-120 mg/day) OR Pregabalin (150-300 mg/day)
            ↓ Inadequate response (4-8 weeks)
Add or switch: Gabapentin OR TCA (amitriptyline 10-150 mg HS)
            ↓ Still inadequate
Topical add-on: Capsaicin 8% patch OR Lidocaine patch
            ↓ Refractory
Combination therapy / Pain management referral
            ↓
Tapentadol (last resort, with monitoring)
AVOID conventional opioids

Key Clinical Pearls

Neuropathy is a diagnosis of exclusion - always rule out B12 deficiency, hypothyroidism, CIDP, paraproteinemia, medications (metformin B12 effect)
Prevention > treatment - glycemic control prevents neuropathy far more effectively than it reverses established damage
DCCT showed 64% risk reduction with intensive insulin therapy in T1DM; evidence in T2DM is less robust
Autonomic neuropathy carries serious cardiovascular risk - DCCT/EDIC showed an association between cardiovascular autonomic neuropathy and left ventricular dysfunction
Sleep and mood disorders frequently accompany painful DSPN and should be treated concurrently
Opioids are not recommended (AAN guideline, reaffirmed 2025) - modest efficacy with significant risk
Metformin depletes B12 - check levels regularly in all T2DM patients on metformin
Dyslipidemia (especially hypertriglyceridemia) is an independent risk factor for DPN in T2DM beyond hyperglycemia alone

Key Sources:

Harrison's Principles of Internal Medicine 22E (2025)
Adams and Victor's Principles of Neurology, 12th Ed.
Bradley and Daroff's Neurology in Clinical Practice
Robbins & Kumar Basic Pathology
Washington Manual of Medical Therapeutics
Goldman-Cecil Medicine
ADA Standards of Care in Diabetes 2026 (Section 12)
AAN Practice Guideline: Oral and Topical Treatment of Painful Diabetic Polyneuropathy (reaffirmed Feb 2025)
Yang Y et al. "Diabetic neuropathy: cutting-edge research and future directions." Signal Transduct Target Ther. 2025 [PMID: 40274830]

Diabetic Neuro pathy and it's treatment deep dive

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Diabetic Neuropathy: A Complete Deep Dive

1. Overview & Epidemiology

Diabetic neuropathy (DN) is the most common complication of diabetes mellitus and the leading cause of peripheral neuropathy in developed countries. It is a clinically heterogeneous condition encompassing multiple distinct syndromes that can occur singly or together.

Key statistics:

~15% of diabetic patients have symptoms and signs of polyneuropathy at diagnosis
~50% show nerve conduction abnormalities on electrodiagnostic testing at any time
Clinically evident polyneuropathy: <10% at diagnosis, rising to 50% after 25 years of diabetes
Lifetime prevalence of DN: approximately 50% of all diabetics
Up to 80% of those with >15 years of disease show peripheral neuropathy evidence
DSPN is responsible for 50-75% of non-traumatic lower extremity amputations
DSPN accounts for more hospitalizations than all other diabetic complications combined
Prevalence is similar in Type 1 and Type 2 diabetes; duration of disease is the single most important risk factor

Sources: Adams and Victor's Principles of Neurology 12th Ed., Washington Manual of Medical Therapeutics

2. Classification

Diabetic neuropathy is not a single entity. Six fairly distinct clinical syndromes exist, which frequently overlap:

Syndrome	Key Features	Mechanism
Distal Symmetric Sensorimotor Polyneuropathy (DSPN)	Most common. Stocking-glove sensory loss starting in toes, paresthesias, burning pain, eventual motor involvement	Metabolic + microvascular
Autonomic Neuropathy	Orthostatic hypotension, gastroparesis, bladder dysfunction, erectile dysfunction, anhidrosis, cardiac arrhythmias	Vagal + sympathetic fiber damage
Diabetic Amyotrophy (Radiculoplexus Neuropathy / Bruns-Garland syndrome)	Acute/subacute severe proximal leg pain, weakness, weight loss; usually unilateral at onset	Ischemic/inflammatory; vasa nervorum vasculopathy
Cranial Mononeuropathies	CN III most common (pupil-sparing - distinguishes from aneurysm); also CN VI, VII	Nerve trunk ischemia
Limb Mononeuropathies	Carpal tunnel (median), ulnar at elbow, peroneal at fibular head	Entrapment + ischemia
Subclinical Neuropathy	No clinical symptoms; abnormal electrodiagnostic testing only	Early metabolic injury

Source: Adams and Victor's Principles of Neurology 12th Ed., Harrison's 22E

3. Pathogenesis

The pathogenesis is multifactorial - both metabolic and ischemic/vascular mechanisms interact to produce nerve injury. No single pathway fully explains all forms.

3a. Metabolic Pathways (Driven by Hyperglycemia)

Polyol Pathway Activation The key metabolic pathway. Hyperglycemia activates aldose reductase, converting excess glucose to sorbitol and then fructose. These accumulate in nerve tissue because they cannot easily cross cell membranes. Consequences:

Depletion of NADPH, reducing glutathione and increasing oxidative stress
Competitive inhibition of myoinositol uptake → myoinositol depletion in nerve
Reduced Na+/K+-ATPase activity → axonal atrophy, slowed nerve conduction velocity (NCV)
Direct measurements of sorbitol and fructose in sural nerve biopsies confirm correlation with neuropathy severity

Advanced Glycation End Products (AGEs) Persistent hyperglycemia causes non-enzymatic glycosylation of structural nerve proteins. AGEs:

Cross-link and stiffen endoneurial collagen and myelin proteins
Activate RAGE (receptor for AGEs) triggering pro-inflammatory NF-κB signaling
Impair axonal transport

Protein Kinase C (PKC) Activation Excess diacylglycerol from the glycolysis overflow activates PKC isoforms, especially PKC-β. This:

Reduces Na+/K+-ATPase activity
Promotes vascular damage and endothelial dysfunction in the vasa nervorum
PKC-β inhibitors showed promising results in animal models but clinical trials disappointed

Reactive Oxygen Species (ROS) / Oxidative Stress Auto-oxidation of glucose generates toxic ROS. These cause:

Mitochondrial dysfunction
Direct axonal and Schwann cell membrane damage
This is the mechanistic rationale for alpha-lipoic acid as a therapeutic target

Hexosamine Pathway Excess glucose flux into the hexosamine pathway alters gene expression, reducing insulin signaling and nerve growth factor (NGF) expression.

3b. Microvascular / Ischemic Mechanisms

Endoneurial hypoxia plays a central role:

Hyperglycemia causes endothelial cell hyperplasia → increased endoneurial vascular resistance
Rheological changes (increased blood viscosity, reduced RBC deformability) reduce nerve blood flow
Once hypoxia is established, a vicious cycle of further capillary damage escalates ischemia
Basement membrane thickening of intraneural capillaries (identical to retinal and renal microangiopathy)
Impaired axonal transport and reduced Na+/K+-ATPase → axonal atrophy
Multiple small foci of fiber loss throughout nerve length, beginning proximally (ischemic pattern)

Nerve biopsy findings in DSPN:

Loss of myelinated nerve fibers (most prominent)
Segmental demyelination and remyelination of remaining axons
Occasional onion-bulb formations (from repeated remyelination)
Reduced unmyelinated fibers
Thickened and duplicated endoneurial capillary basement membranes
Perivascular inflammation in some cases (especially amyotrophy)

Source: Adams and Victor's Principles of Neurology 12th Ed. (p. 2424-2431), Bradley and Daroff's Neurology in Clinical Practice (p. 2689)

3c. Insulin Deficiency Effects

Insulin has independent neurotrophic effects beyond glucose regulation. Deficiency:

Reduces IGF-1 signaling critical for axonal survival
Lowers NGF (nerve growth factor) levels, impairing Schwann cell support
C-peptide (lost in T1DM) has been shown to prevent neuropathy in diabetic animal models in a dose-dependent manner, creating interest in C-peptide replacement therapy

3d. Inflammatory / Immune Mechanisms

Increasingly recognized as contributing, especially in amyotrophy:

Perivascular inflammation found on proximal nerve biopsies in radiculoplexus neuropathy
TNF-α, IL-6 upregulation in endoneurium
Provides rationale for glucocorticoids in diabetic amyotrophy
Autoimmune mechanisms further modulate susceptibility

3e. Additional Risk Factors

Beyond duration and glycemic control:

Metabolic syndrome components: hypertriglyceridemia (strongest independent predictor in T2DM), elevated BMI, hypertension
Presence of retinopathy correlates with higher neuropathy incidence (shared microangiopathy)
Age >50 years; neuropathy is rare in childhood
Tobacco smoking; alcohol use (direct neurotoxin)
Metformin-induced B12 deficiency

4. Clinical Presentation

Distal Symmetric Polyneuropathy (DSPN)

Onset: Insidious, often unnoticed by patient initially
Distribution: Stocking-glove pattern; starts in toes, progresses proximally up legs, later affects fingers
When severe: Sensory loss spreads to trunk - midline anterior chest/abdomen first, then laterally
Small fiber symptoms (early): Burning, tingling, dysesthesias, allodynia (pain from normally non-painful stimuli), lancinating pains
Large fiber signs (later): Loss of vibration sense, proprioception; balance impairment; falls risk; pseudoataxia
Motor involvement: Distal weakness and wasting in advanced disease; intrinsic foot muscle wasting → foot deformities
NCS findings: Reduced amplitude potentials, mild-moderate slowing of conduction velocity (mixed axonal + demyelinating)
Painful diabetic neuropathy (PDN): Affects ~15-20% of diabetics; often worse at night; severely impacts sleep and quality of life

Autonomic Neuropathy

Typically co-exists with DSPN. Multi-system involvement:

System	Manifestations
Cardiovascular	Resting tachycardia, orthostatic hypotension, reduced heart rate variability, silent MI, increased CV mortality
GI	Gastroparesis (nausea, vomiting, early satiety, bloating); nocturnal diarrhea alternating with constipation; dysphagia
Genitourinary	Erectile dysfunction, retrograde ejaculation, neurogenic bladder (retention → overflow incontinence, recurrent UTIs), female sexual dysfunction
Sudomotor	Anhidrosis distally, compensatory hyperhidrosis proximally; dry cracked skin on feet (ulcer risk)
Ocular	Pupillary abnormalities, reduced dark adaptation

Cardiovascular autonomic neuropathy (CAN) is associated with left ventricular dysfunction (DCCT/EDIC data) and is a marker of significantly increased mortality risk.

