What is the initial treatment for a patient presenting with neurosarcoidosis, particularly in those with a late-onset presentation (LETM)?

Neurosarcoidosis with LETM: Age of Presentation and Initial Treatment

For patients presenting with neurosarcoidosis, including those with longitudinally extensive transverse myelitis (LETM), initiate treatment immediately with high-dose glucocorticoids as first-line therapy, regardless of age at presentation. 1

Initial Treatment Approach

First-Line Therapy: Glucocorticoids

• Glucocorticoids are the mandatory initial treatment for all patients with clinically significant neurosarcoidosis, including LETM presentations 1
• This is a strong recommendation from the European Respiratory Society (ERS) 2021 guidelines, despite very low quality of evidence 1
• The strong recommendation is justified by the high risk of irreversible neurologic loss if treatment is delayed 1
• In a meta-analysis of 1,088 neurosarcoidosis patients, 71% (95% CI 65-77%) who received glucocorticoid monotherapy achieved favorable outcomes 1

Clinical Reasoning for Immediate Treatment

• Neurosarcoidosis is an important cause of death in sarcoidosis patients, with deaths occurring at younger ages compared to pulmonary disease 1
• Symptomatic neurosarcoidosis occurs in 5-20% of sarcoidosis patients 1
• The clinical manifestations have significant deleterious impact on quality of life and can cause permanent disability 1
• LETM represents severe spinal cord involvement requiring urgent intervention to prevent irreversible myelopathy 1

Escalation Algorithm for Refractory Disease

Second-Line: Add Methotrexate

• If disease continues despite glucocorticoids or if glucocorticoid tapering causes relapse, add methotrexate 1
• Methotrexate demonstrated statistically significant reduction in neurosarcoidosis relapse rate (hazard ratio 0.47,95% CI 0.25-0.87; p=0.02) 1
• This is a conditional recommendation with very low quality of evidence 1
• Methotrexate has the strongest evidence among second-line agents 1

Third-Line: Add Infliximab

• For patients failing glucocorticoids plus a second-line agent (methotrexate, azathioprine, or mycophenolate mofetil), add infliximab 1
• Infliximab is typically used in combination with second-line agents, not as monotherapy 1
• A retrospective study of 66 neurosarcoidosis patients showed good neuroimaging and functional outcomes with infliximab-containing regimens 1
• This is a conditional recommendation with very low quality of evidence 1

Alternative Agents for Refractory Cases

• Hydroxychloroquine showed statistically significant reduction in relapse rate (hazard ratio 0.37,95% CI 0.15-0.92; p=0.03) 1
• Azathioprine and mycophenolate mofetil can be considered as second-line alternatives, though evidence is weaker 1
• Cyclophosphamide demonstrated benefit (hazard ratio 0.26,95% CI 0.11-0.59; p=0.001) but is less preferred due to side-effect profile 1

Age-Related Considerations

Important Caveat About Age

• The evidence does not differentiate treatment approaches based on age of presentation 1
• While the question mentions "late-onset presentation (LETM)," LETM refers to longitudinally extensive transverse myelitis (spinal cord involvement), not late age of onset
• Treatment principles remain the same regardless of patient age at presentation 1, 2
• Deaths from neurosarcoidosis occur at younger ages compared to pulmonary sarcoidosis, emphasizing the need for aggressive treatment in all age groups 1

Monitoring and Follow-Up

• Monitor for glucocorticoid response and ability to taper without relapse 1, 2
• In one study, 69% of patients treated with alternative immunosuppressive therapies (started early) improved, compared to only 35% with corticosteroids alone 2
• Early intervention with immunosuppressive therapy in high-risk patients (such as those with LETM) may yield better outcomes 2, 3

Common Pitfalls to Avoid

• Do not delay treatment waiting for biopsy confirmation if clinical and imaging findings are consistent with neurosarcoidosis 1, 4
• Do not use glucocorticoids alone indefinitely—approximately 5-10% of neurosarcoidosis patients die despite treatment, and many require steroid-sparing agents 4, 5
• Do not mistake LETM for late-onset disease—LETM describes the extent of spinal cord involvement (≥3 vertebral segments), not the age at presentation 1
• Do not wait for treatment failure before considering early combination therapy in severe presentations like LETM—early aggressive therapy may prevent irreversible neurologic damage 2, 3