Clinical Summary (Key Features)

• 62M, no comorbidities
• New-onset GTCS x3, refractory, now intubated
• MRI: bilateral caudate hyperintensities + left insular T2/FLAIR signal
• EEG: left temporal slowing, epileptiform discharges phase-reversing at T5
• CSF: protein 131, cells 2 (lymphocytes), glucose normal, MTB negative, HSV PCR pending
• Behavioral change (aggression, low mood ~1 week)
• Ammonia 161 µmol/L (elevated)
• LFT normal (as stated)

Differential Diagnosis

1. Autoimmune Encephalitis (Top differential)

• Best explains: subacute behavioral change, refractory seizures, caudate + insular MRI signal, CSF lymphocytic pleocytosis with elevated protein, no infection markers
• Caudate involvement is characteristic of anti-NMDAR or anti-CASPR2 encephalitis
• Insular involvement also seen in LGI1 encephalitis (which also causes faciobrachial dystonic seizures and hyponatremia - though Na was normal here)
• Panel sent - await results
• Age 62M: also consider paraneoplastic encephalitis (anti-Hu, anti-Ma2) - needs tumor workup (CT chest/abdomen/pelvis, PET if needed)

2. HSV Encephalitis (Must not miss)

• HSV PCR pending - critical result
• Classically involves temporal lobes; left temporal EEG changes fit
• However, caudate involvement is less typical for HSV
• Insular involvement can occur
• Empirical acyclovir should already be running - if not, start immediately

3. Hyperammonemic Encephalopathy

• Ammonia 161 is significantly elevated (normal <50 µmol/L)
• LFT reportedly normal - raises question of:
  • Valproate-induced hyperammonemia (he was given valproate! - this is a well-known cause of elevated ammonia without LFT abnormality)
  • Occult liver disease not reflected yet in LFT
  • Urea cycle disorder (rare in adults, but late-onset can occur)
  • Urease-producing UTI (less likely without pyuria)
• Valproate-induced hyperammonemic encephalopathy (VHE) can worsen seizure control paradoxically and cause encephalopathy - this is clinically very relevant here

4. Prion Disease (CJD)

• Bilateral caudate hyperintensities on DWI/FLAIR is a classic CJD pattern (pulvinar sign, caudate/putamen involvement)
• Rapidly progressive dementia + psychiatric features + seizures + EEG changes fit
• CSF 14-3-3 protein, RT-QuIC should be sent if not done
• Rapidly progressive course supports this

5. Viral Encephalitis (non-HSV)

• EBV, CMV, HHV-6, enterovirus, arboviral (JE in appropriate epidemiological context)
• CSF lymphocytosis with elevated protein fits
• Less characteristic MRI pattern

6. Metabolic/Toxic Encephalopathy

• The elevated ammonia now makes this a standalone consideration
• However, the focal MRI changes and epileptiform discharges make a purely metabolic cause insufficient to explain the whole picture

Immediate Action Points

Most Likely Diagnosis

Valproate-Induced Hyperammonemic Encephalopathy (VHE) - Evidence Summary

Mechanism (Well-Established)

1. Urea cycle disruption: VPA inhibits carbamoyl phosphate synthetase I (CPS-I), the first enzyme in the hepatic urea cycle, directly blocking ammonia conversion to urea. It also inhibits N-acetylglutamate synthase, a cofactor required for CPS-I activation.
2. Carnitine depletion: VPA binds to carnitine, depleting free L-carnitine. This impairs mitochondrial beta-oxidation of fatty acids, generating toxic VPA metabolites (particularly 4-en-VPA) that further inhibit the urea cycle.

The paradox in your patient: VPA was given to treat seizures but may now be worsening encephalopathy and paradoxically lowering the seizure threshold - VHE itself can cause EEG slowing and new-onset or breakthrough seizures.

