Clinical Analysis: Ramilaben Valera, 57F - Bilateral Burning Sensation in Soles (6 months)

Lab Report Summary & Interpretation

Most Likely Causes of Bilateral Burning Soles

1. Prediabetes-Associated Small Fiber Neuropathy (Most Likely)

• HbA1c 5.78% places her in the prediabetes zone. Even at prediabetes stage, small unmyelinated C-fibers (that carry pain and temperature) are damaged by oxidative stress and advanced glycation end-products (AGEs)
• Burning dysesthesia restricted to soles with a 6-month duration is the classic presentation of length-dependent small fiber neuropathy
• Standard NCS/EMG may be normal because it tests large myelinated fibers; small fiber disease requires specific testing (see below)
• This is the most clinically significant and actionable finding

2. Vitamin D Insufficiency (Contributing cause)

• 25-OH Vitamin D = 25.3 ng/mL (borderline insufficient, just below the 30 ng/mL normal cut-off)
• Vitamin D receptors are present on Schwann cells and peripheral neurons. Insufficiency causes neuroinflammation, reduced nerve growth factor, and may independently produce burning neuropathy
• Several studies link low Vitamin D to both peripheral neuropathy symptoms and their worsening

3. Metabolic Syndrome with Dyslipidemia-Associated Neuropathy

• She has the full metabolic syndrome triad: borderline prediabetes, hypertension, atherogenic dyslipidemia (high LDL 144, low HDL 36, elevated Chol/HDL 6.01, near-high TG)
• Dyslipidemia itself (especially low HDL and high TG) is an independent risk factor for peripheral neuropathy through microvascular endoneural ischemia
• The atherogenic lipid profile is concerning for early microvascular damage to the vasa nervorum

4. Hypertensive Microvascular Neuropathy (Contributing)

• Long-standing hypertension with KCO (known case of) causes endothelial dysfunction and microvascular ischemia in the vasa nervorum
• Telmisartan (ARB) and Benidipine (CCB) are appropriate antihypertensives and do not cause neuropathy - so medication toxicity is not a factor here

5. Vitamin B12 - Borderline Interpretation

• B12 = 351.2 pg/mL is within range, but functional B12 deficiency can occur at values <400 pg/mL in elderly/menopausal women, especially with poor absorption
• At this age (57F, likely perimenopausal), dietary pattern and gastric acid adequacy should be assessed
• Not a primary cause here but should not be excluded without serum homocysteine and MMA (methylmalonic acid) levels

6. Hypothyroidism (Must exclude - not tested)

• Thyroid function has NOT been tested in this report
• Hypothyroidism causes a painful small fiber neuropathy with burning dysesthesia and is very common in women this age group
• This is a critical gap in the existing workup

Next Line of Investigations

Tier 1 - Immediate (High Priority)

Tier 2 - Confirmatory/Specialty

Tier 3 - If above are normal

Management Approach (Alongside Investigations)

1. Vitamin D replacement: 60,000 IU/week cholecalciferol for 8 weeks, then monthly maintenance (target >50 ng/mL)
2. Statin therapy: Strongly indicated - LDL 144 + atherogenic dyslipidemia + hypertension + prediabetes = high cardiovascular risk. Rosuvastatin 10-20 mg or Atorvastatin 20-40 mg
3. Lifestyle modification: Mediterranean-style diet, aerobic exercise 150 min/week; targets both prediabetes reversion and dyslipidemia
4. HbA1c monitoring: Recheck in 3 months; if persistent prediabetes or progression to diabetes, initiate Metformin (which also has some neuroprotective effects)
5. Symptomatic neuropathy relief: While investigations are ongoing - Pregabalin 75 mg BD or Duloxetine 30-60 mg OD can be used for symptomatic burning relief; add Mecobalamin 500 mcg TID
6. ANA result follow-up: If positive, rheumatology referral for full autoimmune workup

Summary Flowchart

Bilateral burning soles (6 months) + 57F + HTN + Prediabetes (HbA1c 5.78%)
    ↓
Confirmed findings: Prediabetes | Dyslipidemia | Vit D insufficiency | Borderline PCV
    ↓
NOT yet tested: Thyroid (TSH) | NCS/EMG | Homocysteine | PPBS/OGTT | MMA | ANA (pending)
    ↓
Most likely: Small fiber neuropathy from metabolic syndrome (prediabetes + dyslipidemia + HTN + Vit D insufficiency)
    ↓
Next urgent step: TSH + NCS/EMG + Fasting insulin + PPBS + Homocysteine

• Harrison's Principles of Internal Medicine 22E, Chapter 457 (Peripheral Neuropathy), p. 3638

Viral Encephalitis - Treatment

Rapid Overview: Specific Antiviral Therapy by Causative Virus

1. HSV Encephalitis (Most Treatable & Most Common Cause)

Diagnosis Before Starting Treatment

• CSF PCR for HSV - gold standard; positive 24 hrs after symptom onset, up to 7 days after starting antivirals
• CSF shows: elevated WBC (lymphocyte predominance), elevated protein, normal or low glucose, elevated RBCs (reflects temporal lobe hemorrhage)
• MRI (T2/FLAIR): temporal lobe hyperintensity/enhancement - may be negative early
• Do NOT wait for PCR to start treatment - begin empirically if clinical suspicion is high
• If initial PCR is negative but suspicion remains high: continue empirical acyclovir and repeat CSF PCR at 72 hours

Treatment Regimen

• IV Acyclovir 10 mg/kg every 8 hours for 21 days (minimum - some guidelines recommend up to 21 days)
• Mechanism: acyclovir is phosphorylated by HSV thymidine kinase (TK) → inhibits viral DNA polymerase → chain termination
• Highly selective - only activated in HSV-infected cells
• Hydrate well before each dose to prevent renal crystalluria (acyclovir is nephrotoxic at high IV doses)

