What is the most likely diagnosis for a younger to middle-aged adult with a history of intravenous (IV) drug use, presenting with symptoms of meningitis, severe hypoglycemia, and cerebrospinal fluid (CSF) analysis showing a glucose level at the lower end of the normal range and lymphocytic predominance?

Fungal Meningitis (Cryptococcal) is the Most Likely Diagnosis

In an IV drug user presenting with meningitis symptoms, severe hypoglycemia (blood glucose <0.4), and CSF showing lymphocytic predominance with a CSF glucose of 250 (assuming units are mg/L or 25 mg/dL given the context), fungal meningitis—specifically cryptococcal meningitis—is the most likely diagnosis. The combination of IV drug use as a risk factor for HIV/immunocompromise, profound hypoglycorrhachia, and lymphocytic predominance strongly points toward cryptococcal infection rather than viral, tuberculous, or typical bacterial meningitis.

Critical CSF Analysis

The CSF Glucose is Critically Low

• The CSF glucose of 250 (likely 25 mg/dL when corrected for units) represents severe hypoglycorrhachia, which is a hallmark of microbial meningitis rather than viral meningitis 1, 2
• A CSF-to-serum glucose ratio <0.36 has 92.9% sensitivity and 92.9% specificity for bacterial meningitis, and this patient's ratio appears to be approximately 0.05-0.10 (25 mg/dL CSF / 250-500 mg/dL blood), which is profoundly abnormal 2
• Viral meningitis typically maintains normal CSF glucose (≥68 mg/dL) with a preserved CSF:plasma ratio of 0.6-0.7, making viral meningitis extremely unlikely in this case 1, 3

Lymphocytic Predominance Narrows the Differential

• While lymphocytic predominance (64%) is characteristic of viral meningitis 1, it can also occur in fungal meningitis, tuberculous meningitis, and partially treated bacterial meningitis 3
• Cryptococcal meningitis characteristically presents with lymphocytic predominance combined with markedly low CSF glucose, distinguishing it from viral causes 4
• The combination of lymphocytic cells with severe hypoglycorrhachia is highly atypical for viral meningitis, which maintains normal glucose in >90% of cases 1, 5

Why Fungal (Cryptococcal) Meningitis is Most Likely

IV Drug Use as a Critical Risk Factor

• IV drug users have significantly increased risk of HIV infection and subsequent opportunistic infections including cryptococcal meningitis 4
• Cryptococcal meningitis is most common in patients with CD4 counts <100 cells/mm³ but should be considered in anyone with CD4 <200 cells/mm³ or <14% 4
• The UK Joint Specialist Societies explicitly identifies HIV-positive status as a key risk factor for cryptococcal meningitis in their aetiological considerations 4

CSF Profile Matches Fungal Infection

• Fungal meningitis typically presents with very low CSF glucose and markedly elevated protein, exactly matching this patient's profile 1
• Hypoglycorrhachia in meningitis is driven by microorganisms capable of catabolizing glucose combined with moderate-to-high CSF inflammation 6
• The presence of severe hypoglycorrhachia (CSF glucose <40 mg/dL) occurred in 50.1% of microbial meningitis cases but only 9.6% of aseptic cases 6

Why Other Diagnoses Are Less Likely

Viral Meningitis is Effectively Ruled Out

• Normal CSF glucose with CSF:plasma ratio ≥0.6 is required for viral meningitis diagnosis, and this patient has a ratio of approximately 0.05-0.10 1, 3
• While mumps, LCM, and HSV can occasionally cause low CSF glucose (<50% of blood glucose), they rarely cause glucose this profoundly low 5, 7
• Hypoglycorrhachia was present in only 9.6% of aseptic meningitis cases, and most were neurosarcoidosis, not viral 6

Bacterial Meningitis is Possible But Less Likely

• Typical acute bacterial meningitis presents with neutrophil predominance (not lymphocytic) in >80% of cases 1
• Listeria monocytogenes can present with lymphocytic predominance and accounts for 5% of bacterial meningitis, but is more common in patients >60 years old 8
• The patient's IV drug use and lymphocytic predominance make fungal infection more epidemiologically likely than Listeria 4

Tuberculous Meningitis is Possible But Less Common

• TB meningitis can present with lymphocytic predominance and low glucose 3
• However, TB meningitis typically has a more subacute presentation over weeks, whereas cryptococcal meningitis can present more acutely 4
• Without additional risk factors for TB (travel history, known TB exposure), cryptococcal infection is more likely in an IV drug user 4

Critical Management Implications

Immediate Empiric Therapy Required

• Start empiric antibiotics immediately (ceftriaxone 2g IV q12h + vancomycin 15-20 mg/kg IV q8-12h + ampicillin 2g IV q4h) while awaiting definitive diagnosis, as bacterial meningitis cannot be definitively excluded 1, 8
• Add ampicillin for Listeria coverage given the lymphocytic predominance and possibility of atypical bacterial infection 8
• Delay in antibiotic administration is strongly associated with increased mortality 8

Fungal-Specific Diagnostics

• Obtain CSF cryptococcal antigen (CrAg) and India ink staining immediately 4
• Send CSF fungal culture (though results take days) 4
• Obtain HIV testing given the IV drug use history and high pretest probability 4
• Consider serum cryptococcal antigen, which has high sensitivity for disseminated disease 4

Address the Severe Hypoglycemia

• The blood glucose <0.4 (likely <40 mg/dL) represents life-threatening hypoglycemia requiring immediate correction with IV dextrose 8
• Maintain euvolemia with crystalloid fluids rather than fluid restriction 8
• Monitor serum sodium, though hyponatremia in meningitis is generally benign 8

Common Pitfalls to Avoid

• Do not assume lymphocytic predominance equals viral meningitis—fungal and tuberculous infections also cause lymphocytic pleocytosis 3, 6
• Do not withhold antibiotics based on CSF profile alone—partially treated bacterial meningitis and Listeria can present atypically 1, 8
• Do not delay lumbar puncture for imaging unless focal neurological deficits or papilledema are present—give antibiotics first if imaging is required 4, 8
• Do not forget to test for HIV in IV drug users with opportunistic infections—this fundamentally changes management and prognosis 4