Clinical Features That Fit Your Patient

Risk Factors Present in Your Patient

• Valproate administered acutely for breakthrough seizures (rapid loading)
• Possible concurrent levetiracetam and lacosamide (polypharmacy)
• ICU state with catabolism
• Note: Topiramate co-use is a major risk factor - verify this is NOT being used

Treatment of VHE - Evidence-Based Steps

1. Stop Valproate (Most effective intervention)

• Resolution typically within 24-72 hours of discontinuation
• In your patient: switch to levetiracetam (already on) + lacosamide (already on) for seizure control - both are ammonia-neutral

2. L-Levocarnitine (Second-line, well-supported)

• Restores mitochondrial function, directly counteracts the carnitine-depletion mechanism
• Dose: 100 mg/kg/day IV (up to 3g/day) in acute severe VHE
• Success rate ~50% in published case series (Rigamonti et al., J Clin Neurosci 2014 - PMID 24119342)
• Recommended for ICU patients - safe, well-tolerated

3. Lactulose (Supportive)

• Traps ammonia as NH4+ in the gut lumen, promotes fecal excretion
• 15-30 mL TDS titrated to 2-3 soft stools/day
• Success rate ~42% as monotherapy
• Can be given via NG tube in intubated patients

4. Rifaximin (Alternative if lactulose insufficient)

• Non-absorbed antibiotic reducing urease-producing gut flora
• Less evidence in VHE specifically vs. hepatic encephalopathy

5. CRRT/Hemodialysis (Severe refractory cases)

• Ammonia is dialyzable
• Reserved for ammonia >200 µmol/L with refractory coma or rapidly rising levels
• Your patient at 161 is approaching this threshold - monitor closely

Seizure Management in Autoimmune Encephalitis (Parallel Issue)

• ASMs alone are insufficient - seizures in autoimmune encephalitis are driven by antibody-mediated neuronal hyperexcitability, so immunotherapy is the definitive treatment
• Levetiracetam and lacosamide are preferred (as you have already done) - both are sodium channel or SV2A-targeted with no interaction with ammonia metabolism
• Avoid valproate in this context (now doubly confirmed given the hyperammonemia)
• Avoid carbamazepine/phenytoin in LGI1 encephalitis (may worsen)
• For status epilepticus in autoimmune encephalitis: benzodiazepines + levetiracetam + lacosamide is the standard triple regimen

• Immunotherapy (IV methylprednisolone + IVIG) should be started empirically even before antibody results return, given the clinical picture
• Early immunotherapy reduces seizure burden and improves outcomes

Immediate Management Recommendations for Your Patient

1. STOP VALPROATE NOW
   → Switch to clobazam 10mg BD via NG or clonazepam IV for bridging

2. START L-LEVOCARNITINE 100 mg/kg/day IV (divided q6-8h)

3. LACTULOSE via NG tube - 30 mL q8h, titrate to stool output

4. Recheck ammonia in 12-24 hours

5. EMPIRIC ACYCLOVIR 10 mg/kg IV q8h - if not already running

6. START EMPIRIC IMMUNOTHERAPY:
   → IV Methylprednisolone 1g/day x 5 days
   → OR IVIG 0.4 g/kg/day x 5 days
   (Do NOT wait for antibody results in deteriorating patient)

7. Send: CSF 14-3-3, RT-QuIC, serum + CSF autoimmune panel
        CT Chest/Abdomen/Pelvis for paraneoplastic workup

8. If ammonia >200 or no improvement in 24h → Nephrology for CRRT

MRI Brain Report - Critical Analysis (14-08-2026)

What the MRI Shows

Finding 1 - The Most Important:

Multiple discrete & confluent DWI restriction with low ADC values in: bilateral medial temporo-parieto-occipital lobes, bilateral thalamus, splenium of corpus callosum, midbrain and pons

Finding 2:

Diffuse effacement of bilateral cerebral sulci with mild cortical swelling, mildly dilated lateral ventricles (13mm) - cerebral edema

Finding 3:

T2/FLAIR hyperintensities in bilateral external capsules - no DWI restriction - post-ictal changes / small vessel disease / metabolic

This MRI Pattern Does NOT Fit Simple PCA Strokes

The DWI + Clinical Mismatch:

Revised Differential - MRI Integrated

🥇 1. Prion Disease (CJD) - NOW TOP DIFFERENTIAL

• Bilateral thalamic DWI restriction (pulvinar sign / "hockey stick" sign in variant CJD)
• Cortical ribboning on DWI in bilateral parieto-occipital regions
• Splenium of corpus callosum involvement
• Basal ganglia (caudate/thalamus) involvement
• Rapidly progressive course: behavioral change → seizures → coma within days-weeks
• Age 56-62M fits sporadic CJD peak incidence

This is NOT a stroke pattern. The radiologist may have reported it as PCA infarcts because the DWI restriction is real, but the distribution and clinical context scream CJD.