Diabetic Amyotrophy (Bruns-Garland Syndrome)

Presents as the first manifestation of DM in ~1/3 of cases
Severe pain: Low back, hip, thigh in one leg; may be bilateral
Rapid weakness + atrophy of proximal and distal leg muscles within days-weeks
Characteristic weight loss often accompanying or preceding weakness
CSF protein elevated, cell count normal
ESR often elevated
EMG: Active denervation in proximal limb and paraspinal muscles
Nerve biopsy: Axonal degeneration + perivascular inflammation
Natural history: Slow recovery over months to years; residual deficits common

Cranial Mononeuropathies

CN III palsy is most common; characteristically pupil-sparing (microvasculature of outer pupillomotor fibers preserved, core ischemia affects somatic fibers first) - distinguishes from compressive CN III palsy (aneurysm) where pupil IS affected
CN VI and CN VII palsies also occur
Usually self-limited over weeks to months

5. Diagnosis & Screening

ADA 2026 Screening Recommendations (Rec. 12.17-12.19)

Diabetes Type	When to Start Screening	Frequency
Type 2 DM	At time of diagnosis	At least annually
Type 1 DM	5 years after diagnosis	At least annually
Autonomic neuropathy	Same as above	At least annually

Minimum Annual Assessment for DSPN (ADA 2026, Rec. 12.18)

10-g Semmes-Weinstein monofilament - identifies loss of protective sensation (LOPS); predicts foot ulceration risk
128-Hz tuning fork - vibration sense (large fiber function)
Pinprick or temperature - small fiber function
Ankle reflexes - typically absent in moderate-severe DSPN

Abnormalities in two or more modalities = high sensitivity for diagnosis of DSPN.

Screening for Autonomic Neuropathy (Rec. 12.19)

Ask about: orthostatic dizziness/syncope, early satiety, erectile dysfunction, sweating changes, dry/cracked feet

Signs: orthostatic hypotension (BP drop ≥20 systolic or ≥10 diastolic on standing), resting tachycardia, peripheral skin dryness

Electrodiagnostic Testing

NCS confirms and quantifies severity; characterizes as axonal vs. demyelinating
EMG: denervation patterns; important for amyotrophy
QSART (quantitative sudomotor axon reflex test): autonomic small fiber function
Skin punch biopsy: intraepidermal nerve fiber density (small fiber assessment)

Key Diagnostic Caveat

Diabetic neuropathy is a diagnosis of exclusion. Non-diabetic neuropathies must be excluded, including: B12 deficiency, hypothyroidism, CIDP, monoclonal gammopathy, vasculitis, drug/toxin-induced neuropathy, hereditary neuropathies. Atypical features (rapid progression, purely motor, asymmetry from the start) warrant further workup.

6. Treatment

6a. Disease-Modifying / Pathogenetic Approaches

Glycemic Control - The Foundation

Type 1 DM (strongest evidence): The landmark DCCT trial demonstrated intensive insulin therapy (pump or multiple daily injections) reduces development of clinical neuropathy by 64% over 5 years vs. conventional therapy. Long-term DCCT/EDIC follow-up showed this benefit persisted for at least 8 years after trial completion - the "metabolic memory" phenomenon. Successful pancreatic transplantation also prevents neuropathy progression with sustained long-term benefit.

Type 2 DM (evidence is mixed):

ACCORD trial (n >10,000, baseline HbA1c 8.1%): Targeting HbA1c <6% reduced new neuropathy cases in the intensive group, but the trial was stopped early due to a 22% relative increase in all-cause mortality at 3.7 years; at the time of transition to standard therapy, significant differences in neuropathy had disappeared
ADVANCE trial (n >11,000, baseline HbA1c 7.5%): Intensive glycemic control did not significantly reduce new or worsening neuropathy after 5 years
A 6-year prospective trial in longstanding poorly-controlled T2DM (baseline HbA1c 9.4%) showed no neuropathy benefit despite reducing HbA1c by 1.5%

Key conclusion: Glycemic control is most powerful as prevention, especially in T1DM. Once DSPN is established, existing damage is largely irreversible. Efforts to improve glycemic control in longstanding T2DM are limited by hypoglycemia unawareness risk.

Cardiovascular Risk Factor Management (ADA 2026, Rec. 12.20)

Optimize weight (obesity is independent DPN risk factor)
Control blood pressure (hypertension contributes to microangiopathy)
Treat dyslipidemia, especially hypertriglyceridemia (strongest lipid link to DPN in T2DM)
Note: Statins and fibrates do not appear effective in treating or preventing DPN development despite their lipid effects
Exercise and diet have demonstrated direct efficacy in DSPN in T2DM
Metabolic surgery (bariatric surgery) shows positive effects on DPN - likely through multiple metabolic mechanisms beyond glucose

Vitamin B12

Metformin reduces intestinal absorption of B12 via competitive inhibition of ileal transport → check B12 in all T2DM patients on metformin
Pernicious anemia is more common in T1DM (autoimmune polyendocrine syndrome with anti-parietal cell antibodies)
Replace if deficient: sublingual or oral B12 usually sufficient; parenteral in pernicious anemia
Check folate also

Alpha-Lipoic Acid (ALA)

Two large multicenter RCTs showed benefit:
- ALADIN trial (IV ALA): Significant reduction in neuropathic symptoms and Total Symptom Score
- SYDNEY trial (oral ALA 600 mg TID): Confirmed reduction in neuropathic deficits and NCS improvements
Mechanism: Potent antioxidant, reduces ROS-mediated nerve damage, improves endoneurial blood flow
Widely used in Europe; not FDA-approved for DN in the US
Dose studied: 600 mg IV infusion or 600 mg PO three times daily
Washington Manual dosing: 600 mg TID for early DPN

Investigational / Experimental Pathogenetic Agents

Agent	Mechanism	Status
Aldose reductase inhibitors (epalrestat, ranirestat)	Block polyol pathway	Modest NCV improvement; no convincing clinical benefit; some toxic; Epalrestat approved in India/China
NGF (nerve growth factor)	Neurotrophic support	Failed Phase III trials
VEGF gene therapy	Improve endoneurial blood flow	Improved NCV and nerve blood flow in animal models; early human trials
C-peptide	Neurotrophic + metabolic	Prevented neuropathy dose-dependently in diabetic rats; human trials
GLP-1 receptor agonists (semaglutide, liraglutide)	Direct neuroprotection + glycemic	Emerging evidence for neuroprotection independent of glucose lowering
DPP-4 inhibitors	SDF-1α / nerve repair	Preclinical and early clinical evidence
Mitochondria-targeted antioxidants (MitoQ)	Mitochondrial ROS	Early investigation
Stem cell therapy	Nerve regeneration	Early trials

6b. Symptomatic Treatment of Painful DSPN

No treatment reverses the underlying nerve damage. All current pharmacologic treatments are symptomatic only. Approximately 20% of patients with chronic painful neuropathy improve spontaneously without treatment.

No direct head-to-head comparisons across all major drug classes were available until recently. A landmark head-to-head trial cited in the ADA 2026 Standards showed therapeutic equivalency among TCAs, SNRIs, and gabapentinoids for pain in DPN, and also supported the role of combination therapy for inadequate monotherapy response.

ADA 2026 & AAN Guideline Recommendations (Rec. 12.22)

The ADA 2026 and AAN guideline (reaffirmed Feb 2025) recommend four drug classes as initial pharmacologic treatments - none is definitively superior, allowing individualization:

Gabapentinoids + SNRIs + TCAs + Sodium Channel Blockers are all recommended first-line. Combinations provide additional relief. Opioids (including tapentadol) are NOT recommended.

First-Line Drug Classes

1. SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Drug	Dose	FDA Approval	Notes
Duloxetine	60-120 mg/day	✅ FDA-approved for DPN	Most widely prescribed; best evidence; benefits mood + sleep too
Venlafaxine	75-225 mg/day (ER)	Off-label	Effective; consider in patients with comorbid depression
Desvenlafaxine	50-100 mg/day	Off-label	Active metabolite of venlafaxine
Milnacipran	50-100 mg BID	Off-label	Recommended by European NeuPSIG

Mechanism: Enhance descending noradrenergic and serotonergic pain inhibition in spinal cord

2. Gabapentinoids

Drug	Dose	FDA Approval	Notes
Pregabalin	150-300 mg/day (divided)	✅ FDA-approved for DPN	More predictable bioavailability vs gabapentin; anxiolytic benefit; improves sleep
Gabapentin	900-3600 mg/day (divided TID)	Off-label	Efficacy enhanced by adding controlled-release morphine or nortriptyline

Mechanism: Bind voltage-gated calcium channel α2-δ subunit → reduce presynaptic calcium influx → decrease neurotransmitter release in dorsal horn

Side effects: Sedation, dizziness, peripheral edema, weight gain; schedule V controlled substance (pregabalin)

3. Tricyclic Antidepressants (TCAs)

Drug	Dose	Notes
Amitriptyline	10-150 mg at bedtime	Most studied; effective; improves sleep
Nortriptyline	10-100 mg at bedtime	Better tolerated; fewer anticholinergic effects
Imipramine	25-150 mg at bedtime	Alternative option

Mechanism: Inhibit norepinephrine and serotonin reuptake + sodium channel blockade + NMDA antagonism → multiple pain-modulating actions; also improve sleep via H1 blockade

Side effects: Anticholinergic (dry mouth, urinary retention, constipation, confusion), sedation, QTc prolongation, orthostatic hypotension Cautions: Elderly patients (fall risk), cardiac disease (QTc), glaucoma, BPH

Note from Barash's Clinical Anesthesia: "TCAs are more effective than SNRIs but given their more favorable side-effect profile, duloxetine is the most widely prescribed agent for DPN."

4. Sodium Channel Blockers (Updated AAN 2021 Guideline) Now formally recommended alongside other classes based on new evidence:

Drug	Dose	Notes
Carbamazepine	100-400 mg BID	Monitor CBC (blood dyscrasias risk); monitor LFTs; CYP inducer
Oxcarbazepine	300-600 mg BID	Better tolerated; hyponatremia risk
Lamotrigine	25-400 mg/day	Slow titration required; rash/SJS risk
Lacosamide	50-200 mg BID	Newer option; PR prolongation

Second-Line / Adjunctive Options

Topical Therapies

Agent	Mechanism	Notes
Capsaicin 8% patch (Qutenza)	Depletes substance P from nociceptors via TRPV1 desensitization	FDA-approved; applied in clinic setting; lasts ~3 months per application; burning on application is major side effect
Capsaicin 0.075% cream	Same but less potent	OTC; BID-QID application; less effective than patch
Glyceryl trinitrate spray	Topical vasodilator; improves local blood flow	Recommended in AAN guideline; evidence from RCTs
Lidocaine patches (5%)	Local Na+ channel blockade	Limited DN-specific evidence; used for focal areas

Non-Pharmacologic Approaches (AAN Guideline 2021/2025)

Exercise: Evidence for direct benefit on neuropathic pain and nerve fiber density
Cognitive behavioral therapy (CBT): Improves pain coping, mood, quality of life
Mindfulness-based stress reduction
Tai chi: Balance, fall prevention; some pain benefit
Transcutaneous electrical nerve stimulation (TENS)
Spinal cord stimulation (SCS): Role under investigation; may help refractory cases
Ginkgo biloba: Mentioned in AAN guideline as potentially helpful; weak evidence

What to Avoid

Opioids - Not Recommended Both the ADA 2026 Standards and the AAN guideline (reaffirmed February 2025) explicitly state that opioids, including tapentadol, are not recommended for painful diabetic neuropathy. Reasons:

Only modest efficacy
Significant addiction risk
Adverse effects (sedation, constipation, respiratory depression)
Evidence does not support a favorable benefit-risk ratio

AAN statement: "Clinicians should not use opioids for the treatment of painful diabetic neuropathy."

