What are the severe central nervous system manifestations of Sjögren's syndrome, their typical clinical presentations, diagnostic work‑up, and recommended acute and maintenance therapies?

Severe CNS Manifestations in Sjögren's Syndrome

Severe CNS involvement in Sjögren's syndrome requires aggressive immunosuppression with intravenous methylprednisolone combined with cyclophosphamide as first-line therapy, initiated within hours of presentation to prevent irreversible neurological damage.

Clinical Presentations of Severe CNS Disease

The spectrum of life-threatening CNS manifestations in Sjögren's syndrome includes:

Myelopathy

• Acute transverse myelitis is the most frequent severe spinal cord manifestation, occurring in approximately 1% of all Sjögren's patients and carrying high mortality 1, 2
• Patients present with rapidly evolving symptoms showing either lower motor neuron dysfunction (flaccidity, hyporeflexia) or upper motor neuron dysfunction (spasticity, hyperreflexia) 3
• Progressive myelitis, Brown-Séquard syndrome, and neurogenic bladder are additional presentations 1, 4
• Longitudinal myelopathy involving more than three spinal cord segments may occur 3
• Optic neuritis frequently accompanies spinal cord involvement (21-48% of cases) 3, 1

Focal Cerebral Disease

• Cerebral vasculitis presenting with focal deficits represents a life-threatening manifestation 3, 2
• Focal cerebral deficits including hemiparesis, aphasia, dysphasia, seizures, monoparesis, cranial nerve palsies, stupor, and coma 2
• Demyelinating disease with motor deficit requires urgent intervention 3

Diffuse CNS Involvement

• Aseptic meningoencephalitis can occur, sometimes recurrently 2
• Subacute encephalopathy with severe intractable neuropathic pain 5

Diagnostic Work-Up

Neuroimaging

• Contrast-enhanced spinal cord MRI is mandatory to exclude cord compression and detect T2-weighted hyperintense lesions (sensitivity 70-93%) 3
• Brain MRI should be performed when other CNS symptoms coexist or to differentiate from demyelinating disorders 3
• MRI demonstrates non-enhancing ill-defined high intensity signals in brain parenchyma and multifocal intramedullary contrast-enhancing lesions with cord swelling 5

Laboratory Studies

• Serum NMO IgG (aquaporin) antibodies should be tested when longitudinal myelopathy (>3 segments) is present to diagnose co-existing neuromyelitis optica 3
• Anti-Ro(SSA) antibodies are detected in approximately 87% (7 of 8) of patients with CNS involvement and correlate with vasculitis 2
• Antiphospholipid antibodies should be checked, as their presence indicates ischemic/thrombotic mechanisms and influences treatment 3

CSF Analysis

• Mild-to-moderate CSF abnormalities occur in 50-70% but are non-specific 3
• Microbiological studies are critical to exclude infectious myelitis before initiating immunosuppression 3
• Intensely inflammatory CSF resembling bacterial or HSV meningitis necessitates antimicrobial/antiviral therapy while awaiting confirmatory studies 3

Electrodiagnostic Studies

• Visual-evoked potentials may detect bilateral optic nerve damage before clinical manifestation 3
• EEG is nonspecific but may support diagnosis 4

Acute Treatment

First-Line Therapy

Intravenous methylprednisolone combined with intravenous cyclophosphamide must be initiated promptly, within the first few hours of presentation 3, 1

• High-dose glucocorticoids should be given early while awaiting MRI confirmation and continued if infection is ruled out 3
• Neurological response paralleled by MRI improvement occurs within days to 3 weeks 3
• Timing is critical: delay >2 weeks in initiating therapy is associated with severe neurological deficit 3

Alternative Acute Therapies

• Plasma exchange therapy should be used in severe cases not responding to initial immunosuppression 3, 1
• Anticoagulation therapy is indicated for antiphospholipid-positive myelopathy with good results 3
• Intravenous immunoglobulin may provide acute symptom relief 1

Critical Prognostic Factors

Poor outcomes are associated with:

• Extensive spinal cord MRI lesions 3
• Reduced muscle strength or sphincter dysfunction at presentation 3
• Presence of antiphospholipid antibodies 3
• Delay (>2 weeks) in treatment initiation 3

Maintenance Therapy

Preventing Relapses

• Relapses occur in 50-60% during corticosteroid dose reduction, underscoring the absolute need for maintenance immunosuppressive therapy 3, 1
• Chronic immunosuppressive therapy is required to prevent recurrence 3

Maintenance Agent Selection

According to EULAR recommendations for systemic Sjögren's:

• Azathioprine or mycophenolate mofetil are first-line maintenance options following initial cyclophosphamide 6
• Azathioprine requires TPMT testing before initiation and monitoring for pneumonitis, GI upset, hepatotoxicity, and bone marrow suppression 6
• Mycophenolate requires monitoring for nausea, diarrhea, hepatotoxicity, and bone marrow suppression 6
• Methotrexate can be considered as an alternative immunosuppressant 1, 7

Refractory Disease

• Rituximab (1 g IV every 15 days x2) should be considered for severe, refractory systemic disease not responding to standard immunosuppression 6, 7
• Chlorambucil may be used when cyclophosphamide fails or is not tolerated 1, 7
• Anti-TNF agents (infliximab, etanercept) have unclear efficacy for CNS manifestations but may be considered when all other modalities fail 1, 7

Symptomatic Management

Neuropathic Pain

• Gabapentin, pregabalin, duloxetine, venlafaxine, or carbamazepine for intractable neuropathic pain 8, 5
• Combination therapy may be necessary for severe pain (e.g., gabapentin + venlafaxine + carbamazepine) 5

Common Pitfalls

• Avoid corticosteroid monotherapy: The combination of steroids with cyclophosphamide is superior to steroids alone 3, 1
• Do not delay treatment: Waiting >2 weeks dramatically worsens prognosis 3
• Rule out infection aggressively: CSF studies must exclude infectious causes before continuing immunosuppression 3
• Screen for antiphospholipid antibodies: Their presence changes management to include anticoagulation 3
• Plan for maintenance therapy from the outset: High relapse rates mandate long-term immunosuppression 3, 1
• Pneumocystis prophylaxis is necessary with cyclophosphamide, and IV route should be used to reduce bladder cancer risk 6