What is the appropriate management for an adult patient with suspected infectious or neurological disease requiring differential diagnosis?

Management of Suspected Encephalitis: Differential Diagnosis Approach

All adult patients with suspected encephalitis should undergo lumbar puncture as soon as possible after hospital admission unless contraindicated, with imaging performed urgently if signs of raised intracranial pressure are present. 1

Immediate Diagnostic Evaluation

Lumbar Puncture Timing and Contraindications

• Perform LP immediately upon admission unless clinical contraindications exist, specifically signs of raised intracranial pressure causing brain shift 1
• If contraindications are present (papilledema, focal neurological signs suggesting mass effect, declining consciousness), obtain urgent CT scan first 1
• Following CT, proceed with LP on a case-by-case basis unless imaging shows significant brain shift, tight basal cisterns, or alternative diagnosis 1
• In anticoagulated patients: reverse with protamine (heparin) or vitamin K plus prothrombin complex concentrate/FFP (warfarin) before LP 1
• Review LP feasibility every 24 hours if initially contraindicated and perform when safe 1

Imaging Strategy

• If CT not needed before LP, perform CT or MRI as soon as possible after LP 1
• MRI is superior to CT (detects abnormalities in 90% vs 25% for CT) and should be obtained within 24-48 hours 1, 2
• In immunocompromised patients, MRI should be performed as soon as possible regardless of other findings 1

Critical History and Examination Elements

Essential History Components 1

• Fever pattern: high fever typical but low-grade pyrexia can occur in HSV encephalitis 1
• Mental status changes: disorientation (76%), speech disturbances (59%), behavioral changes (41%) 1
• Seizure activity: new-onset seizures, especially focal or subtle motor seizures 1
• Epidemiologic clues: travel history, animal/insect contact, immunocompromise status, vaccination history, HIV risk factors 1
• Subacute presentations: consider antibody-mediated encephalitis if gradual onset over days-weeks 1

Physical Examination Priorities 1

• Airway, breathing, circulation assessment first 1
• Cognitive function testing: mini-mental state, behavior, subtle confusion 1
• Focal neurological signs: asymmetric findings, meningism, papilledema 1
• Rash examination: vesicular (VZV), purpuric (meningococcus), hand-foot-mouth disease 1
• Movement disorders: orofacial dyskinesia, choreoathetosis, faciobrachial dystonia suggest antibody-mediated disease 1

Differential Diagnosis Framework

Infectious Causes

CSF studies for all patients 1:

• HSV-1/2, VZV, enterovirus PCR (standard panel) 1
• Blood and CSF bacterial cultures 1
• Consider EBV, CMV in immunocompromised 1

Additional infectious workup based on context 1:

• Serum microbiological cultures, serology, PCR for septic encephalopathy 1
• Cryptococcal antigen, Indian ink staining if immunocompromised 1
• Toxoplasma antibodies in HIV patients 3
• Mycobacterium tuberculosis culture in appropriate populations 1

Autoimmune/Inflammatory Encephalitis 1

Consider when:

• Subacute presentation over days-weeks 1
• Hyponatremia (60% of VGKC-complex cases) 1
• Intractable seizures without fever 1
• Faciobrachial dystonic seizures (pathognomonic for VGKC) 1

Diagnostic testing 1:

• FBC, ESR, CRP, ANA, ENA, dsDNA, ANCA, complement levels 1
• VGKC-complex and NMDA receptor antibodies in serum (CSF may be negative) 1
• Thyroid antibodies (thyroglobulin, thyroperoxidase) 1
• MRI shows bilateral hippocampal high signal in 60% of VGKC cases 1

Paraneoplastic Encephalitis 1, 2

Screening required 2:

• Anti-neuronal and onconeuronal antibodies in serum and CSF 1, 2
• CT or PET chest/abdomen/pelvis to identify occult malignancy 1, 2
• Alpha-fetoprotein, beta-hCG for germ cell tumors 1, 2
• Thymoma screening in VGKC-complex cases (<10% association) 1

