What do vacuolated neutrophils, macrophages showing erythrophagocytosis, some with hemosiderin granules, and occasional hematoidin crystals in the cerebrospinal fluid (CSF) indicate?

CSF Findings of Subarachnoid Hemorrhage

The presence of vacuolated neutrophils, macrophages with erythrophagocytosis, hemosiderin granules, and hematoidin crystals in cerebrospinal fluid is diagnostic of a prior subarachnoid hemorrhage that occurred at least several days before the lumbar puncture.

Interpretation of the CSF Findings

These CSF findings represent the cellular response to blood in the subarachnoid space and can be interpreted as follows:

1. Vacuolated neutrophils:

   • Indicate an inflammatory response to blood products in the CSF
   • May persist for several days after the hemorrhagic event

2. Macrophages showing erythrophagocytosis:

   • These are macrophages that have engulfed red blood cells
   • This process begins approximately 48-72 hours after blood enters the subarachnoid space
   • Confirms that the blood is not from a traumatic tap, as erythrophages do not develop in vitro when CSF and blood are mixed 1

3. Hemosiderin granules within macrophages:

   • Represent the breakdown products of hemoglobin
   • Typically appear 3-4 days after hemorrhage
   • Indicate that the bleeding event occurred several days prior to the CSF examination

4. Hematoidin (hematin) crystals:

   • These are crystallized bilirubin derivatives from hemoglobin breakdown
   • Form approximately 5-7 days after hemorrhage
   • Their presence indicates a subacute hemorrhage that occurred at least several days before the lumbar puncture

Clinical Significance

The constellation of these findings is pathognomonic for subarachnoid hemorrhage (SAH) that occurred days before the lumbar puncture was performed. According to the Stroke guidelines, CSF findings sufficient to support recent hemorrhage from a cerebrovascular malformation include "heavily—and uniformly—blood-stained CSF (not attributable to a traumatic tap), or visible xanthochromia, or bilirubin on CSF spectrophotometry" 2.

The presence of erythrophages is particularly significant because:

• They definitively distinguish genuine subarachnoid hemorrhage from a traumatic lumbar puncture
• Research has shown that erythrophages do not develop when lumbar CSF and blood samples are mixed in vitro 1
• Their presence confirms an autochthonous bleeding in the subarachnoid space

Timing of the Hemorrhage

The temporal sequence of cellular changes in CSF after SAH allows for estimation of when the bleeding occurred:

• Acute phase (0-24 hours): Fresh RBCs and neutrophils
• Early subacute phase (24-72 hours): Beginning of erythrophagocytosis
• Late subacute phase (3-7 days): Hemosiderin-laden macrophages appear
• Chronic phase (>7 days): Hematoidin crystals form

The presence of all these elements suggests a hemorrhage that occurred at least 5-7 days before the CSF examination.

Differential Diagnosis

While subarachnoid hemorrhage is the most likely explanation, other conditions to consider include:

• Hemorrhagic encephalitis: May show similar findings but would typically have additional inflammatory markers
• Cerebral amyloid angiopathy with inflammation: Can present with similar CSF findings but usually affects older patients 2
• Mycotic aneurysm rupture: Can cause SAH with similar CSF findings, especially in patients with infective endocarditis 2

Clinical Implications

These findings warrant immediate neuroimaging (CT/CTA or MRI/MRA) to identify the source of bleeding, with particular attention to:

• Cerebral aneurysms
• Arteriovenous malformations
• Cavernous malformations
• Mycotic aneurysms (if there's suspicion of endocarditis)

The presence of hemosiderin in the CSF is particularly concerning as it has been associated with secondary brain injury after SAH 3. Hemoglobin and its breakdown products in CSF can drive vasospasm and oxidative stress, contributing to poor outcomes.

Conclusion

The CSF findings of vacuolated neutrophils, macrophages with erythrophagocytosis, hemosiderin granules, and hematoidin crystals represent the cellular response to a subarachnoid hemorrhage that occurred approximately 5-7 days before the lumbar puncture. These findings are diagnostic and should prompt immediate neurological consultation and appropriate neuroimaging to identify the source of bleeding.