Combination Therapy When monotherapy is insufficient, the ADA 2026 confirms that combinations of the four recommended drug classes provide additional pain relief and are supported by evidence. A logical approach: SNRI + gabapentinoid is commonly used.

6c. Pain Management Algorithm for Painful DSPN

Step 1: Foundation
├── Optimize glycemic control (HbA1c target)
├── Lifestyle: exercise, weight loss, smoking cessation, alcohol avoidance
├── Check and replace B12 / folate
└── Treat comorbid depression, sleep disorders

Step 2: First-Line Monotherapy (choose based on comorbidities)
├── Duloxetine 60-120 mg/day  ← comorbid depression/anxiety
├── Pregabalin 150-300 mg/day ← comorbid anxiety/insomnia
├── Gabapentin 900-3600 mg/day ← cost-effective option
├── Amitriptyline 10-150 mg HS ← insomnia-dominant, younger patients
└── Sodium channel blocker (carbamazepine, oxcarbazepine) ← shooting/lancinating pain

Step 3: Inadequate Response (4-8 weeks)
├── Switch to different drug CLASS (not same class)
└── Add second agent from different class (combination therapy)

Step 4: Add-on / Adjunctive
├── Capsaicin 8% patch (clinic procedure)
├── Topical glyceryl trinitrate spray
├── Alpha-lipoic acid 600 mg TID
└── Non-pharmacologic: exercise, CBT, TENS, mindfulness

Step 5: Refractory Pain
├── Pain management specialist referral
├── Spinal cord stimulation consideration
└── AVOID opioids

6d. Treatment of Autonomic Neuropathy

Orthostatic Hypotension

Non-pharmacologic (first-line):

Adequate salt and fluid intake (NaCl 1-4 g/day)
Avoid dehydration, diuretics, vasodilators
Graduated compression stockings + abdominal binders
Slow positional changes; leg crossing maneuvers
Physical activity; head-of-bed elevation at night (reduces nocturnal natriuresis)
Avoid large carbohydrate meals (postprandial hypotension)

Pharmacologic:

Midodrine (alpha-1 agonist): FDA-approved; first-line agent; give before rising; avoid in supine hypertension
Droxidopa (Northera - norepinephrine prodrug): FDA-approved; also treats neurogenic OH
Fludrocortisone 0.1-0.3 mg/day: Mineralocorticoid; volume expansion; monitor for supine hypertension, edema, hypokalemia
Resting tachycardia: Beta-blockers with caution (risk of masking hypoglycemia and worsening exercise tolerance)
T1DM + orthostatic hypotension → screen for Addison's disease (autoimmune polyendocrine syndrome)

Gastroparesis

Diet: Small, frequent meals (6-8/day); soft, low-fat, low-fiber; avoid carbonated beverages
Metoclopramide 10-20 mg PO/suppository before meals and HS - dopamine antagonist + 5-HT4 agonist; limit to <12 weeks due to tardive dyskinesia risk (black box warning)
Erythromycin 125-500 mg QID - motilin receptor agonist; short-term only (tachyphylaxis)
Domperidone - peripherally acting dopamine antagonist; fewer CNS side effects; not FDA-approved in US; widely used elsewhere
Cyclical vomiting not from GI dysmotility: Amitriptyline 25-50 mg HS
Refractory cases: Parenteral nutrition; gastric electrical stimulation

Neurogenic Bladder (Cystopathy)

Manifestations: Urgency, dribbling, incomplete emptying, overflow incontinence, urinary retention; recurrent UTIs from residual urine
Bethanechol 10 mg TID (cholinergic agonist; stimulates detrusor contraction)
Intermittent self-catheterization for urinary retention
Treat UTIs aggressively; post-void residual urine monitoring

Diabetic Diarrhea

Usually multifactorial (dysmotility + bacterial overgrowth + bile acid malabsorption)
Tetracycline or metronidazole (if bacterial overgrowth component)
Loperamide for symptomatic relief
Clonidine (last resort) - may worsen orthostasis
Cholestyramine (bile acid sequestrant)

Erectile Dysfunction

PDE5 inhibitors (sildenafil, tadalafil, vardenafil): First-line; use with caution if on nitrates
Vacuum erection devices
Intracavernosal alprostadil injection
Penile prosthesis (surgical last resort)

6e. Treatment of Diabetic Amyotrophy

Primarily supportive with expectation of gradual improvement
Acute phase pain: Often severe; may require opioids temporarily (this is one context where short-term opioids may be necessary)
Glucocorticoids (IV methylprednisolone or oral prednisone): Used empirically based on the inflammatory/immune pathology (perivascular inflammation on biopsy); no RCT evidence but observational benefit; particularly in severely painful, rapidly progressive cases
IVIg or plasma exchange: Tried in refractory immunotherapy-responsive cases
Physical and occupational therapy: Critical for rehabilitation and functional recovery
Timeline: Weakness usually progresses for weeks to months, may continue for 18+ months; slow recovery follows but residual weakness and sensory loss are common

6f. Foot Care and Prevention of Complications

Per ADA 2026 Standards:

Annual foot examination: Musculoskeletal deformities, skin integrity, pulses, sensory testing (monofilament + tuning fork)
Daily self-inspection of feet by patient
No barefoot walking (even indoors)
Protective footwear; avoid sandals outdoors; no heating pads or hot-water bottles on feet
Callus, deformity, or sensory loss → podiatry referral

Diabetic foot ulcers:

Aggressive debridement of necrotic tissue
Systemic antibiotics (culture-guided) for infection
Pressure offloading (total contact cast - gold standard; special orthotics/footwear)
Revascularization if significant PAD (toe systolic BP <30 mmHg = unable to heal)
Additional options: bioengineered skin substitutes, negative-pressure wound therapy, hyperbaric oxygen (evidence limited)

PAD screening: ADA 2026 + Society for Vascular Surgery recommend all diabetics >50 years undergo non-invasive arterial studies; repeat every 5 years if normal.

Charcot arthropathy: Immobilization and offloading; long-term protective footwear; orthopedic/podiatry co-management.

7. Emerging Diagnostics and Future Directions (2025-2026)

From Yang et al., Signal Transduction and Targeted Therapy 2025 [PMID: 40274830] and Dillon et al., Annual Review of Medicine 2024 [PMID: 38285516]:

Novel Diagnostics

Corneal confocal microscopy (CCM): Non-invasive, in-vivo imaging of corneal nerve fiber density and morphology; validated biomarker for small fiber neuropathy; allows monitoring of treatment response
Skin punch biopsy IENFD: Intraepidermal nerve fiber density from 3-mm punch biopsy; validated small fiber assessment; now recommended in guidelines for atypical presentations
Serum neurofilament light chain (NfL): Blood biomarker reflecting axonal damage; elevated in DPN; potential for early detection and monitoring
Automated point-of-care devices: Bedside corneal nerve assessment; handheld NCS devices

Promising Therapeutic Targets

Target	Agent	Rationale
GLP-1 receptor	Semaglutide, liraglutide	Direct neuroprotection + AMPK activation + anti-inflammatory independent of glucose
DPP-4 / SDF-1α	Saxagliptin, sitagliptin	SDF-1α promotes nerve repair via CXCR4; early clinical signals
PARP inhibition	PARP inhibitors	Reduce oxidative stress-induced DNA damage in neurons
SIRT1 activation	Resveratrol, SRT compounds	Deacetylase activity; mitochondrial protection
Mitochondria	MitoQ, SS-31	Targeted antioxidants; preserve mitochondrial function in neurons
Gene therapy	VEGF, neurotrophin gene transfer	Improve endoneurial blood flow; enhance neurotrophic support
Stem cell therapy	MSCs, iPSC-derived neurons	Nerve regeneration; paracrine neurotrophic effects
Anti-inflammatory	TNF-α blockers, IL-6 inhibitors	Address neuroinflammation component

Despite advances, no disease-modifying treatment for established DSPN has cleared Phase III trials as of 2026. Prevention through glycemic and metabolic control remains the only proven strategy to reduce incidence. Symptom management remains the therapeutic mainstay.

8. Summary of Key Clinical Pearls

DN is a diagnosis of exclusion - always rule out B12/folate deficiency, hypothyroidism, CIDP, paraproteinemia, vasculitis, and drug toxicity before attributing neuropathy to diabetes alone
Prevention is far more powerful than treatment - DCCT showed 64% risk reduction with intensive insulin therapy in T1DM; established damage is largely irreversible
Glycemic control evidence differs by diabetes type: Robust benefit in T1DM (DCCT); inconsistent and potentially dangerous in aggressive T2DM targets (ACCORD mortality signal)
Metformin depletes B12 - check levels regularly; sublingual/oral supplementation usually sufficient
All four drug classes are equivalent first-line (ADA 2026, AAN guideline): SNRIs, gabapentinoids, TCAs, sodium channel blockers - choose based on comorbidities and side effect profile
Opioids are not recommended for painful DPN (AAN, reaffirmed February 2025) - modest benefit, significant harm
Autonomic neuropathy carries serious cardiovascular risk - CAN is associated with LV dysfunction and significantly increased mortality (DCCT/EDIC data)
Hypertriglyceridemia is the strongest lipid-related independent risk factor for DPN in T2DM
CN III palsy in diabetics is pupil-sparing (ischemic core injury); a CN III palsy with pupil involvement in a diabetic demands urgent imaging to exclude posterior communicating artery aneurysm
Sleep and mood disorders frequently accompany painful DSPN and should be treated concurrently - they amplify pain perception and treatment should address them
Diabetic amyotrophy (Bruns-Garland) has an inflammatory component and often responds partially to glucocorticoids - do not miss it as it mimics other proximal myopathies
Annual foot screening saves lives and limbs - the 10-g monofilament is the single most important clinical tool for identifying patients at risk for ulceration and amputation

Primary Sources:

Harrison's Principles of Internal Medicine, 22E (2025, McGraw-Hill)
Adams and Victor's Principles of Neurology, 12th Edition
Bradley and Daroff's Neurology in Clinical Practice
Robbins & Kumar Basic Pathology
Washington Manual of Medical Therapeutics
Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Ed.
Goldman-Cecil Medicine
ADA Standards of Care in Diabetes 2026 - Section 12: Retinopathy, Neuropathy, and Foot Care [PMID: 41358886]
AAN Practice Guideline: Oral and Topical Treatment of Painful Diabetic Polyneuropathy (2021, reaffirmed February 2025) - Neurology 98(1):31-43
Yang Y et al. "Diabetic neuropathy: cutting-edge research and future directions." Signal Transduct Target Ther. 2025 Apr 25 [PMID: 40274830]
Dillon BR, Ang L, Pop-Busui R. "Spectrum of Diabetic Neuropathy: New Insights in Diagnosis and Treatment." Annu Rev Med. 2024 [PMID: 38285516]