🥈 2. Autoimmune Encephalitis (still high on list)

• NMDAR/LGI1/CASPR2 can cause DWI changes
• Thalamic involvement seen in anti-GABA-B encephalitis
• Behavioral prodrome fits
• CSF changes fit
• Awaiting antibody panel

🥉 3. Top-of-Basilar / Bilateral PCA Infarction

• Cannot be excluded entirely
• Would require urgent CT angiography or MR angiography
• Look for basilar artery occlusion / cardiac source
• However: seizure as the presenting feature is very atypical for bilateral PCA stroke

4. Hyperammonemic Encephalopathy with Metabolic DWI Changes

• Severe hyperammonemia (>150 µmol/L) can cause DWI restriction, particularly in the splenium of corpus callosum and cortex (cytotoxic edema)
• External capsule involvement is also described in metabolic encephalopathy
• Splenium DWI restriction is a well-known reversible finding in metabolic/toxic encephalopathy (RESLES - Reversible Splenial Lesion Syndrome)
• However: ammonia at 161 with this extent of involvement seems disproportionate unless VPA has only recently been given

5. PRES (Posterior Reversible Encephalopathy Syndrome)

• Posterior predominant T2/FLAIR - fits
• But: no hypertension, no immunosuppression described
• DWI restriction argues against PRES (which is typically vasogenic edema with facilitated diffusion)

6. HSV Encephalitis

• Temporal lobe involvement fits EEG findings
• Thalamic involvement can occur in HSV
• But HSV typically does NOT cause bilateral symmetric distribution
• PCR still pending - must continue acyclovir

Urgent Investigations to Add NOW

Bottom Line

• Rapid progression (days to coma)
• Behavioral/psychiatric prodrome
• Seizures
• Bilateral thalamic + cortical + splenial DWI restriction
• Elevated CSF protein
• Age and sex

Bilateral PCA Territory Infarcts - Working Diagnosis

What Territory Is Involved

• Bilateral medial temporo-parieto-occipital lobes
• Bilateral thalamus
• Splenium of corpus callosum
• Midbrain and pons

Etiology Workup - What's Causing Bilateral PCA Infarcts?

Most Likely Mechanisms

How This Reframes the Clinical Picture

Seizure Management in the Context of Acute Stroke

• Levetiracetam - correct first-line choice, no interactions, renal-dosed
• Lacosamide - appropriate add-on
• Valproate - now stop given hyperammonemia (161) - not ideal here anyway
• Seizures in posterior circulation strokes can be difficult to control acutely; this is not necessarily treatment failure

Immediate Priorities

1. CT Angiography head & neck (posterior circulation) - URGENT
   → Look for basilar artery stenosis/occlusion, vertebral artery disease/dissection

2. ECG + continuous cardiac monitoring - look for AF (paroxysmal)

3. Echocardiogram (TTE, then TEE if TTE unremarkable)
   → Look for thrombus, PFO, valvular disease, wall motion abnormality

4. STOP VALPROATE → treat hyperammonemia (levocarnitine + lactulose)

5. Anticoagulation decision:
   → If cardioembolic source found: anticoagulation after hemorrhagic transformation
     risk assessment (usually 2-4 weeks after large infarct)
   → If basilar stenosis: antiplatelet therapy + statin

6. Aspirin 150mg via NG for now (if no hemorrhagic transformation on MRI)

7. Keep HSV acyclovir running until PCR returns negative
   (CSF protein 131 + lymphocytes still need infectious cause excluded)

8. Continue awaiting autoimmune encephalitis panel
   (bilateral PCA infarcts + seizures + behavioral change - autoimmune
   vasculitis/CNS vasculitis can also cause this picture)

9. Neurovascular / Interventional Neurology consult
   → If basilar occlusion identified, thrombectomy window assessment

One Additional Thought

Document Structure (8 sections, 16 tables)

This Changes Everything - New Synthesis

What the Timeline Now Tells Us

What the DWI Images Actually Show

• Massive, confluent, highly symmetric bilateral restricted diffusion
• Bilateral occipital lobes (cortical ribbon + subcortical)
• Bilateral thalami
• Splenium of corpus callosum
• Midbrain and pons

The Key Question: Are These True Ischaemic Infarcts or Something Else?