Metabolic Causes 1

• Renal, liver, bone, thyroid profiles 1
• Arterial blood gas, plasma/CSF lactate, ammonia, pyruvate 1
• Amino acids, very long-chain fatty acids, urinary organic acids 1

Vascular Causes 1

• CT or MRI with venogram and/or angiogram 1
• Especially important in elderly (stroke more common than in younger adults) 1

Toxic Causes 1

• Blood/urine levels: alcohol, paracetamol, salicylate, tricyclics, heavy metals 1
• Urinary illicit drug screen 1
• Critical in patients with behavioral changes mistaken for psychiatric illness 1

Septic Encephalopathy 1

• Most common infection-associated encephalopathy (50-70% of septic patients) 1
• Diagnosis of exclusion with extracranial sepsis focus 1
• Progression: slowed mentation → impaired attention → delirium → coma 1
• Symmetrical neurological findings; asterixis/multifocal myoclonus rare 1

Special Population Considerations

Elderly Patients 1

• Higher risk of stroke and systemic sepsis causing altered mental status 1
• HSV encephalitis more common in elderly than younger adults—maintain high suspicion 1
• Presentations often more subtle than in younger patients 1

Immunocompromised Patients 1

Expanded infectious workup mandatory 1:

• HSV-1/2, VZV, enterovirus, EBV, CMV, HHV-6/7 PCR 1
• JC/BK virus PCR 1
• Toxoplasma, Cryptococcus, Listeria, Mycobacterium tuberculosis 1
• Coccidioides, Histoplasma in endemic areas 1

Key differences 1:

• CSF may be acellular despite active infection—perform full microbial workup regardless of cell count 1
• CT lesions may lack surrounding edema due to impaired inflammatory response 1
• Subacute presentations more common 1
• HIV patients require treatment in specialized HIV center 1

HIV Patients with Mass Effect 3

Immediate empiric treatment 3:

• Start pyrimethamine plus sulfadiazine plus leucovorin immediately for presumed toxoplasmosis 3
• Initiate or optimize antiretroviral therapy simultaneously 3
• MRI with contrast and DWI within 24 hours 3
• For cryptococcomas ≥3cm: amphotericin B (0.7-1 mg/kg/day IV) plus flucytosine (100 mg/kg/day PO) for ≥6 weeks 3
• Dexamethasone 10mg IV then 4mg q6h for fungal mass lesions with significant edema 3

Critical Pitfalls to Avoid

• Never delay empiric aciclovir while awaiting HSV PCR results in suspected viral encephalitis 1
• Never perform LP before neuroimaging in patients with focal signs or altered consciousness 3, 2
• Never rely on normal CSF cell count to exclude infection in immunocompromised patients 1
• Do not dismiss subtle presentations: low-grade fever, speech disturbances, behavioral changes can represent HSV encephalitis 1
• Do not miss antibody-mediated encephalitis: poor outcome if untreated, but excellent response to immunotherapy if caught early 1
• Do not delay immunotherapy while awaiting antibody results in suspected autoimmune encephalitis 2
• Chronic alcohol abuse associated with delayed diagnosis—maintain high suspicion in this population 1
• Non-convulsive status epilepticus can mimic encephalitis (found in 8% of comatose patients)—consider EEG 1

Treatment Implications Based on Differential

Antibody-Mediated Encephalitis 1, 2

• High-dose IV methylprednisolone as first-line 2
• IVIG (0.4 g/kg/day for 5 days) or plasma exchange for severe cases 4, 2
• For VGKC-complex: oral steroids 0.5 mg/kg/day, taper over 12 months 1
• Early treatment improves outcomes significantly 1

Seizure Management 3, 2

• Levetiracetam preferred (minimal ART interactions, broad spectrum) 3
• IV levetiracetam 30-60 mg/kg/day or IV valproate 20-30 mg/kg loading dose 2
• Avoid phenytoin as first-line 2