What are hypoglycorrhachia (low glucose levels in the cerebrospinal fluid) and hyperproteinorrachia (elevated protein levels in the cerebrospinal fluid)?

Hypoglycorrhachia and Hyperproteinorrachia: Clinical Significance and Diagnostic Implications

Hypoglycorrhachia refers to abnormally low glucose levels in cerebrospinal fluid (CSF), while hyperproteinorrachia refers to elevated protein levels in CSF, both representing important diagnostic markers for various neurological conditions.

Hypoglycorrhachia

Definition and Pathophysiology

• Hypoglycorrhachia is defined as CSF glucose <40-45 mg/dL or a CSF/serum glucose ratio <0.6 1
• Normal CSF glucose is typically 60-70% of blood glucose concentration
• Results from increased glucose utilization by microorganisms, inflammatory cells, or malignant cells, or from impaired glucose transport across the blood-brain barrier

Etiologies

Hypoglycorrhachia is associated with several conditions:

1. Infectious causes:

   • Bacterial meningitis (most common cause, 24% of cases) 1
   • Fungal meningitis (15% of cases, most common in HIV-infected patients at 38%) 1
   • Tuberculous meningitis
   • Viral meningitis (6% of cases) 1
   • Neurosyphilis (4% of cases) 1
   • Cerebral toxoplasmosis (3% of cases) 1

2. Non-infectious causes:

   • Stroke/intracranial hemorrhage (13% of cases) 1
   • Malignancy/meningeal carcinomatosis (11% of cases) 1
   • Neurosarcoidosis (4% of cases) 1
   • Systemic hypoglycemia 2

Clinical Significance

• Markedly low CSF glucose values are primarily seen in bacterial meningitis 2
• In CMV polyradiculomyelopathy, hypoglycorrhachia is typically accompanied by neutrophilic pleocytosis and elevated protein levels 3
• Hypoglycorrhachia is associated with worse clinical outcomes in community-acquired meningitis (22.4% adverse outcomes vs 8.9% in normal CSF glucose) 4
• In patients without HIV or neurosurgical history, non-infectious etiologies (stroke/bleed, malignancy) are the most common causes 1

Hyperproteinorrachia

Definition and Pathophysiology

• Hyperproteinorrachia is defined as elevated protein levels in CSF (typically >45 mg/dL)
• Results from increased blood-brain barrier permeability, intrathecal protein production, or decreased CSF flow

Etiologies

Hyperproteinorrachia is associated with:

1. Infectious causes:

   • Bacterial, fungal, and tuberculous meningitis
   • Viral meningitis/encephalitis
   • Neurosyphilis

2. Non-infectious causes:

   • Autoimmune encephalitis (common finding) 3
   • Guillain-Barré syndrome and other demyelinating disorders
   • Malignancy
   • Stroke/intracranial hemorrhage
   • Neurosarcoidosis

Clinical Significance

• In autoimmune encephalitis, hyperproteinorrachia is a common finding, often accompanied by mild to moderate lymphocytic pleocytosis 3
• Hyperproteinorrachia without pleocytosis (albuminocytologic dissociation) is characteristic of Guillain-Barré syndrome
• In CMV neurologic disease, hyperproteinorrachia often accompanies hypoglycorrhachia 3

Diagnostic Approach

CSF Analysis

• Complete CSF analysis should include:
  • Cell count and differential
  • Protein and glucose levels (with simultaneous blood glucose)
  • CSF/serum glucose ratio
  • IgG index and synthesis rate
  • Oligoclonal bands
  • Appropriate microbiological studies

Additional Testing Based on Clinical Context

• For suspected infection:

  • Broad viral studies including HSV1/2 PCR and VZV PCR
  • Bacterial/fungal cultures
  • Specific PCR tests for suspected pathogens

• For suspected autoimmune encephalitis:

  • Neural autoantibody panels in both CSF and serum 3

• For suspected malignancy:

  • Cytology
  • Flow cytometry

Clinical Pearls and Pitfalls

Important Considerations

• Pitfall: Relying solely on CSF glucose without calculating the CSF/serum glucose ratio can lead to misdiagnosis, especially in patients with abnormal blood glucose levels
• Pitfall: Culturing CMV from CSF is not sufficient to establish the diagnosis of CMV neurologic disease, as some patients with low CD4+ counts may be viremic without clinical disease 3
• Pearl: When bacterial cultures are negative, consider fungal meningitis, particularly in immunocompromised patients 1
• Pearl: In patients with meningitis and hypoglycorrhachia who have received prior antibiotics, positive CSF viral cultures may allow early cessation of antibiotic therapy 2

Monitoring

• Serial CSF analyses may be necessary to monitor treatment response in certain conditions
• Normalization of CSF glucose and protein levels often correlates with clinical improvement

Conclusion

The presence of hypoglycorrhachia and/or hyperproteinorrachia should prompt a thorough diagnostic evaluation. While infectious etiologies (particularly bacterial meningitis) are common causes, clinicians should consider the full spectrum of potential diagnoses, including non-infectious conditions such as malignancy, stroke, and autoimmune disorders. The pattern of CSF abnormalities, along with clinical presentation and other diagnostic tests, guides the differential diagnosis and appropriate management.