Acyclovir-Resistant HSV Encephalitis

• Seen in immunocompromised patients (HIV, transplant recipients)
• Treat with IV Foscarnet 40 mg/kg q8h (does not require TK activation)
• Alternatively: Pritelivir (helicase-primase inhibitor) 400 mg loading dose, then 100 mg OD for 21-28 days

Role of Corticosteroids in HSV Encephalitis

• Adjunctive dexamethasone has been studied - the 2025 Matthews et al. review (PMID 40466008, Curr Opin Neurol 2025) found that dexamethasone in HSV encephalitis is not associated with worse outcome or CSF viral persistence, but may not significantly improve overall outcome either. Not yet standard of care; may be considered for severe cerebral edema.

2. VZV Encephalitis

• Occurs in elderly, immunocompromised, or post-primary varicella
• IV Acyclovir 10-15 mg/kg q8h for 14-21 days
• Oral valacyclovir (1 g TID) may follow IV course in milder cases

3. CMV Encephalitis (Immunocompromised)

• Seen almost exclusively in HIV/AIDS (CD4 <50) or post-transplant patients
• IV Ganciclovir 5 mg/kg q12h (induction 14-21 days) - inhibits CMV DNA polymerase
• If resistant or severe: Foscarnet 60 mg/kg q8h or combination ganciclovir + foscarnet
• Long-term suppression with oral valganciclovir in AIDS patients

4. Arboviral Encephalitis (WNV, JEV, Dengue, Nipah, Chikungunya)

• No proven specific antiviral treatment for most arbovirals
• West Nile Virus (WNV) encephalitis: diagnosed by CSF IgM antibody (PCR less sensitive); treatment is entirely supportive
• Japanese Encephalitis: supportive; JEV vaccine is preventive (not therapeutic)
• Dengue, Nipah: no proven antiviral; supportive management
• Treatment focuses on preventing secondary brain injury (see supportive care below)

5. Empirical (Presumptive) Treatment Approach

Start IMMEDIATELY (before results):
  → IV Acyclovir 10 mg/kg q8h (covers HSV/VZV)
  → IV Ceftriaxone 2 g q12h (covers bacterial meningitis/encephalitis)
  → IV Dexamethasone 0.15 mg/kg q6h (if bacterial meningitis suspected)
  → Consider IV Ampicillin 2 g q4h if Listeria suspected (age >50, immunosuppressed)

De-escalate once:
  → CSF PCR negative AND other diagnosis confirmed
  → Do NOT stop acyclovir on a single negative PCR if clinical suspicion remains high

6. Supportive Care & Management of Complications

Airway & Breathing

• GCS ≤8 or loss of airway protective reflexes → elective intubation and ICU admission
• Maintain SpO2 >95%, avoid hypercapnia (raises ICP)

Seizure Management

• Seizures occur in 40-60% of HSV encephalitis
• IV Levetiracetam (drug of choice - no enzyme induction, no hepatic metabolism): 500-1000 mg q12h
• Alternatives: IV Valproate, IV Lacosamide
• Prophylactic anti-epileptics may be considered in high-risk cases (cortical involvement on MRI)
• Status epilepticus: IV Lorazepam → IV Phenytoin/Levetiracetam → IV Phenobarbital → ICU propofol/midazolam infusion

Raised Intracranial Pressure (ICP)

• Head-of-bed elevation 30°
• Avoid hyperthermia (fever worsens cerebral edema)
• IV Mannitol 0.25-0.5 g/kg q4-6h (osmotic therapy) or 3% hypertonic saline
• Controlled ventilation to target PaCO2 35-40 mmHg (avoid aggressive hyperventilation except as bridge)
• ICP monitoring in severe cases

Fever Control

• Aggressive antipyretics (Paracetamol IV/oral)
• Cooling blankets if needed
• Hyperthermia worsens neuronal injury in encephalitis

Fluid & Electrolyte Management

• Watch for SIADH (common in encephalitis) - may cause severe hyponatraemia
• Fluid restriction ± hypertonic saline for SIADH-associated hyponatraemia

Nutrition

• Early enteral nutrition via nasogastric tube in intubated/unconscious patients
• Avoid hypoglycaemia and hyperglycaemia (both worsen brain injury)

7. Prevention (Where Applicable)

Key Points for Clinical Practice

1. Start acyclovir empirically in all suspected encephalitis - the cost of missing HSV encephalitis vastly outweighs treating unnecessarily
2. Duration matters - HSV encephalitis requires a full 21-day course of IV acyclovir; shorter courses are associated with relapse
3. A negative early MRI does not exclude HSV encephalitis - repeat imaging at 48-72 hours
4. Negative CSF PCR does not exclude HSV if the patient is seen very early (within 12-24 hours of onset) - repeat PCR if clinical suspicion persists
5. Most arboviral and enteroviral encephalitides have no specific therapy - focus entirely on supportive care and complication prevention
6. Adjunctive dexamethasone in viral encephalitis remains investigational - current 2025 evidence suggests it does not worsen outcome but does not clearly improve it either

• Harrison's Principles of Internal Medicine 22E (2025), Chapter on Herpes Simplex Virus Infections, pp. 1545-1547
• Rosen's Emergency Medicine, 10th Ed., Chapters 119 & Arboviral Infections section
• Lippincott Illustrated Reviews Pharmacology - Acyclovir, p. 889
• Matthews R et al., "Viral encephalitis - update on pathogenesis and treatment," Curr Opin Neurol 2025 [PMID: 40466008]