What is the best course of treatment for a 50-year-old patient with follicular lymphoma on immunotherapy presenting with lower extremity weakness, diplopia, and vertigo, with bacteriuria and proteinuria, and negative CT, CTA, and MRI scans?

Immunotherapy-Related Neurological Toxicity Requiring Urgent Evaluation

This patient is presenting with a constellation of neurological symptoms (lower extremity weakness, diplopia, vertigo) while on immunotherapy for follicular lymphoma, which raises immediate concern for immune-related adverse events affecting the nervous system, particularly immune-mediated encephalitis, meningitis, or neuromyelitis—this requires urgent discontinuation of immunotherapy, high-dose corticosteroids, and comprehensive infectious workup given the concurrent bacteriuria.

Immediate Management Priorities

Discontinue Immunotherapy and Initiate Immunosuppression

• Immunotherapy must be held immediately given the high suspicion for immune-related neurological toxicity presenting with multifocal CNS symptoms (diplopia suggesting cranial nerve involvement, vertigo suggesting brainstem/cerebellar involvement, and lower extremity weakness suggesting spinal cord or peripheral nerve involvement) 1
• Initiate high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day IV) as first-line treatment for suspected immune-related neurological adverse events, as these can be life-threatening if untreated 1

Rule Out Infectious Etiologies

• Lumbar puncture with comprehensive CSF analysis is mandatory including:

  • Cell count with differential, protein, glucose
  • Bacterial culture and Gram stain
  • PCR for Borrelia burgdorferi (Lyme disease), given the case report of seronegative neuroborreliosis in a patient with follicular lymphoma post-rituximab presenting with neurological symptoms 2
  • Viral PCR panel (HSV, VZV, enterovirus)
  • Cryptococcal antigen and fungal studies given immunosuppression
  • Cytology to rule out lymphomatous meningitis

• The bacteriuria identified on urinalysis requires immediate attention with urine culture and sensitivity, as systemic infection could contribute to neurological symptoms or represent concurrent sepsis 2

Additional Urgent Diagnostic Studies

• MRI of the entire neuraxis (brain and spine) with and without gadolinium should be repeated with specific attention to:

  • Leptomeningeal enhancement suggesting meningitis or lymphomatous involvement
  • Spinal cord signal abnormalities suggesting transverse myelitis
  • Brainstem lesions that could explain diplopia and vertigo
  • The initial "negative" MRI may have missed subtle findings or the process may be evolving 2

• Nerve conduction studies and EMG if peripheral neuropathy is suspected as a cause of lower extremity weakness, as immune-related peripheral neuropathies (including Guillain-Barré syndrome) can occur with immunotherapy 1

• Serum autoantibody panel including anti-neuronal antibodies (anti-Hu, anti-Yo, anti-NMDA receptor) to evaluate for paraneoplastic neurological syndromes, which can occur in lymphoma patients 1

Critical Differential Diagnosis Considerations

Immune-Related Adverse Events (Most Likely)

• Immune-mediated encephalitis, meningitis, or myelitis are well-documented complications of immunotherapy, particularly with checkpoint inhibitors but also reported with rituximab-based regimens 1, 2
• The temporal relationship to immunotherapy and multifocal neurological presentation strongly suggests this etiology 2

Infectious Complications in Immunocompromised Host

• Rituximab causes profound B-cell depletion and increases infection risk, particularly for opportunistic pathogens 2
• Neuroborreliosis (Lyme disease) can present with cranial neuropathies, meningitis, and radiculopathy—critically, serology may be falsely negative in rituximab-treated patients, making CSF PCR essential 2
• Progressive multifocal leukoencephalopathy (PML) from JC virus reactivation is a rare but devastating complication of rituximab 2

Lymphomatous CNS Involvement

• While less likely given negative imaging, follicular lymphoma can rarely involve the CNS, and transformation to aggressive lymphoma with CNS spread must be excluded 1
• CSF cytology and flow cytometry are essential 1

Metabolic/Toxic Etiologies

• The proteinuria raises concern for renal dysfunction potentially contributing to metabolic encephalopathy
• Comprehensive metabolic panel, ammonia, and thyroid function should be checked 1

Treatment Algorithm Based on Findings

If CSF/Infectious Workup Positive

• For confirmed neuroborreliosis: Initiate IV ceftriaxone 2g daily for 2-4 weeks, as demonstrated effective in the case of seronegative neuroborreliosis post-rituximab 2
• For bacterial meningitis: Broad-spectrum antibiotics (vancomycin + ceftriaxone + ampicillin) pending culture results
• Continue corticosteroids cautiously if immune-mediated component suspected, but prioritize antimicrobial therapy

If Immune-Related Adverse Event Confirmed

• Continue high-dose corticosteroids for minimum 4-6 weeks with slow taper based on clinical response 1
• If inadequate response to corticosteroids within 48-72 hours, escalate to:
  • IVIG 2 g/kg divided over 2-5 days, OR
  • Plasmapheresis for severe cases
  • Consider additional immunosuppression (mycophenolate, cyclophosphamide) for refractory cases 1

If Lymphomatous CNS Involvement Confirmed

• High-dose methotrexate-based CNS-directed chemotherapy is required 1
• Intrathecal chemotherapy may be indicated 1

Management of Underlying Follicular Lymphoma

Reassess Disease Status

• Repeat biopsy is strongly recommended to rule out transformation to aggressive lymphoma, which occurs in a critical minority of patients and dramatically worsens prognosis 1, 3
• PET/CT to assess systemic disease burden and identify sites for biopsy 1

Future Treatment Considerations

• If immunotherapy-related toxicity confirmed, permanent discontinuation of the offending agent is typically required 1
• Alternative treatment options for follicular lymphoma include:
  • Bendamustine-based regimens if CHOP was previously used 1
  • Radioimmunotherapy for elderly patients with comorbidities 1
  • Lenalidomide with rituximab for relapsed disease 4, 5
  • Targeted agents (tazemetostat for EZH2-mutated disease, PI3K inhibitors) 4, 5

Common Pitfalls to Avoid

• Do not attribute neurological symptoms to "anxiety" or "deconditioning" in immunotherapy patients—always assume immune-related toxicity until proven otherwise 1
• Do not rely solely on serology for Lyme disease in rituximab-treated patients, as B-cell depletion can cause false-negative results; CSF PCR is essential 2
• Do not delay corticosteroids while awaiting diagnostic confirmation if immune-related neurological toxicity is suspected, as these conditions can rapidly progress to permanent disability or death 1
• Do not overlook the proteinuria—this may indicate immune-related nephritis, tumor lysis syndrome, or infection-related glomerulonephritis, all requiring specific management 1
• Do not assume negative initial imaging rules out CNS pathology—repeat imaging with specific sequences and consider lumbar puncture even with normal MRI 2