Revised Top Differentials

🥇 1. Prolonged/Repeated Seizure-Related Changes (Post-ictal / Peri-ictal DWI Changes)

• Well-documented phenomenon: status epilepticus and repeated GTCS cause cytotoxic edema with DWI restriction in the regions of maximal ictal activity
• Distribution: posterior > anterior (occipital + parietal), thalamic involvement from seizure propagation via thalamocortical circuits
• Splenium DWI restriction is a classic marker of seizure-related changes (RESLES)
• These changes are potentially reversible on follow-up MRI
• The bilateral symmetry and posterior predominance fits seizure propagation via the posterior thalamocortical network

🥈 2. Autoimmune Encephalitis with Seizure-Induced DWI Changes

• Initial MRI: caudate + insular signal = autoimmune encephalitis (NMDAR, CASPR2, anti-GABA-B all affect these regions)
• Repeated seizures from autoimmune encephalitis → secondary cytotoxic edema on DWI
• This is the most unifying diagnosis:
  • Explains the prodrome (behavioral, mood)
  • Explains initial MRI pattern (caudate, insula)
  • Explains refractory seizures
  • Explains CSF findings (elevated protein, mild pleocytosis)
  • Explains evolution to massive DWI changes after seizures
  • Antibody panel pending

🥉 3. PRES (Posterior Reversible Encephalopathy Syndrome)

• Bilateral posterior DWI changes, occipital predominance
• Usually vasogenic edema (ADC elevated) - but cytotoxic PRES with DWI restriction is recognized
• No hypertension documented, but seizures themselves + ICU stress can trigger PRES
• Valproate-associated PRES has been reported

4. True Bilateral PCA Infarcts Secondary to Hemodynamic Compromise

• Repeated seizures + post-ictal state + possible hypoxia during seizures
• Can cause watershed/posterior circulation ischemia
• Less likely given the massive symmetric extent

5. Hyperammonemic Encephalopathy

• Ammonia 161 + valproate → can cause DWI restriction in splenium and cortex
• The splenial component likely has a metabolic contribution
• But does not fully explain the massive bilateral occipital pattern

What This Means Practically

The Infarct vs. Seizure-Related DWI Change Distinction Matters Enormously:

Immediate Recommendations

1. DO NOT commit to antiplatelet/anticoagulation yet
   → The DWI changes may be seizure-related and reversible

2. START EMPIRIC IMMUNOTHERAPY NOW - cannot wait
   → IV Methylprednisolone 1g/day x 5 days
   → IVIG 0.4 g/kg/day x 5 days (in parallel or sequential)
   → This is the most treatable cause and time-critical

3. Control seizures aggressively
   → Continuous EEG monitoring
   → If ongoing electrographic seizures: add midazolam infusion
   → Stop valproate (hyperammonemia)

4. Get MR Spectroscopy / repeat MRI in 5-7 days
   → Reversibility of DWI changes confirms seizure-related etiology

5. Vascular workup still needed (CTA) to exclude co-existing pathology
   but should NOT delay immunotherapy

6. URGENTLY chase: HSV PCR, autoimmune panel

Bottom Line

Fever in This Patient - Structured Analysis

Context Recap

• Intubated, ICU, low GCS
• Refractory seizures x3
• Autoimmune encephalitis vs HSV encephalitis (results pending)
• Elevated CSF protein 131, mild lymphocytosis
• Ammonia 161 (valproate-induced)
• Bilateral DWI changes post-seizure
• Now: new fever from this morning

Fever Sources - Prioritised

🔴 MUST EXCLUDE FIRST (Life-threatening, time-sensitive)

1. HSV Encephalitis

• Fever + encephalitis + temporal lobe EEG changes = HSV until proven otherwise
• HSV PCR still pending - this fever makes it more urgent
• If acyclovir is NOT running → start immediately
• If acyclovir IS running → confirm adequate dosing (10 mg/kg IV q8h, renal-adjusted)
• Do NOT stop acyclovir until PCR is confirmed negative

