What diagnostic tests should be done for a patient with a sore throat followed by persistent fever, lethargy, and mental confusion?

Diagnostic Workup for Sore Throat with Persistent Fever, Lethargy, and Mental Confusion

This patient requires immediate evaluation for encephalitis or meningitis with urgent lumbar puncture, neuroimaging, and blood cultures, as mental confusion following sore throat and persistent fever represents a potentially life-threatening CNS infection until proven otherwise. 1

Immediate Priority Testing

Neurological Evaluation (Highest Priority)

• Lumbar puncture with CSF analysis including cell count with differential, protein, glucose, Gram stain, bacterial culture, and PCR for HSV-1/2, enterovirus, and other viral pathogens 1
• Brain MRI with contrast (preferred) or CT scan if MRI unavailable to evaluate for encephalitis, abscess, or other parenchymal abnormalities 1, 2
• Electroencephalography (EEG) to detect subclinical seizures or encephalopathic patterns consistent with encephalitis 1

The International Encephalitis Consortium defines encephalitis as altered mental status lasting ≥24 hours plus at least 2 of the following: documented fever ≥38°C within 72 hours, new seizures, new focal neurological findings, CSF WBC ≥5/mm³, abnormal neuroimaging, or abnormal EEG. 1 This patient meets criteria with mental confusion, persistent fever, and lethargy.

Blood Work

• Complete blood count with differential to assess for leukocytosis, lymphocytosis (viral), or thrombocytopenia (severe infection) 1
• Blood cultures (aerobic and anaerobic) drawn before antibiotics to identify bacteremia or sepsis 1
• Comprehensive metabolic panel including electrolytes, renal function, liver enzymes, and glucose to exclude metabolic encephalopathy and assess for hyponatremia (seen in encephalitis) 1
• Lactate and blood gas if sepsis suspected 1
• C-reactive protein and procalcitonin to differentiate bacterial from viral etiology 1

Throat and Respiratory Evaluation

• Throat culture or rapid antigen detection test for Group A Streptococcus, though this is lower priority given CNS symptoms 1, 3
• Nasopharyngeal swab for respiratory viral panel including influenza, COVID-19, adenovirus, and other respiratory viruses 1
• Chest X-ray to evaluate for pneumonia or pulmonary complications 1

Critical Differential Diagnoses to Exclude

Life-Threatening Bacterial Infections

• Lemierre's syndrome (Fusobacterium necrophorum): Presents with pharyngitis followed by septic thrombophlebitis of internal jugular vein with septic emboli. Requires neck CT with contrast to visualize jugular vein thrombosis and blood cultures. 4
• Bacterial meningitis: Requires immediate lumbar puncture with CSF Gram stain, culture, and empiric antibiotics (ceftriaxone + vancomycin) before results if suspected. 1
• Brain abscess (retropharyngeal or epidural extension): Requires contrast-enhanced MRI or CT of brain and neck. 5, 2

Viral Encephalitis

• HSV encephalitis: Most common treatable viral encephalitis. CSF PCR for HSV-1/2 is diagnostic. MRI may show temporal lobe involvement. Start empiric acyclovir immediately while awaiting results. 1, 2
• COVID-19 with neurological manifestations: Can present with encephalopathy preceding respiratory symptoms. Requires nasopharyngeal and potentially CSF SARS-CoV-2 PCR. 1
• Epstein-Barr virus (infectious mononucleosis): Can cause pharyngitis with CNS complications. Check EBV serology (VCA-IgM, VCA-IgG, EBNA). 1, 2

Imported Infections (If Travel History)

• Malaria: Presents with fever, confusion, and can follow nonspecific symptoms. Requires thick and thin blood smears examined immediately and repeated every 12-24 hours if initial negative. Cerebral malaria (Plasmodium falciparum) is a medical emergency. 1

Common Pitfalls to Avoid

• Assuming viral pharyngitis and missing bacterial complications: Exclusion of streptococcal infection does not exclude other bacterial causes like Fusobacterium or abscess formation. 4
• Delaying lumbar puncture: Mental confusion with fever mandates CSF analysis unless contraindicated by signs of increased intracranial pressure or mass effect on imaging. 1
• Waiting for confirmatory tests before starting treatment: Empiric acyclovir for HSV encephalitis and appropriate antibiotics for bacterial meningitis must be started immediately based on clinical suspicion. 1
• Overlooking metabolic causes: Hypoglycemia, hyponatremia, and uremia can cause confusion and must be rapidly corrected. 1
• Missing COVID-19 neurological manifestations: SARS-CoV-2 can cause encephalitis with CSF positivity even when nasopharyngeal swabs are negative. 1

Algorithmic Approach

1. Stabilize airway and hemodynamics if patient shows signs of respiratory compromise or shock 5
2. Obtain blood cultures, CBC, CMP, lactate immediately 1
3. Neuroimaging (CT or MRI) before lumbar puncture if focal neurological signs, papilledema, or altered consciousness suggest mass effect 1
4. Lumbar puncture with comprehensive CSF studies including viral PCR panel 1
5. Start empiric treatment (acyclovir + ceftriaxone + vancomycin) immediately after obtaining cultures if encephalitis or meningitis suspected 1
6. Throat culture and respiratory viral testing as adjunctive studies 1
7. EEG within 24 hours to detect subclinical seizures 1
8. Repeat blood smears if travel history to endemic malaria regions 1