Make ppt above

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    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: by, w: 3.0, h: 0.18,
      fill: { color: t.color }, line: { color: t.color }
    });
    // Number badge
    s.addShape(pres.shapes.ELLIPSE, {
      x: bx + 0.12, y: by + 0.28, w: 0.38, h: 0.38,
      fill: { color: t.color }, line: { color: t.color }
    });
    s.addText(t.icon, {
      x: bx + 0.12, y: by + 0.28, w: 0.38, h: 0.38,
      fontSize: 12, bold: true, color: C.navy, align: "center", valign: "middle", margin: 0
    });
    s.addText(t.name, {
      x: bx + 0.58, y: by + 0.22, w: 2.3, h: 0.6,
      fontSize: 10, bold: true, color: C.white, lineSpacingMultiple: 1.2, margin: 0
    });
    s.addText(t.desc, {
      x: bx + 0.12, y: by + 0.9, w: 2.76, h: 1.0,
      fontSize: 9, color: C.lightGray, lineSpacingMultiple: 1.3, margin: 0
    });
  });

  sourceBar(s, "Sources: Harrison's 22E (p.3270) · Adams & Victor 12th Ed. · Washington Manual · Robbins & Kumar Basic Pathology");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 4 — PATHOGENESIS (Metabolic)
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "PATHOGENESIS — METABOLIC MECHANISMS");

  s.addText("Hyperglycemia", {
    x: 3.8, y: 0.7, w: 2.4, h: 0.45,
    fontSize: 14, bold: true, color: C.red, align: "center",
    fill: { color: C.white },
    shadow: { type: "outer", color: "000000", blur: 6, offset: 2, angle: 135, opacity: 0.15 }
  });
  // Center box
  s.addShape(pres.shapes.RECTANGLE, {
    x: 3.9, y: 1.08, w: 2.2, h: 0.55,
    fill: { color: C.red }, line: { color: C.red }
  });
  s.addText("NERVE DAMAGE", {
    x: 3.9, y: 1.08, w: 2.2, h: 0.55,
    fontSize: 12, bold: true, color: C.white, align: "center", valign: "middle", margin: 0
  });

  // 4 pathway cards arranged around center
  const paths = [
    {
      title: "Polyol Pathway",
      body: "Aldose reductase converts glucose\n→ sorbitol → fructose accumulation\n→ myoinositol depletion\n→ ↓ Na+/K+-ATPase\n→ axonal atrophy, ↓ NCV",
      x: 0.15, y: 0.65, color: C.teal
    },
    {
      title: "AGE Formation",
      body: "Non-enzymatic glycosylation of\nnerve proteins → AGE crosslinks\n→ RAGE activation → NF-κB\n→ pro-inflammatory cascade\n→ impaired axonal transport",
      x: 7.3, y: 0.65, color: C.amber
    },
    {
      title: "PKC Activation",
      body: "Excess DAG activates PKC-β\n→ ↓ Na+/K+-ATPase\n→ vascular endothelial\ndysfunction → ↓ endoneurial\nblood flow",
      x: 0.15, y: 2.8, color: "#5B8DD9"
    },
    {
      title: "Oxidative Stress",
      body: "Glucose auto-oxidation → ROS\n→ mitochondrial dysfunction\n→ direct axon + Schwann\ncell membrane damage\n→ rationale for α-lipoic acid",
      x: 7.3, y: 2.8, color: "#C77DFF"
    },
  ];

  paths.forEach(p => {
    card(s, p.x, p.y, 2.85, 2.1, { bg: C.navy });
    s.addShape(pres.shapes.RECTANGLE, {
      x: p.x, y: p.y, w: 2.85, h: 0.2,
      fill: { color: p.color }, line: { color: p.color }
    });
    s.addText(p.title, {
      x: p.x + 0.1, y: p.y + 0.25, w: 2.65, h: 0.35,
      fontSize: 11, bold: true, color: p.color, margin: 0
    });
    s.addText(p.body, {
      x: p.x + 0.1, y: p.y + 0.62, w: 2.65, h: 1.35,
      fontSize: 9, color: C.offWhite, lineSpacingMultiple: 1.3, margin: 0
    });
  });

  // Hexosamine note in center bottom
  card(s, 3.5, 2.8, 3.0, 1.2, { bg: C.navyMid });
  s.addText("+ Insulin Deficiency", {
    x: 3.6, y: 2.85, w: 2.8, h: 0.3,
    fontSize: 10, bold: true, color: C.amber, align: "center", margin: 0
  });
  s.addText("↓ IGF-1 & NGF signaling\n→ impaired Schwann cell support\n→ axonal degeneration", {
    x: 3.6, y: 3.15, w: 2.8, h: 0.75,
    fontSize: 8.5, color: C.offWhite, align: "center", lineSpacingMultiple: 1.3, margin: 0
  });

  sourceBar(s, "Sources: Bradley & Daroff's Neurology (p.2689) · Adams & Victor 12th Ed. · Robbins & Kumar Basic Pathology");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 5 — PATHOGENESIS (Vascular + Nerve Pathology)
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  sectionBar(s, "PATHOGENESIS — VASCULAR & NERVE PATHOLOGY");

  // Left: vascular mechanism
  card(s, 0.2, 0.68, 4.6, 3.5, { bg: C.cardBg });
  s.addText("Microvascular / Ischemic Mechanism", {
    x: 0.35, y: 0.75, w: 4.3, h: 0.38,
    fontSize: 12, bold: true, color: C.tealLight, margin: 0
  });
  accentLine(s, 0.35, 1.16, 4.3, C.teal);
  const vasc = [
    "Hyperglycemia → endothelial hyperplasia → ↑ endoneurial vascular resistance",
    "Rheological changes (↑ blood viscosity) → ↓ nerve blood flow",
    "Endoneurial hypoxia → impairs axonal transport → ↓ Na+/K+-ATPase",
    "Vicious cycle: capillary damage → more hypoxia → axonal atrophy",
    "Basement membrane thickening of intraneural capillaries (shared with retina/kidney)",
    "Multiple foci of fiber loss from proximal to distal (ischemic pattern on biopsy)",
  ];
  vasc.forEach((v, i) => {
    s.addText(`${i + 1}. ${v}`, {
      x: 0.35, y: 1.25 + i * 0.47, w: 4.3, h: 0.43,
      fontSize: 9.5, color: C.offWhite, lineSpacingMultiple: 1.25, margin: 0
    });
  });

  // Right: nerve biopsy findings
  card(s, 5.1, 0.68, 4.7, 1.8, { bg: C.cardBg });
  s.addText("Nerve Biopsy Findings (DSPN)", {
    x: 5.25, y: 0.75, w: 4.4, h: 0.38,
    fontSize: 12, bold: true, color: C.amber, margin: 0
  });
  accentLine(s, 5.25, 1.16, 4.3, C.amber);
  const biopsy = [
    "Loss of myelinated nerve fibers (predominant)",
    "Segmental demyelination & remyelination",
    "Onion-bulb formations (repeated remyelination)",
    "Reduced unmyelinated fibers",
    "Thickened, duplicated capillary basement membranes",
    "Perivascular inflammation (especially amyotrophy)",
  ];
  biopsy.forEach((b, i) => {
    s.addText("• " + b, {
      x: 5.25, y: 1.23 + i * 0.2, w: 4.4, h: 0.2,
      fontSize: 8.5, color: C.offWhite, margin: 0
    });
  });

  // Right bottom: Inflammatory
  card(s, 5.1, 2.65, 4.7, 1.5, { bg: C.cardBg });
  s.addText("Inflammatory / Immune Component", {
    x: 5.25, y: 2.72, w: 4.4, h: 0.38,
    fontSize: 12, bold: true, color: "#C77DFF", margin: 0
  });
  accentLine(s, 5.25, 3.13, 4.3, "#C77DFF");
  s.addText([
    { text: "• Perivascular inflammation in radiculoplexus neuropathy (amyotrophy)\n", options: {} },
    { text: "• TNF-α and IL-6 upregulation in endoneurium\n", options: {} },
    { text: "• Provides rationale for glucocorticoids in amyotrophy\n", options: {} },
    { text: "• Autoimmune mechanisms modulate susceptibility", options: {} },
  ], {
    x: 5.25, y: 3.2, w: 4.4, h: 0.9,
    fontSize: 9, color: C.offWhite, lineSpacingMultiple: 1.3, margin: 0
  });

  sourceBar(s, "Sources: Adams & Victor 12th Ed. (p.2424-2431) · Bradley & Daroff's Neurology in Clinical Practice (p.2689)");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 6 — CLINICAL FEATURES: DSPN
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "CLINICAL FEATURES — DISTAL SYMMETRIC POLYNEUROPATHY (DSPN)");

  // Stocking-glove visual (schematic)
  card(s, 0.2, 0.7, 2.2, 4.5, { bg: C.navy });
  s.addText("Distribution", {
    x: 0.3, y: 0.78, w: 2.0, h: 0.3,
    fontSize: 10, bold: true, color: C.amber, align: "center", margin: 0
  });
  // Stocking
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.55, y: 3.0, w: 1.5, h: 1.9,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  s.addText("Stocking", {
    x: 0.55, y: 3.05, w: 1.5, h: 0.4,
    fontSize: 8, bold: true, color: C.white, align: "center", valign: "middle", margin: 0
  });
  // Glove
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.55, y: 2.35, w: 1.5, h: 0.55,
    fill: { color: C.tealLight }, line: { color: C.tealLight }
  });
  s.addText("Glove (late)", {
    x: 0.55, y: 2.35, w: 1.5, h: 0.55,
    fontSize: 7.5, bold: true, color: C.navy, align: "center", valign: "middle", margin: 0
  });
  // Trunk (severe)
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.55, y: 1.7, w: 1.5, h: 0.55,
    fill: { color: C.amber }, line: { color: C.amber }
  });
  s.addText("Trunk (severe)", {
    x: 0.55, y: 1.7, w: 1.5, h: 0.55,
    fontSize: 7, bold: true, color: C.navy, align: "center", valign: "middle", margin: 0
  });
  s.addText("Proximal", {
    x: 0.35, y: 1.2, w: 1.9, h: 0.4,
    fontSize: 8, color: C.lightGray, align: "center", margin: 0
  });
  s.addText("Distal\n(starts here)", {
    x: 0.35, y: 4.65, w: 1.9, h: 0.45,
    fontSize: 8, color: C.lightGray, align: "center", margin: 0
  });

  // Small fiber column
  card(s, 2.6, 0.7, 3.4, 4.5, { bg: C.cardBg });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 2.6, y: 0.7, w: 3.4, h: 0.22,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  s.addText("SMALL FIBER (Early Onset)", {
    x: 2.7, y: 0.73, w: 3.2, h: 0.2,
    fontSize: 9.5, bold: true, color: C.white, align: "center", margin: 0
  });
  const sf = [
    "Burning pain — often worse at night",
    "Tingling and dysesthesias",
    "Allodynia (pain from light touch)",
    "Lancinating / electric shock pains",
    "Hyperalgesia",
    "Temperature sensation loss",
    "Autonomic features co-occur",
  ];
  sf.forEach((f, i) => {
    s.addText("• " + f, {
      x: 2.75, y: 1.0 + i * 0.5, w: 3.1, h: 0.45,
      fontSize: 10, color: C.offWhite, margin: 0
    });
  });