2. Bacterial Meningitis / Meningoencephalitis

• CSF was: 2 WBC, normal glucose, protein 131
• 2 WBC is low for bacterial meningitis BUT:
  • LP may have been done early before pleocytosis developed
  • Immunocompromised state (ICU, intubated)
  • Consider repeat LP if fever persists and no source found
• Cover empirically: Ceftriaxone 2g IV q12h + Vancomycin if not already on antibiotics

3. Ventilator-Associated Pneumonia (VAP)

• Most common cause of new fever in intubated ICU patients (>48h intubation)
• Check: new infiltrate on CXR, increased secretions, purulent sputum, worsening oxygenation
• Send: tracheal aspirate culture, sputum gram stain, blood cultures x2

4. Sepsis from another source

• Catheter-related bloodstream infection (CRBSI) - check all IV line sites
• UTI (Foley catheter in place)
• Send: Urine culture, blood cultures x2, CRP, Procalcitonin, lactate

🟡 DISEASE-RELATED FEVER (Part of the primary pathology)

5. Central / Neurogenic Fever

• Thalamic + hypothalamic involvement on MRI can disrupt thermoregulation
• Diagnosis of exclusion - only after infectious causes excluded
• Pattern: high-grade, resistant to antipyretics, no diaphoresis

6. Autoimmune Encephalitis Fever

• Some autoimmune encephalitides (especially anti-NMDAR) cause fever as part of the syndrome
• Autonomic instability is a hallmark of NMDAR encephalitis
• However, always exclude infection before attributing fever to autoimmune cause

7. Drug Fever

• Levetiracetam, lacosamide, acyclovir - all can occasionally cause fever
• Less likely acutely but keep in mind

🟢 ICU-RELATED CAUSES

8. Aspiration Pneumonitis / Pneumonia

• Patient had repeated seizures before intubation = high risk for aspiration
• Consolidation in dependent lobes
• CXR + CT chest if CXR equivocal

9. DVT / Pulmonary Embolism

• Immobile, ICU patient
• Fever + tachycardia in this setting
• D-dimer, lower limb Doppler

10. Drug reactions / transfusion reaction

• Review any recent blood products or new medications

Immediate Workup

SEND NOW:
□ Blood cultures x2 (peripheral + central line if in-situ)
□ Urine culture (catheter specimen)
□ Tracheal aspirate culture + gram stain
□ CXR (portable, bedside)
□ CBC with differential
□ CRP + Procalcitonin + Lactate
□ LFTs (drug-related hepatitis?)
□ Repeat blood ammonia

REVIEW:
□ Confirm acyclovir 10 mg/kg q8h IV is running
□ All IV line sites for infection
□ Foley catheter - when inserted, any signs of UTI
□ Temperature trend - when exactly did fever start, how high?

CONSIDER:
□ CT Chest (if CXR equivocal - exclude VAP/aspiration)
□ Repeat LP - if fever persists >24h with no peripheral source
  → Repeat CSF: WBC, glucose, protein, gram stain, culture
  → Will also allow sending 14-3-3 and RT-QuIC if not yet done

Antibiotic Strategy

Most Likely Cause in This Patient

1. HSV Encephalitis - fever + encephalitis + temporal EEG findings + pending PCR = do not wait, ensure acyclovir is running at full dose
2. VAP / Aspiration pneumonia - intubated after repeated seizures with likely aspiration events

The Core Dilemma

The Decision Framework

🔴 ABSOLUTE HOLD - One situation only:

✅ YES - Give Steroids IF:

CONDITION 1: Acyclovir running at full dose (10 mg/kg q8h)
             → HSV is covered empirically

CONDITION 2: Broad-spectrum antibiotics started
             → Ceftriaxone 2g q12h (covers bacterial meningitis)
             → Add Vancomycin if MRSA risk / gram positive concern

CONDITION 3: Blood cultures, tracheal aspirate, urine culture SENT
             → Source identified, culture-guided therapy can follow

THEN: Start IV Methylprednisolone 1g/day

Practical "Treat and Cover" Protocol for This Patient

Step 1 - Infections Covered (start simultaneously):

Step 2 - Then Start Immunotherapy:

Step 3 - Decision Gates:

HSV PCR RETURNS POSITIVE?
  → STOP steroids immediately
  → Continue acyclovir 14-21 days
  → Reassess after viral clearance

HSV PCR RETURNS NEGATIVE?
  → Continue steroids full course
  → If autoimmune panel positive → complete immunotherapy
  → If autoimmune panel negative but clinical response → continue anyway

No improvement after steroids + IVIG (10-14 days)?
  → Second-line: Rituximab or Cyclophosphamide

Why You Should NOT Wait

• Every 24-48 hours of delay in immunotherapy = more neuronal injury
• Antibody-mediated receptor internalization causes structural changes that become harder to reverse the longer treatment is delayed
• Multiple studies show outcome is directly correlated with time to immunotherapy initiation
• The fever itself, if neurogenic or autoimmune in origin, will not resolve until immunotherapy starts

One Important Caveat - Steroids and Ammonia

• Increase protein catabolism → raise ammonia further
• Worsen hyperglycemia

• Continue levocarnitine + lactulose
• Recheck ammonia daily
• Strict glycemic control (target 6-10 mmol/L)
• If ammonia spikes >200 → nephrology for CRRT

Bottom Line

🔑 RESULTS ARE IN - This is the Turning Point

Result 1: HSV PCR CSF

✅ HSV Type 1 - NOT DETECTED

✅ HSV Type 2 - NOT DETECTED

Result 2: Autoimmune Encephalitis Panel CSF

⚠️ BUT - Read the Report Carefully

"No reaction at 1:10 dilution" = Negative

• NMDA-R → NMDA receptor encephalitis
• AMPAR1/2 → Limbic encephalitis
• GABARB1/B2 → Limbic encephalitis
• CASPR2 → Limbic encephalitis + neuromyotonia + Morvan's
• LGI1 → Limbic encephalitis

What This Means Clinically

HSV NEGATIVE = Green light for steroids

• Stop acyclovir - no longer needed
• The absolute contraindication to steroids is now removed
• Start IV Methylprednisolone 1g/day immediately

Autoimmune Panel Negative = Does NOT rule out autoimmune encephalitis

Revised Management - Right Now

STOP:

✗ Acyclovir - HSV definitively excluded (CSF PCR negative)

START IMMEDIATELY:

✅ IV Methylprednisolone 1g OD x 5 days
   → No longer any contraindication
   → HSV negative = safe to proceed
   → Clinical picture strongly supports autoimmune encephalitis
     regardless of antibody result

✅ Send SERUM autoimmune encephalitis panel (if not done)
   → Must check serum NMDAR, LGI1, CASPR2, AMPAR, GABA-B
   → Also add: anti-GFAP, anti-MOG, anti-DPPX

✅ Send extended CSF panel to reference lab (if available)
   → Anti-GFAP (astrocyte autoimmunity - fits this MRI pattern)
   → Anti-IgLON5
   → Anti-Glycine receptor

CONTINUE:

✅ Levetiracetam + Lacosamide
✅ Levocarnitine IV (ammonia still elevated)
✅ Lactulose NG
✅ Aspirin 150mg + Atorvastatin (bilateral DWI changes)
✅ Broad-spectrum antibiotics for fever workup
   (Ceftriaxone - pending culture results)

The Diagnosis Now

• ✅ Subacute onset (<3 months)
• ✅ Psychiatric symptoms (aggression, low mood)
• ✅ Seizures refractory to AEDs
• ✅ CSF inflammation (elevated protein, mild pleocytosis)
• ✅ MRI changes (caudate + insular initially, then posterior)
• ✅ No alternative diagnosis established

If no response to steroids in 5 days → add IVIG 0.4g/kg/day x 5 days → then consider Rituximab.

