What is the appropriate diagnosis and treatment approach for a patient with lymphocytic pleocytosis, considering their age, immune status, and past medical history?

Lymphocytic Pleocytosis: Diagnosis and Treatment

Lymphocytic pleocytosis in cerebrospinal fluid requires immediate differentiation between infectious causes (particularly viral meningoencephalitis and Lyme neuroborreliosis), the benign self-limited syndrome of transient headache with neurological deficits (HaNDL syndrome), and malignancy, with treatment directed at the underlying etiology rather than the pleocytosis itself.

Diagnostic Approach

Initial CSF Analysis Requirements

• Obtain cell count with differential, protein, glucose, Gram stain, bacterial culture, and flow cytometry to characterize the lymphocytic population 1, 2.
• Lymphocytic pleocytosis is defined as >5 leukocytes/μL with lymphocyte predominance 2.
• The degree of pleocytosis provides diagnostic clues: counts >100/μL are mainly caused by CNS infection, whereas counts <50/μL have a broader differential including non-infectious neurological diseases, malignancy, and seizures 2.

Critical Immunophenotyping

• Flow cytometry must include B-cell and T-cell markers, plus plasmacytic markers (CD38, CD138) with cytoplasmic light chain analysis to distinguish reactive from malignant processes 1.
• Polytypic B lymphocytes with plasmacytic differentiation suggest infectious etiology (particularly Lyme disease), while monoclonal populations raise concern for lymphoma 1.
• In Lyme neuroborreliosis specifically, B-cell-predominant lymphocytosis with increased plasmacytoid cells and plasma cells is characteristic, which is atypical since most CNS infections produce T-cell predominance 1.

Infectious Workup

• Obtain Lyme screening test and Western blot if B-cell predominance is present, as Lyme neuroborreliosis characteristically produces B-cell-predominant pleocytosis 1.
• Viral serologies including HIV, HSV, VZV, and enterovirus PCR should be performed based on clinical presentation 3.
• Adenosine deaminase levels may be obtained if tuberculous meningitis is suspected, though values are typically normal in other causes 3.

Imaging and Additional Studies

• Brain MRI with contrast is mandatory to exclude structural lesions, malignancy, and inflammatory processes 3, 4.
• EEG frequently shows focal slowing in HaNDL syndrome but is nonspecific 3, 5.
• SPECT imaging may reveal focal areas of decreased uptake corresponding to clinical symptoms in HaNDL syndrome, though this is not routinely necessary 3.

Differential Diagnosis by Clinical Pattern

HaNDL Syndrome (Transient Headache with Neurological Deficits and CSF Lymphocytosis)

• Suspect HaNDL when patients present with 1-12 episodes of changing neurological deficits (sensory symptoms 78%, aphasia 66%, motor symptoms 56%) accompanied by moderate-to-severe throbbing headache lasting mean 19 hours 3.
• Lymphocytic pleocytosis ranges 10-760 cells/mm³ (mean 199), with elevated protein in 96% but normal IgG in 80% and absent oligoclonal bands 3.
• Episodes occur over maximum 3 months (typically within 25-49 days) with complete resolution and no recurrence, distinguishing this from other causes 3, 4, 5.
• One-quarter of patients report viral-like illness within 3 weeks prior to onset 3.

Lyme Neuroborreliosis

• B-cell predominance with plasmacytoid cells and plasma cells on cytology is highly suggestive 1.
• Confirmation requires positive Lyme screening test and Western blot 1.
• Flow cytometry showing polytypic B lymphocytes with plasmacytic differentiation helps exclude lymphoma 1.

Non-Infectious Causes

• Seizures, non-infectious neurological diseases, and malignancy collectively account for 30-40% of cases with pleocytosis 2.
• Malignancy accounts for 8.8% of pleocytosis cases and requires careful cytological examination and flow cytometry for monoclonal populations 2.

Treatment Approach

Infectious Causes

• Initiate appropriate antibiotic therapy based on suspected bacterial pathogens, with full 10-day course in immunocompromised patients 6.
• For severe cases with systemic symptoms, hospitalize for intravenous antibiotics 6.
• Antiviral therapy is indicated for specific viral infections (HSV, VZV) but is not directed at the reactive lymphocytes themselves 6.

HaNDL Syndrome

• No specific treatment is required as this is a self-limited benign condition 3, 4, 5.
• Reassurance is critical: symptoms resolve spontaneously within maximum 3 months 4, 5.
• Symptomatic management of headache with standard analgesics is appropriate 3.
• Follow-up lumbar puncture at 3-4 months should demonstrate resolution of pleocytosis 4.

Autoimmune-Associated Pleocytosis

• Corticosteroids (prednisone) are first-line treatment for autoimmune cytopenias associated with reactive lymphocytes 6.
• Rituximab may be considered for patients not responding to corticosteroids before proceeding to splenectomy 6.
• Treat any underlying condition such as chronic lymphocytic leukemia in patients with resistant autoimmune manifestations 6.

Critical Pitfalls to Avoid

• Do not assume all lymphocytic pleocytosis is infectious: non-infectious neurological diseases and malignancy are common causes, particularly when cell counts are <50/μL 2.
• Do not miss Lyme neuroborreliosis: the B-cell predominance can mimic lymphoma, making flow cytometry with plasmacytic markers essential 1.
• Do not over-investigate or over-treat HaNDL syndrome: once infectious and malignant causes are excluded, recognize this as a benign self-limited condition requiring only reassurance and symptomatic management 3, 4, 5.
• Do not perform conventional angiography routinely: it rarely shows abnormalities and can paradoxically trigger symptoms in HaNDL syndrome 3.
• Do not initiate immunosuppression without excluding infection: obtain comprehensive infectious workup including Lyme, viral serologies, and cultures before considering autoimmune treatment 6, 1.