  // Large fiber column
  card(s, 6.2, 0.7, 3.6, 4.5, { bg: C.cardBg });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 6.2, y: 0.7, w: 3.6, h: 0.22,
    fill: { color: C.amber }, line: { color: C.amber }
  });
  s.addText("LARGE FIBER (Progressive)", {
    x: 6.3, y: 0.73, w: 3.4, h: 0.2,
    fontSize: 9.5, bold: true, color: C.navy, align: "center", margin: 0
  });
  const lf = [
    "Numbness / sensory loss",
    "Loss of vibration sense",
    "Loss of proprioception",
    "Balance impairment / falls",
    "Areflexia (absent ankle reflexes)",
    "Distal weakness + wasting (late)",
    "Foot ulceration risk (LOPS)",
  ];
  lf.forEach((f, i) => {
    s.addText("• " + f, {
      x: 6.3, y: 1.0 + i * 0.5, w: 3.3, h: 0.45,
      fontSize: 10, color: C.offWhite, margin: 0
    });
  });

  sourceBar(s, "NCS findings: Reduced amplitudes + mild-moderate slowing (mixed axonal + demyelinating). LOPS = Loss of Protective Sensation");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 7 — AUTONOMIC NEUROPATHY
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  sectionBar(s, "AUTONOMIC NEUROPATHY");

  const systems = [
    {
      sys: "Cardiovascular",
      features: "• Resting tachycardia\n• Orthostatic hypotension\n• Reduced heart rate variability\n• Silent MI risk\n• ↑ Cardiovascular mortality (DCCT/EDIC)",
      alert: "Associated with LV dysfunction — major mortality risk",
      color: C.red,
    },
    {
      sys: "Gastrointestinal",
      features: "• Gastroparesis (nausea, vomiting, early satiety, bloating)\n• Nocturnal diarrhea alternating with constipation\n• Dysphagia\n• DKA must be excluded when acute",
      alert: "Scintigraphy documents delayed gastric emptying",
      color: C.amber,
    },
    {
      sys: "Genitourinary",
      features: "• Erectile dysfunction\n• Retrograde ejaculation\n• Neurogenic bladder (retention → overflow incontinence)\n• Recurrent UTIs from residual urine\n• Female sexual dysfunction",
      alert: "Check post-void residual urine; treat UTIs aggressively",
      color: C.teal,
    },
    {
      sys: "Sudomotor / Skin",
      features: "• Anhidrosis distally\n• Compensatory hyperhidrosis proximally\n• Dry, cracked skin on feet\n• Pupillary abnormalities\n• Reduced dark adaptation",
      alert: "Dry cracked feet = ulcer risk — daily inspection mandatory",
      color: "#7C65C0",
    },
  ];

  systems.forEach((sys, i) => {
    const col = i % 2;
    const row = Math.floor(i / 2);
    const bx = 0.2 + col * 4.95;
    const by = 0.7 + row * 2.3;

    card(s, bx, by, 4.6, 2.1, { bg: C.cardBg });
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: by, w: 1.8, h: 0.38,
      fill: { color: sys.color }, line: { color: sys.color }
    });
    s.addText(sys.sys, {
      x: bx + 0.05, y: by + 0.02, w: 1.7, h: 0.34,
      fontSize: 11, bold: true, color: sys.color === C.amber ? C.navy : C.white,
      valign: "middle", margin: 0
    });
    s.addText(sys.features, {
      x: bx + 0.12, y: by + 0.45, w: 4.35, h: 1.2,
      fontSize: 9, color: C.offWhite, lineSpacingMultiple: 1.3, margin: 0
    });
    // Alert banner
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: by + 1.72, w: 4.6, h: 0.32,
      fill: { color: sys.color }, line: { color: sys.color }
    });
    s.addText("▶ " + sys.alert, {
      x: bx + 0.08, y: by + 1.74, w: 4.44, h: 0.28,
      fontSize: 8.5, color: sys.color === C.amber ? C.navy : C.white,
      italic: true, valign: "middle", margin: 0
    });
  });

  sourceBar(s, "Sources: Harrison's 22E · Adams & Victor 12th Ed. (p.2417) · DCCT/EDIC Research Group");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 8 — DIABETIC AMYOTROPHY + CRANIAL/FOCAL
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "FOCAL SYNDROMES — DIABETIC AMYOTROPHY & CRANIAL MONONEUROPATHIES");

  // Amyotrophy card
  card(s, 0.2, 0.7, 5.8, 4.5, { bg: C.navy });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.2, y: 0.7, w: 5.8, h: 0.28,
    fill: { color: C.red }, line: { color: C.red }
  });
  s.addText("Diabetic Amyotrophy  (Bruns-Garland Syndrome)", {
    x: 0.3, y: 0.72, w: 5.6, h: 0.26,
    fontSize: 11, bold: true, color: C.white, valign: "middle", margin: 0
  });

  const amy = [
    { label: "Presentation", val: "Severe pain in low back, hip, thigh (unilateral at onset)\nRapid proximal + distal leg weakness within days-weeks\nCharacteristic severe weight loss\nMay be first manifestation of DM in ~1/3 of cases" },
    { label: "Investigations", val: "CSF: ↑ protein, normal cell count\nESR: often elevated\nEMG: active denervation in proximal limb + paraspinal muscles\nNerve biopsy: axonal degeneration + perivascular inflammation" },
    { label: "Treatment", val: "Supportive; expect gradual improvement (months-years)\nGlucocorticoids (IV methylprednisolone or oral prednisone)\n— empirical; observational benefit; no RCT data\nIVIg in refractory immunotherapy-responsive cases\nIntensive physical + occupational therapy" },
  ];
  amy.forEach((a, i) => {
    s.addText(a.label, {
      x: 0.35, y: 1.12 + i * 1.3, w: 5.5, h: 0.3,
      fontSize: 10.5, bold: true, color: C.amber, margin: 0
    });
    accentLine(s, 0.35, 1.44 + i * 1.3, 5.5, C.amber);
    s.addText(a.val, {
      x: 0.35, y: 1.5 + i * 1.3, w: 5.5, h: 0.75,
      fontSize: 9.5, color: C.offWhite, lineSpacingMultiple: 1.3, margin: 0
    });
  });

  // Cranial mono card
  card(s, 6.2, 0.7, 3.6, 2.1, { bg: C.cardBg });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 6.2, y: 0.7, w: 3.6, h: 0.28,
    fill: { color: C.teal }, line: { color: C.teal }
  });
  s.addText("Cranial Mononeuropathies", {
    x: 6.3, y: 0.72, w: 3.4, h: 0.26,
    fontSize: 11, bold: true, color: C.white, valign: "middle", margin: 0
  });
  s.addText("CN III (most common) → pupil-sparing\n   Ischemia affects core first; pupillomotor\n   fibers (outer) spared\n   PUPIL INVOLVEMENT = rule out aneurysm!\nCN VI — lateral rectus palsy\nCN VII — facial nerve palsy\nUsually self-limited over weeks-months", {
    x: 6.3, y: 1.07, w: 3.4, h: 1.6,
    fontSize: 9.5, color: C.offWhite, lineSpacingMultiple: 1.35, margin: 0
  });

  // Limb mono card
  card(s, 6.2, 2.95, 3.6, 2.25, { bg: C.cardBg });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 6.2, y: 2.95, w: 3.6, h: 0.28,
    fill: { color: "#5B8DD9" }, line: { color: "#5B8DD9" }
  });
  s.addText("Limb Mononeuropathies", {
    x: 6.3, y: 2.97, w: 3.4, h: 0.26,
    fontSize: 11, bold: true, color: C.white, valign: "middle", margin: 0
  });
  s.addText("• Carpal tunnel (median nerve at wrist)\n• Ulnar nerve at elbow\n• Peroneal nerve at fibular head\n• Lateral femoral cutaneous nerve\n• Sciatic nerve\nMechanism: entrapment + ischemia", {
    x: 6.3, y: 3.3, w: 3.4, h: 1.75,
    fontSize: 9.5, color: C.offWhite, lineSpacingMultiple: 1.35, margin: 0
  });

  sourceBar(s, "Sources: Adams & Victor 12th Ed. (p.2363-2432) · Harrison's 22E · Goldman-Cecil Medicine");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 9 — DIAGNOSIS & SCREENING
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  sectionBar(s, "DIAGNOSIS & SCREENING — ADA 2026 RECOMMENDATIONS");

  // Screening timeline
  card(s, 0.2, 0.7, 9.6, 1.5, { bg: C.cardBg });
  s.addText("When to Screen (ADA 2026 Rec. 12.17-12.19)", {
    x: 0.35, y: 0.76, w: 9.3, h: 0.32,
    fontSize: 12, bold: true, color: C.amber, margin: 0
  });

  const screen = [
    { type: "TYPE 2 DM", when: "At diagnosis", freq: "Annually", color: C.teal },
    { type: "TYPE 1 DM", when: "5 years post-diagnosis", freq: "Annually", color: C.tealLight },
    { type: "AUTONOMIC", when: "Same as above", freq: "Annually", color: "#7C65C0" },
  ];
  screen.forEach((sc, i) => {
    const bx = 0.3 + i * 3.2;
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: 1.1, w: 2.9, h: 0.9,
      fill: { color: sc.color }, line: { color: sc.color }
    });
    s.addText(sc.type, {
      x: bx + 0.05, y: 1.12, w: 2.8, h: 0.3,
      fontSize: 10, bold: true, color: C.navy, align: "center", margin: 0
    });
    s.addText(`Start: ${sc.when}  |  Repeat: ${sc.freq}`, {
      x: bx + 0.05, y: 1.42, w: 2.8, h: 0.5,
      fontSize: 8.5, color: C.navy, align: "center", margin: 0
    });
  });

  // Clinical tests
  card(s, 0.2, 2.35, 5.8, 2.85, { bg: C.cardBg });
  s.addText("Annual Clinical Assessment (Rec. 12.18)", {
    x: 0.35, y: 2.42, w: 5.5, h: 0.32,
    fontSize: 11.5, bold: true, color: C.teal, margin: 0
  });
  accentLine(s, 0.35, 2.77, 5.5, C.teal);
  const tests = [
    { test: "10-g Semmes-Weinstein Monofilament", what: "Protective sensation loss (LOPS) — predicts ulceration/amputation risk", key: true },
    { test: "128-Hz Tuning Fork", what: "Vibration sense — large fiber function", key: false },
    { test: "Pinprick / Temperature", what: "Small fiber function — earliest to be affected", key: false },
    { test: "Ankle Reflexes", what: "Typically absent in moderate-severe DSPN", key: false },
    { test: "NCS / EMG", what: "Confirms, quantifies severity; axonal vs. demyelinating", key: false },
  ];
  tests.forEach((t, i) => {
    s.addShape(pres.shapes.RECTANGLE, {
      x: 0.35, y: 2.85 + i * 0.44, w: 0.07, h: 0.34,
      fill: { color: t.key ? C.amber : C.teal }, line: { color: t.key ? C.amber : C.teal }
    });
    s.addText(t.test, {
      x: 0.5, y: 2.87 + i * 0.44, w: 2.5, h: 0.32,
      fontSize: 9.5, bold: t.key, color: t.key ? C.amber : C.white, margin: 0
    });
    s.addText(t.what, {
      x: 3.05, y: 2.87 + i * 0.44, w: 2.8, h: 0.32,
      fontSize: 8.5, color: C.lightGray, margin: 0
    });
  });