Vancomycin Dosing

Standard ICU Dosing

For This Patient (assuming ~65-70 kg)

⚠️ Renal Adjustment - CRITICAL

Therapeutic Drug Monitoring (TDM)

In This Patient's Context

• Indication here is empiric cover for VAP / line infection / gram-positive source pending cultures
• If cultures return gram-negative only → stop vancomycin
• If no source found and fever resolves → reassess at 48-72h
• CNS penetration of vancomycin is poor (10-20% CSF penetration) - adequate only if meninges are inflamed. Since bacterial meningitis is now low probability (HSV negative, autoimmune picture), vancomycin is primarily covering peripheral infectious sources here

🚨 SEPTIC SHOCK - Act in the Next 60 Minutes

Immediate Resuscitation - Do RIGHT NOW

1. Fluid Resuscitation

IV Crystalloid (Normal Saline or Ringer's Lactate)
→ 30 mL/kg IV BOLUS over 30 minutes
→ For 70kg patient = 2100 mL stat
→ Reassess BP, HR, urine output after each 500 mL
→ Target MAP ≥65 mmHg

2. If MAP <65 mmHg despite fluids → Vasopressors

NOREPINEPHRINE (first choice)
→ Start 0.1-0.2 mcg/kg/min IV infusion
→ Titrate up by 0.05 mcg/kg/min every 5-10 min
→ Target MAP ≥65 mmHg
→ Central line preferred - peripheral line acceptable short-term
→ Max ~1-2 mcg/kg/min before adding second agent

If refractory → Add VASOPRESSIN 0.03 units/min (fixed dose)

3. Broad-Spectrum Antibiotics - If Not Already Running

MEROPENEM 2g IV q8h  (covers VAP + gram negatives + anaerobes)
+
VANCOMYCIN 25-30 mg/kg IV loading dose  (gram positives / MRSA)

→ DO NOT DELAY antibiotics waiting for cultures
→ Blood cultures x2 BEFORE first antibiotic dose if possible
   but if already delayed → give antibiotics immediately

Simultaneous Workup - Do in Parallel

□ Blood cultures x2 (one peripheral, one from central line)
□ Tracheal aspirate - urgent gram stain + culture
□ Urine culture (catheter specimen)
□ Urgent bloods:
   - CBC with differential
   - CRP + Procalcitonin
   - Serum Lactate (venous) → if >2 mmol/L = sepsis; >4 = severe
   - RFT / Creatinine (vancomycin dosing, AKI assessment)
   - LFTs
   - Coagulation (PT/APTT/fibrinogen) - check for DIC
   - Blood glucose
   - ABG (ventilated patient - assess oxygenation + acid-base)
□ Portable CXR - new infiltrate = VAP/aspiration
□ Bedside echo if available - assess cardiac function, fluid responsiveness

Identify the Source

⚠️ Steroid Consideration in Septic Shock

This is now a double-edged situation:

Surviving Sepsis Campaign - 1-Hour Bundle

Within 60 MINUTES:
✅ 1. Measure lactate
✅ 2. Blood cultures BEFORE antibiotics
✅ 3. Broad-spectrum antibiotics (Meropenem + Vancomycin)
✅ 4. 30 mL/kg crystalloid if hypotensive OR lactate ≥4
✅ 5. Norepinephrine if MAP <65 despite fluids

Monitoring Targets

Bottom Line

Procalcitonin 0.11 ng/mL - Interpretation

What This Value Means

This PCT of 0.11 is Very Reassuring

✅ Bacterial sepsis is UNLIKELY as the primary cause

• Classic bacterial VAP, bacteraemia, or gram-negative sepsis would typically drive PCT to >2-5 ng/mL even in early stages
• PCT 0.11 argues strongly against a bacterial infectious source driving the fever and hypotension

What CAN cause fever + hypotension with LOW PCT?

This Changes Management Significantly

1. Antibiotics

PCT 0.11 = bacterial source very unlikely
→ If cultures return negative at 48h → STOP antibiotics
→ Do not escalate antibiotics based on fever alone
→ PCT can be used serially to guide de-escalation

2. The Fever + Hypotension is Likely AUTOIMMUNE / NEUROGENIC in Origin

• Anti-NMDAR encephalitis - autonomic dysfunction is a core feature (fever, tachycardia, BP instability, hypersalivation)
• Seronegative autoimmune encephalitis - same autonomic features
• Thalamic injury - hypothalamic thermoregulatory dysfunction

3. This is NOW a Green Light for Immunotherapy

PCT 0.11 = bacterial infection unlikely
HSV PCR = negative
Fever + hypotension = likely autoimmune/neurogenic

→ START IV Methylprednisolone 1g/day NOW
→ No credible infectious contraindication remaining
→ Vasopressors for MAP support while immunotherapy begins
→ Treat the underlying cause - autoimmune encephalitis