  // Diagnostic caveat
  card(s, 6.2, 2.35, 3.6, 2.85, { bg: C.navy });
  s.addShape(pres.shapes.RECTANGLE, {
    x: 6.2, y: 2.35, w: 3.6, h: 0.32,
    fill: { color: C.red }, line: { color: C.red }
  });
  s.addText("⚠  DIAGNOSIS OF EXCLUSION", {
    x: 6.25, y: 2.37, w: 3.5, h: 0.28,
    fontSize: 10, bold: true, color: C.white, valign: "middle", margin: 0
  });
  s.addText("Always rule out:", {
    x: 6.3, y: 2.74, w: 3.4, h: 0.28,
    fontSize: 9.5, bold: true, color: C.amber, margin: 0
  });
  const excl = ["B12 / folate deficiency", "Hypothyroidism", "CIDP", "Monoclonal gammopathy", "Vasculitis", "Drug/toxin-induced neuropathy", "Hereditary neuropathies (CMT)"];
  excl.forEach((e, i) => {
    s.addText("• " + e, {
      x: 6.3, y: 3.05 + i * 0.32, w: 3.4, h: 0.3,
      fontSize: 9, color: C.offWhite, margin: 0
    });
  });

  sourceBar(s, "ADA Standards of Care in Diabetes 2026 — Section 12 (Rec. 12.17-12.19) [PMID: 41358886]");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 10 — TREATMENT: GLYCEMIC CONTROL & PATHOGENETIC
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "TREATMENT — DISEASE-MODIFYING APPROACHES");

  // Key trials banner
  card(s, 0.2, 0.7, 9.6, 0.85, { bg: C.navy });
  s.addText("Glycemic Control — The Foundation  (ADA 2026 Rec. 12.20)", {
    x: 0.35, y: 0.74, w: 9.3, h: 0.3,
    fontSize: 12, bold: true, color: C.amber, margin: 0
  });
  s.addText("Prevent > Treat  |  Existing damage is largely irreversible once DSPN is established", {
    x: 0.35, y: 1.03, w: 9.3, h: 0.28,
    fontSize: 9.5, color: C.lightGray, margin: 0
  });

  // Trial cards
  const trials = [
    {
      name: "DCCT (T1DM)",
      result: "64% reduction in neuropathy development\nwith intensive insulin therapy vs. conventional\nBenefit persisted 8+ years (metabolic memory)",
      verdict: "STRONG EVIDENCE",
      vcolor: C.green,
    },
    {
      name: "ACCORD (T2DM)",
      result: "Target HbA1c <6%: ↓ new neuropathy cases\nBUT trial stopped early — 22% ↑ all-cause mortality\nDifference lost at transition to standard care",
      verdict: "CAUTION: MORTALITY SIGNAL",
      vcolor: C.red,
    },
    {
      name: "ADVANCE (T2DM)",
      result: "Intensive vs. standard glycemic control\n(n>11,000, HbA1c 7.5% baseline)\nNo significant reduction in neuropathy at 5 years",
      verdict: "NEGATIVE",
      vcolor: C.amber,
    },
  ];
  trials.forEach((t, i) => {
    const bx = 0.2 + i * 3.27;
    card(s, bx, 1.65, 3.0, 1.9, { bg: C.cardBg });
    s.addText(t.name, {
      x: bx + 0.1, y: 1.72, w: 2.8, h: 0.35,
      fontSize: 11, bold: true, color: C.white, margin: 0
    });
    s.addText(t.result, {
      x: bx + 0.1, y: 2.1, w: 2.8, h: 0.95,
      fontSize: 8.5, color: C.offWhite, lineSpacingMultiple: 1.3, margin: 0
    });
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: 3.22, w: 3.0, h: 0.3,
      fill: { color: t.vcolor }, line: { color: t.vcolor }
    });
    s.addText(t.verdict, {
      x: bx + 0.05, y: 3.24, w: 2.9, h: 0.26,
      fontSize: 9, bold: true, color: t.vcolor === C.amber ? C.navy : C.white,
      align: "center", margin: 0
    });
  });

  // Additional modifiable targets
  card(s, 0.2, 3.65, 9.6, 1.6, { bg: C.navyMid });
  s.addText("Additional Modifiable Targets & Adjunctive Therapies", {
    x: 0.35, y: 3.71, w: 9.3, h: 0.3,
    fontSize: 11, bold: true, color: C.teal, margin: 0
  });
  const adj = [
    { item: "Weight loss / Exercise", note: "Direct efficacy in DSPN in T2DM; metabolic surgery shows positive DPN effects" },
    { item: "BP & Lipid control", note: "Hypertriglyceridemia strongest lipid link; statins/fibrates do NOT prevent DPN" },
    { item: "Vitamin B12", note: "Metformin depletes B12 → check + replace; sublingual/oral or parenteral in PA" },
    { item: "Alpha-Lipoic Acid", note: "ALADIN + SYDNEY RCTs: ↓ symptoms and deficits; 600 mg TID; antioxidant mechanism" },
    { item: "Avoid neurotoxins", note: "Alcohol (direct neurotoxin), tobacco; optimize metabolic milieu" },
  ];
  adj.forEach((a, i) => {
    const col = i % 2 === 0 ? 0 : 1;
    const row = Math.floor(i / 2);
    const bx = 0.3 + col * 4.8;
    const by = 4.05 + row * 0.55;
    if (i === 4) {
      s.addText("• " + a.item + ": " + a.note, {
        x: 0.3, y: by, w: 9.3, h: 0.42,
        fontSize: 8.5, color: C.offWhite, margin: 0
      });
    } else {
      s.addText("• " + a.item + ": " + a.note, {
        x: bx, y: by, w: 4.6, h: 0.42,
        fontSize: 8.5, color: C.offWhite, lineSpacingMultiple: 1.2, margin: 0
      });
    }
  });

  sourceBar(s, "Sources: Bradley & Daroff (DCCT/ACCORD/ADVANCE trials) · ADA 2026 Rec.12.20 · Washington Manual · Harrison's 22E");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 11 — PHARMACOTHERAPY FOR PAINFUL DSPN
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  sectionBar(s, "PHARMACOTHERAPY FOR PAINFUL DSPN — ADA 2026 & AAN GUIDELINE 2025");

  // Header note
  card(s, 0.2, 0.68, 9.6, 0.65, { bg: C.cardBg });
  s.addText("All four drug classes are EQUIVALENT first-line (ADA 2026 Rec. 12.22) — choose based on comorbidities and side-effect profile. No direct head-to-head superiority demonstrated.", {
    x: 0.35, y: 0.73, w: 9.3, h: 0.5,
    fontSize: 9.5, color: C.offWhite, italic: true, lineSpacingMultiple: 1.2, margin: 0
  });

  const drugs = [
    {
      cls: "SNRIs",
      color: C.teal,
      drugs: "Duloxetine 60-120 mg/day (FDA ✓)\nVenlafaxine 75-225 mg/day (ER)\nDesvenlafaxine 50-100 mg/day",
      mech: "↑ descending noradrenergic + serotonergic\npain inhibition in spinal cord",
      pros: "Benefits mood + sleep\nGood tolerability\nMost widely prescribed",
      side: "Nausea, dry mouth, sexual dysfunction,\n↑ BP (venlafaxine), serotonin syndrome",
    },
    {
      cls: "Gabapentinoids",
      color: C.amber,
      drugs: "Pregabalin 150-300 mg/day (FDA ✓)\nGabapentin 900-3600 mg/day",
      mech: "Binds α2-δ subunit of VGCC\n→ ↓ presynaptic Ca²⁺ → ↓ neurotransmitter\nrelease in dorsal horn",
      pros: "Pregabalin: consistent bioavailability\nAnxiolytic; improves sleep",
      side: "Sedation, dizziness, peripheral edema,\nweight gain; Schedule V (pregabalin)",
    },
    {
      cls: "TCAs",
      color: C.tealLight,
      drugs: "Amitriptyline 10-150 mg HS\nNortriptyline 10-100 mg HS\nImipramine 25-150 mg HS",
      mech: "NE + serotonin reuptake inhibition\n+ Na⁺ channel blockade\n+ NMDA antagonism + H1 blockade",
      pros: "Excellent for pain + sleep\nLow cost; long track record",
      side: "Anticholinergic, sedation, QTc ↑,\northostatic hypotension; caution elderly",
    },
    {
      cls: "Na⁺ Channel Blockers",
      color: "#7C65C0",
      drugs: "Carbamazepine 100-400 mg BID\nOxcarbazepine 300-600 mg BID\nLacosamide 50-200 mg BID\nLamotrigine 25-400 mg/day",
      mech: "Stabilize neuronal membranes\n→ ↓ ectopic firing in damaged\nperipheral sensory fibers",
      pros: "Particularly effective for\nshooting/lancinating pains",
      side: "CBZ: blood dyscrasias, CYP inducer\nOXC: hyponatremia; LAM: rash/SJS",
    },
  ];

  drugs.forEach((d, i) => {
    const bx = 0.2 + i * 2.45;
    card(s, bx, 1.43, 2.3, 3.85, { bg: C.cardBg });
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: 1.43, w: 2.3, h: 0.25,
      fill: { color: d.color }, line: { color: d.color }
    });
    s.addText(d.cls, {
      x: bx + 0.05, y: 1.45, w: 2.2, h: 0.22,
      fontSize: 11, bold: true, color: d.color === C.amber ? C.navy : C.white,
      align: "center", valign: "middle", margin: 0
    });
    s.addText("Drugs & Doses", {
      x: bx + 0.07, y: 1.73, w: 2.15, h: 0.22,
      fontSize: 8, bold: true, color: d.color, margin: 0
    });
    s.addText(d.drugs, {
      x: bx + 0.07, y: 1.94, w: 2.15, h: 0.72,
      fontSize: 8, color: C.white, lineSpacingMultiple: 1.25, margin: 0
    });
    s.addText("Mechanism", {
      x: bx + 0.07, y: 2.69, w: 2.15, h: 0.22,
      fontSize: 8, bold: true, color: d.color, margin: 0
    });
    s.addText(d.mech, {
      x: bx + 0.07, y: 2.9, w: 2.15, h: 0.62,
      fontSize: 7.5, color: C.lightGray, lineSpacingMultiple: 1.25, margin: 0
    });
    s.addText("Advantages", {
      x: bx + 0.07, y: 3.55, w: 2.15, h: 0.22,
      fontSize: 8, bold: true, color: d.color, margin: 0
    });
    s.addText(d.pros, {
      x: bx + 0.07, y: 3.76, w: 2.15, h: 0.48,
      fontSize: 7.5, color: C.white, lineSpacingMultiple: 1.25, margin: 0
    });
    s.addText("Side Effects", {
      x: bx + 0.07, y: 4.26, w: 2.15, h: 0.22,
      fontSize: 8, bold: true, color: C.red, margin: 0
    });
    s.addText(d.side, {
      x: bx + 0.07, y: 4.46, w: 2.15, h: 0.65,
      fontSize: 7, color: C.lightGray, lineSpacingMultiple: 1.2, margin: 0
    });
  });

  sourceBar(s, "ADA 2026 Rec. 12.22 · AAN Guideline (reaffirmed Feb 2025) · Barash Clinical Anesthesia 9E · Harrison's 22E");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 12 — ADJUNCTIVE THERAPIES + TREATMENT ALGORITHM
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "ADJUNCTIVE THERAPIES & PAIN MANAGEMENT ALGORITHM");

  // Left: adjunctive therapies
  card(s, 0.2, 0.7, 4.5, 4.5, { bg: C.navy });
  s.addText("Topical & Non-Pharmacologic Options", {
    x: 0.35, y: 0.77, w: 4.2, h: 0.32,
    fontSize: 11, bold: true, color: C.tealLight, margin: 0
  });
  accentLine(s, 0.35, 1.12, 4.2, C.teal);

  const adj2 = [
    { name: "Capsaicin 8% Patch (Qutenza)", note: "FDA-approved; clinic application; TRPV1 desensitization → depletes substance P; lasts ~3 months; burning on application" },
    { name: "Topical Capsaicin 0.075%", note: "OTC; BID-QID; less potent; useful as add-on" },
    { name: "Glyceryl Trinitrate Spray", note: "Topical vasodilator; AAN guideline recommendation; RCT evidence for pain relief" },
    { name: "Alpha-Lipoic Acid 600 mg TID", note: "ALADIN/SYDNEY RCT evidence; antioxidant; widely used in Europe" },
    { name: "Exercise", note: "Direct benefit on pain + nerve fiber density; improves insulin sensitivity" },
    { name: "CBT / Mindfulness", note: "Improves pain coping, mood, quality of life; AAN guideline" },
    { name: "TENS / Spinal Cord Stimulation", note: "TENS: adjunct option; SCS: role under investigation for refractory pain" },
    { name: "Tai Chi", note: "Balance + fall prevention; mild pain benefit; recommended in AAN guideline" },
  ];
  adj2.forEach((a, i) => {
    s.addShape(pres.shapes.RECTANGLE, {
      x: 0.35, y: 1.2 + i * 0.42, w: 0.07, h: 0.32,
      fill: { color: i < 4 ? C.teal : C.amber }, line: { color: i < 4 ? C.teal : C.amber }
    });
    s.addText(a.name + "  —  " + a.note, {
      x: 0.5, y: 1.22 + i * 0.42, w: 4.1, h: 0.38,
      fontSize: 8.5, color: C.offWhite, lineSpacingMultiple: 1.2, margin: 0
    });
  });

  // NOT recommended box
  s.addShape(pres.shapes.RECTANGLE, {
    x: 0.2, y: 4.9, w: 4.5, h: 0.4,
    fill: { color: C.red }, line: { color: C.red }
  });
  s.addText("⛔  OPIOIDS NOT RECOMMENDED  (AAN 2025 + ADA 2026)  — Modest efficacy, significant addiction risk", {
    x: 0.3, y: 4.92, w: 4.3, h: 0.36,
    fontSize: 8.5, bold: true, color: C.white, valign: "middle", margin: 0
  });

  // Right: Algorithm
  card(s, 4.9, 0.7, 4.9, 4.6, { bg: C.cardBg });
  s.addText("Treatment Algorithm for Painful DSPN", {
    x: 5.05, y: 0.77, w: 4.6, h: 0.3,
    fontSize: 11, bold: true, color: C.amber, margin: 0
  });

  const steps = [
    { step: "Step 1", label: "Foundation", body: "Optimize glycemic control + lifestyle\nCheck B12/folate\nTreat depression + sleep disorders" },
    { step: "Step 2", label: "First-Line Monotherapy", body: "SNRI (duloxetine) OR Gabapentinoid\n(pregabalin/gabapentin) OR TCA\n(amitriptyline) OR Na+ channel blocker" },
    { step: "Step 3", label: "Inadequate Response (4-8 wks)", body: "Switch to DIFFERENT drug class\nOR add second agent (combination)" },
    { step: "Step 4", label: "Adjunctive Add-on", body: "Capsaicin 8% patch + GTN spray\nAlpha-lipoic acid + Exercise/CBT" },
    { step: "Step 5", label: "Refractory Pain", body: "Pain management specialist referral\nSpinal cord stimulation\nAVOID opioids" },
  ];
  steps.forEach((st, i) => {
    const by = 1.15 + i * 0.82;
    s.addShape(pres.shapes.RECTANGLE, {
      x: 5.0, y: by, w: 1.0, h: 0.68,
      fill: { color: C.teal }, line: { color: C.teal }
    });
    s.addText(st.step, {
      x: 5.0, y: by + 0.03, w: 1.0, h: 0.3,
      fontSize: 9, bold: true, color: C.white, align: "center", margin: 0
    });
    s.addText(st.label, {
      x: 5.0, y: by + 0.33, w: 1.0, h: 0.3,
      fontSize: 7, color: C.navy, align: "center", lineSpacingMultiple: 1.1, margin: 0
    });
    s.addText(st.body, {
      x: 6.1, y: by + 0.05, w: 3.55, h: 0.6,
      fontSize: 8.5, color: C.offWhite, lineSpacingMultiple: 1.25, margin: 0
    });
    if (i < 4) {
      s.addText("▼", {
        x: 5.2, y: by + 0.7, w: 0.6, h: 0.12,
        fontSize: 8, color: C.teal, align: "center", margin: 0
      });
    }
  });

  sourceBar(s, "Sources: ADA 2026 Rec. 12.22 · AAN Painful Diabetic Neuropathy Guideline (reaffirmed Feb 2025) · Harrison's 22E");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 13 — AUTONOMIC NEUROPATHY TREATMENT
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  darkBg(s);
  sectionBar(s, "TREATMENT — AUTONOMIC NEUROPATHY");

  const autTx = [
    {
      sys: "Orthostatic\nHypotension",
      non: "• Adequate salt (NaCl 1-4 g/day) + fluids\n• Avoid diuretics, vasodilators\n• Compression stockings + abdominal binder\n• Slow positional changes; leg crossing\n• Head-of-bed elevation at night",
      pharm: "Midodrine (α1 agonist) — FDA-approved\nDroxidopa (NE prodrug) — FDA-approved\nFludrocortisone 0.1-0.3 mg/day",
      color: C.red,
    },
    {
      sys: "Gastroparesis",
      non: "• 6-8 small meals/day\n• Soft, low-fat, low-fiber diet\n• Avoid carbonated drinks",
      pharm: "Metoclopramide 10-20 mg AC+HS (<12 wks)\nErythromycin 125-500 mg QID (short-term)\nDomperidone (non-US)",
      color: C.amber,
    },
    {
      sys: "Neurogenic\nBladder",
      non: "• Post-void residual monitoring\n• Timed voiding\n• Avoid bladder irritants",
      pharm: "Bethanechol 10 mg TID\nIntermittent self-catheterization\nTreat UTIs aggressively",
      color: C.teal,
    },
    {
      sys: "Erectile\nDysfunction",
      non: "• Vacuum erection devices\n• Psychosexual counseling",
      pharm: "PDE5 inhibitors (sildenafil, tadalafil)\n— first line; caution with nitrates\nIntracavernosal alprostadil\nPenile prosthesis (last resort)",
      color: "#7C65C0",
    },
    {
      sys: "Diabetic\nDiarrhea",
      non: "• Dietary modification\n• Identify bacterial overgrowth component",
      pharm: "Tetracycline / metronidazole (if SIBO)\nLoperamide (symptomatic)\nCholestyramine\nClonidine (last resort; worsens OH)",
      color: "#5B8DD9",
    },
    {
      sys: "Resting\nTachycardia",
      non: "• Exclude reversible causes\n• Screen for associated CAN",
      pharm: "Beta-blockers — use with caution\n(risk: masking hypoglycemia)\nIn T1DM: screen for Addison's disease",
      color: C.lightGray,
    },
  ];

  autTx.forEach((a, i) => {
    const col = i % 2;
    const row = Math.floor(i / 3 === 0 ? i : i - (i % 3 === 0 ? 0 : i % 3));
    const cols3 = [0, 1, 2, 0, 1, 2];
    const rows2 = [0, 0, 0, 1, 1, 1];
    const bx = 0.15 + cols3[i] * 3.28;
    const by = 0.7 + rows2[i] * 2.35;

    card(s, bx, by, 3.1, 2.15, { bg: C.cardBg });
    s.addShape(pres.shapes.RECTANGLE, {
      x: bx, y: by, w: 1.5, h: 0.28,
      fill: { color: a.color }, line: { color: a.color }
    });
    s.addText(a.sys, {
      x: bx + 0.05, y: by + 0.02, w: 1.4, h: 0.24,
      fontSize: 9.5, bold: true,
      color: a.color === C.amber ? C.navy : C.white,
      valign: "middle", margin: 0
    });
    s.addText("Non-pharm:", {
      x: bx + 0.1, y: by + 0.33, w: 2.9, h: 0.2,
      fontSize: 8, bold: true, color: a.color, margin: 0
    });
    s.addText(a.non, {
      x: bx + 0.1, y: by + 0.52, w: 2.9, h: 0.75,
      fontSize: 7.8, color: C.offWhite, lineSpacingMultiple: 1.2, margin: 0
    });
    s.addText("Pharmacologic:", {
      x: bx + 0.1, y: by + 1.28, w: 2.9, h: 0.2,
      fontSize: 8, bold: true, color: a.color, margin: 0
    });
    s.addText(a.pharm, {
      x: bx + 0.1, y: by + 1.47, w: 2.9, h: 0.6,
      fontSize: 7.8, color: C.white, lineSpacingMultiple: 1.2, margin: 0
    });
  });

  sourceBar(s, "Sources: Harrison's 22E · Washington Manual of Medical Therapeutics · ADA 2026 Standards of Care");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 14 — FOOT CARE + EMERGING THERAPIES
// ═══════════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  lightBg(s);
  sectionBar(s, "FOOT CARE, COMPLICATIONS & EMERGING THERAPIES");