Revised Picture - Putting It All Together

Immediate Action

1. START methylprednisolone 1g IV OD - do it now
   PCT 0.11 removes the last hesitation

2. Vasopressors for MAP ≥65 (norepinephrine)
   - Autonomic instability responds to immunotherapy over days
   - Bridge with vasopressors in the meantime

3. Antipyretics regularly - paracetamol 1g IV q6h
   - Neurogenic fever is often resistant but worth treating

4. De-escalate / stop antibiotics at 48h if cultures negative
   PCT does not support continuing empiric antibiotics long-term

5. If no response to methylprednisolone at 5 days
   → Add IVIG 0.4g/kg/day x 5 days
   → Then consider Rituximab (second-line)

6. Send serum autoimmune panel if not yet done
   → Anti-GFAP, anti-MOG in addition to standard panel

🚨 250 mL/hr Urine Output - This is Dangerous

Immediate Question - What Type of Polyuria?

Check RIGHT NOW:

□ Serum sodium - URGENT
□ Serum osmolality
□ Urine osmolality (spot)
□ Urine specific gravity
□ Serum glucose (rule out osmotic diuresis)
□ Recent fluid input - how much fluid was given during resuscitation?

Differential Diagnosis

🥇 1. Central Diabetes Insipidus (CDI) - TOP CONCERN

• Bilateral thalamic + hypothalamic involvement on MRI → ADH deficiency
• Hypothalamus produces ADH; posterior pituitary releases it
• Thalamic/hypothalamic injury from autoimmune encephalitis or ischaemia → central DI
• Pattern: massive dilute urine output + rising serum sodium + hyperosmolality

🥈 2. Post-Fluid Resuscitation Diuresis

• You just gave 30 mL/kg bolus (~2L) for hypotension
• Kidneys excreting the fluid load
• Urine would be dilute but serum sodium NORMAL
• Self-limiting - watch and reassess

🥉 3. Osmotic Diuresis

• Hyperglycaemia (steroids were being considered)
• Mannitol if given for cerebral oedema
• Check blood glucose and urine glucose

4. Nephrogenic DI

• Less likely acutely - but drugs (amphotericin, lithium) can cause
• Review drug chart

Management Based on Most Likely Cause

If Central DI Confirmed (dilute urine + rising Na + high serum osm):

🔴 DESMOPRESSIN (DDAVP) - START IMMEDIATELY

Intranasal: NOT suitable in ICU
IV / SC: Desmopressin 1-2 mcg IV/SC q12-24h
         Start with 1 mcg IV - reassess urine output in 1-2h
         Titrate to urine output <100 mL/hr

FLUID REPLACEMENT:
→ Replace urine output mL for mL with 5% Dextrose or 0.45% NaCl
→ DO NOT use Normal Saline for replacement - will worsen hypernatraemia
→ Calculate free water deficit if Na already elevated:
   Free water deficit = 0.6 × weight × [(Na/140) - 1]
→ Correct hypernatraemia SLOWLY - no faster than 10 mmol/L per 24h
   (rapid correction → cerebral oedema)

MONITOR:
→ Serum Na every 2-4 hours
→ Urine output hourly
→ Strict fluid balance

If Post-Resuscitation Diuresis (Na normal, urine dilute):

→ Watch and wait
→ Replace 50% of urine output with 0.45% NaCl
→ Recheck Na in 2 hours
→ If output self-limits in 2-4h → no further action needed

Why This Matters Enormously Here

• Bilateral thalamic injury on MRI - the hypothalamus sits directly adjacent
• Autoimmune encephalitis affecting deep structures
• Already haemodynamically unstable (hypotension)
• Intubated - cannot drink to compensate for losses

• Severe hypernatraemia (Na can rise to 160-170 rapidly)
• Worsening cerebral dehydration
• Further brain injury on top of already compromised brain
• Cardiovascular collapse from volume depletion

Bottom Line

URGENT:
1. Check serum Na NOW
2. Check urine osmolality / specific gravity NOW
3. If Na rising + dilute urine → DDAVP 1-2 mcg IV immediately
4. Replace fluid losses with 5% Dextrose, not Normal Saline
5. Hourly urine output monitoring
6. Na every 2-4 hours until stable