  // Foot care left
  card(s, 0.2, 0.7, 4.7, 4.5, { bg: C.navy });
  s.addText("Diabetic Foot Care & Ulcer Prevention", {
    x: 0.35, y: 0.77, w: 4.4, h: 0.32,
    fontSize: 11.5, bold: true, color: C.amber, margin: 0
  });
  accentLine(s, 0.35, 1.12, 4.4, C.amber);
  const foot = [
    { t: "Annual Foot Exam", d: "Musculoskeletal deformity, skin integrity, pulses, sensory testing (monofilament + tuning fork)" },
    { t: "Daily Self-Inspection", d: "Check feet daily for cuts, cracks, blisters; no barefoot walking indoors or outdoors" },
    { t: "Footwear", d: "Protective shoes; avoid sandals; no heating pads or hot-water bottles on feet" },
    { t: "Podiatry Referral", d: "Any sensory loss, foot deformity, extensive callus, or non-healing ulcers" },
    { t: "Ulcer Management", d: "Aggressive debridement; culture-guided antibiotics; total contact cast (gold standard offloading); revascularization if PAD" },
    { t: "PAD Screening", d: "Diabetics >50 yrs → non-invasive arterial studies; toe BP <30 mmHg = unable to heal; repeat every 5 years if normal" },
    { t: "Charcot Arthropathy", d: "Immobilization + offloading; long-term orthopedic/podiatry co-management" },
  ];
  foot.forEach((f, i) => {
    s.addText(f.t + ":  ", {
      x: 0.35, y: 1.22 + i * 0.48, w: 4.4, h: 0.2,
      fontSize: 9.5, bold: true, color: C.amber, margin: 0
    });
    s.addText(f.d, {
      x: 0.35, y: 1.41 + i * 0.48, w: 4.4, h: 0.26,
      fontSize: 8.5, color: C.offWhite, margin: 0
    });
  });

  // Emerging therapies right
  card(s, 5.1, 0.7, 4.7, 4.5, { bg: C.cardBg });
  s.addText("Emerging & Future Directions (2025-26)", {
    x: 5.25, y: 0.77, w: 4.4, h: 0.32,
    fontSize: 11.5, bold: true, color: C.tealLight, margin: 0
  });
  accentLine(s, 5.25, 1.12, 4.4, C.teal);
  const emerg = [
    { cat: "Diagnostics", color: C.teal, items: "Corneal confocal microscopy (CCM) — non-invasive small fiber\nSkin punch biopsy IENFD — validated small fiber assessment\nSerum neurofilament light chain (NfL) — axonal damage biomarker" },
    { cat: "GLP-1 RAs / DPP-4i", color: C.amber, items: "Semaglutide, liraglutide: direct neuroprotection + AMPK activation\nIndependent of glucose lowering; growing clinical evidence" },
    { cat: "Antioxidant / Metabolic", color: "#5B8DD9", items: "MitoQ, SS-31: mitochondria-targeted antioxidants\nPARP inhibitors, SIRT1 activators" },
    { cat: "Gene & Cell Therapy", color: "#C77DFF", items: "VEGF gene transfer → ↑ endoneurial blood flow\nMesenchymal stem cells → paracrine neurotrophic effects\nC-peptide replacement (T1DM)" },
    { cat: "Anti-inflammatory", color: C.red, items: "TNF-α inhibitors, IL-6 blockade targeting neuroinflammation" },
  ];
  let ey = 1.22;
  emerg.forEach((e) => {
    s.addShape(pres.shapes.RECTANGLE, {
      x: 5.15, y: ey, w: 0.08, h: 0.3,
      fill: { color: e.color }, line: { color: e.color }
    });
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  sourceBar(s, "Sources: ADA 2026 Standards · Yang Y et al. Signal Transduct Target Ther 2025 [PMID: 40274830] · Dillon et al. Annu Rev Med 2024 [PMID: 38285516]");
}

// ═══════════════════════════════════════════════════════════════
// SLIDE 15 — KEY CLINICAL PEARLS (SUMMARY)
// ═══════════════════════════════════════════════════════════════
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    { n: "2", text: "Prevention >> Treatment — DCCT: 64% risk reduction with intensive insulin in T1DM; established DSPN damage is largely irreversible", color: C.teal },
    { n: "3", text: "T1DM vs. T2DM glycemic evidence differs — DCCT robust for T1DM; ACCORD showed mortality signal targeting HbA1c <6% in T2DM", color: C.tealLight },
    { n: "4", text: "Metformin depletes B12 — check levels regularly in all T2DM patients on metformin; supplement if deficient", color: C.amber },
    { n: "5", text: "Four equivalent first-line drug classes (ADA 2026): SNRIs, Gabapentinoids, TCAs, Sodium Channel Blockers — individualize by comorbidities", color: C.teal },
    { n: "6", text: "Opioids NOT recommended (AAN 2025 + ADA 2026) — modest efficacy, significant addiction risk; combination non-opioid therapy preferred", color: C.red },
    { n: "7", text: "Autonomic neuropathy + serious CV risk — CAN associated with LV dysfunction and ↑ mortality (DCCT/EDIC data)", color: "#7C65C0" },
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    { n: "9", text: "CN III palsy in diabetics is pupil-SPARING (ischemic core); pupil involvement → urgent imaging to rule out aneurysm", color: "#5B8DD9" },
    { n: "10", text: "Annual 10-g monofilament test is the most important clinical tool for identifying feet at risk for ulceration and amputation", color: C.teal },
    { n: "11", text: "Diabetic amyotrophy has an inflammatory component — consider glucocorticoids; do not confuse with proximal myopathy", color: C.amber },
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// ═══════════════════════════════════════════════════════════════
// SLIDE 16 — REFERENCES
// ═══════════════════════════════════════════════════════════════
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  const refs = [
    "1. Harrison's Principles of Internal Medicine, 22nd Ed. (2025, McGraw-Hill) — Chapters 405, 457",
    "2. Adams and Victor's Principles of Neurology, 12th Ed. — Chapter on Diabetic Neuropathy (pp. 2363-2432)",
    "3. Bradley and Daroff's Neurology in Clinical Practice — Pathogenesis of Diabetic Neuropathy (p. 2689)",
    "4. Robbins & Kumar Basic Pathology — Diabetic Peripheral Neuropathy (pp. 459-467)",
    "5. Washington Manual of Medical Therapeutics — Diabetic Neuropathy (p. 906)",
    "6. Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Ed. — Diabetic Painful Neuropathy (p. 4764)",
    "7. Goldman-Cecil Medicine, International Ed. — Diabetic Neuropathy",
    "8. American Diabetes Association. Standards of Care in Diabetes—2026. Section 12: Retinopathy, Neuropathy, and Foot Care.",
    "   Diabetes Care. 2026;49(Suppl 1):S261-S276. DOI: 10.2337/dc26-S012. PMID: 41358886",
    "9. AAN Practice Guideline: Oral and Topical Treatment of Painful Diabetic Polyneuropathy.",
    "   Neurology. 2022;98(1):31-43. DOI: 10.1212/WNL.0000000000013038. Reaffirmed February 2025.",
    "10. Yang Y, et al. Diabetic neuropathy: cutting-edge research and future directions.",
    "    Signal Transduct Target Ther. 2025;Apr 25. PMID: 40274830. DOI: 10.1038/s41392-025-02175-1",
    "11. Dillon BR, Ang L, Pop-Busui R. Spectrum of Diabetic Neuropathy: New Insights in Diagnosis and Treatment.",
    "    Annu Rev Med. 2024;Jan 29. PMID: 38285516.",
    "12. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications.",
    "    N Engl J Med. 1993;329:977-986.",
  ];

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// ─── Write file ──────────────────────────────────────────────────
pres.writeFile({ fileName: "/home/daytona/workspace/diabetic-neuropathy-ppt/Diabetic_Neuropathy_Deep_Dive.pptx" })
  .then(() => console.log("SUCCESS: PPTX written"))
  .catch(e => { console.error("ERROR:", e); process.exit(1); });

Running Command

cd /home/daytona/workspace/diabetic-neuropathy-ppt && node build.js 2>&1

Running Command

node -e "const p = require('pptxgenjs'); const pr = new p(); console.log(Object.keys(pr.shapes).join('\n'));" 2>&1 | head -40

Running Command

node -e "const p = require('pptxgenjs'); const pr = new p(); console.log(Object.keys(pr.shapes).join('\n'));" 2>&1 | grep -i "oval\|ellipse\|circle"

Running Command

sed -i 's/pres\.shapes\.ELLIPSE/pres.shapes.OVAL/g' /home/daytona/workspace/diabetic-neuropathy-ppt/build.js && echo "Fixed"

Running Command

grep -n "ELLIPSE" /home/daytona/workspace/diabetic-neuropathy-ppt/build.js

Editing File

~/diabetic-neuropathy-ppt/build.js

Error: String not found in file: 'pres.shapes.ELLIPSE, {
    x: bx + 0.12, y: by + 0.28, w: 0.38, h: 0.38,
    fill: { color: t.color }, line: { color: t.color }
  });'

Reading File

Running Command

python3 -c " content = open('/home/daytona/workspace/diabetic-neuropathy-ppt/build.js').read() content = content.replace('pres.shapes.ELLIPSE', 'pres.shapes.OVAL') open('/home/daytona/workspace/diabetic-neuropathy-ppt/build.js', 'w').write(content) print('Done, replacements:', content.count('pres.shapes.OVAL')) "

Running Command

cd /home/daytona/workspace/diabetic-neuropathy-ppt && node build.js 2>&1

Running Command

ls -lh /home/daytona/workspace/diabetic-neuropathy-ppt/Diabetic_Neuropathy_Deep_Dive.pptx

Your presentation is ready!

Diabetic Neuropathy Deep Dive

Presentation · PPTX

494 KB — 16 slides with a deep navy + teal + amber color scheme.

Here's what's inside:

Slide	Content
1	Title slide with key stats (50% prevalence, 75% amputations)
2	Overview & Epidemiology — risk factors, key numbers
3	Classification — all 6 types in card layout
4	Pathogenesis — Metabolic (Polyol, AGEs, PKC, Oxidative Stress)
5	Pathogenesis — Microvascular/Ischemic + Nerve Biopsy Findings + Inflammation
6	Clinical Features DSPN — stocking-glove visual, small vs. large fiber columns
7	Autonomic Neuropathy — 4 system cards (CV, GI, GU, Sudomotor)
8	Focal Syndromes — Amyotrophy/Bruns-Garland + Cranial + Limb Mononeuropathies
9	Diagnosis & Screening — ADA 2026 Rec. 12.17-12.19 + diagnostic exclusion list
10	Disease-Modifying Treatment — DCCT/ACCORD/ADVANCE trials + adjunctive therapies
11	Pharmacotherapy for Painful DSPN — all 4 drug class cards with doses/mechanism/side effects
12	Adjunctive Therapies + 5-Step Treatment Algorithm
13	Autonomic Neuropathy Treatment — 6 system treatment cards
14	Foot Care + Emerging Therapies (CCM, GLP-1 RAs, gene/stem cell therapy)
15	12 Key Clinical Pearls
16	Full References

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