Beyond multiple sclerosis, neurology encompasses a growing spectrum of immune-mediated disorders that require targeted pharmacotherapy: neuromyelitis optica spectrum disorder (NMOSD), MOG antibody-associated disease (MOGAD), autoimmune encephalitis, paraneoplastic syndromes, autoimmune dementias, IgG4-related disease, and others. Each has distinct pharmacology, and the rapid emergence of disease-specific biologics has transformed outcomes. This page covers the major non-MS neuroimmunological conditions and their pharmacotherapy.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Pathophysiology

  • Autoantibodies against aquaporin-4 (AQP4-IgG) → complement-mediated astrocyte damage.
  • ~10-15% are seronegative; some MOG-IgG positive.
  • Severe optic neuritis, transverse myelitis, area postrema syndrome (intractable vomiting/hiccups), brainstem syndromes.
  • Higher relapse rate than MS; greater disability per relapse.

Acute Treatment

  • High-dose IV methylprednisolone (1 g/day × 3-5 days).
  • Plasmapheresis for steroid-refractory or severe.
  • IVIG occasionally.

Chronic Maintenance (Disease Prevention)

  • Eculizumab (Soliris): terminal complement (C5) inhibitor; FDA-approved for AQP4-IgG+ NMOSD; SC every 2 weeks; high cost; meningococcal vaccination required.
  • Ravulizumab (Ultomiris): longer-acting C5 inhibitor; every 8 weeks; FDA-approved.
  • Inebilizumab (Uplizna): anti-CD19; depletes B cells (broader than CD20); FDA-approved for AQP4-IgG+ NMOSD.
  • Satralizumab (Enspryng): anti-IL-6 receptor; FDA-approved; SC every 4 weeks.
  • Rituximab (off-label): anti-CD20; commonly used despite not being FDA-approved for NMOSD; lower cost than newer biologics.
  • Mycophenolate, azathioprine: older alternatives; less effective; less commonly used now.

Avoid in NMOSD

  • Interferon-β (can worsen NMOSD).
  • Fingolimod (can worsen NMOSD).
  • Natalizumab (can worsen NMOSD).
  • Critical: differentiate NMOSD from MS before DMT choice; testing AQP4-IgG essential when atypical features (severe ON, longitudinally extensive transverse myelitis, area postrema syndrome).

MOG Antibody-Associated Disease (MOGAD)

  • Distinct from NMOSD; antibodies against myelin oligodendrocyte glycoprotein.
  • Bilateral optic neuritis, transverse myelitis, ADEM-like presentations.
  • Often monophasic but can relapse.
  • Some patients respond to NMOSD treatments; some require different approach.
  • Acute: methylprednisolone; consider plasmapheresis.
  • Maintenance: rituximab, IVIG, mycophenolate; emerging data on satralizumab and inebilizumab.

Autoimmune Encephalitis

Categories

  • Antibody-mediated (cell surface antigens): anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-AMPA receptor, anti-GABA-B receptor, anti-DPPX.
  • Antibody-mediated (intracellular antigens): anti-Hu, anti-Yo, anti-Ri, anti-Ma2 — often paraneoplastic; poorer response to immunotherapy.
  • Some seronegative; respond to immunotherapy.

Treatment Approach

  • First-line immunotherapy: high-dose IV methylprednisolone (1 g/day × 3-5 days); IVIG (2 g/kg over 2-5 days); plasmapheresis.
  • Second-line: rituximab (anti-CD20), cyclophosphamide.
  • Third-line / refractory: tocilizumab (anti-IL-6R), bortezomib (proteasome inhibitor); experimental approaches.
  • Maintenance: mycophenolate, azathioprine, rituximab.
  • Tumor screen: critical for paraneoplastic; ovarian teratoma for anti-NMDA receptor.
  • Tumor removal: often dramatically helps if paraneoplastic.

Anti-NMDA Receptor Encephalitis Specifically

  • Young women (often); psychiatric symptoms, dyskinesias, autonomic instability, seizures.
  • Ovarian teratoma in ~50% of women.
  • First-line: steroids + IVIG or plasmapheresis + tumor removal if present.
  • Second-line: rituximab + cyclophosphamide.
  • Good prognosis with early treatment; weeks to months recovery.

Paraneoplastic Neurological Syndromes

  • Often associated with: small cell lung cancer, breast cancer, ovarian, testicular, lymphoma.
  • Intracellular antibodies (anti-Hu, anti-Yo): often refractory to immunotherapy; tumor treatment is mainstay.
  • Cell-surface antibodies: better immunotherapy response.
  • Immunotherapy: steroids, IVIG, plasmapheresis, rituximab, cyclophosphamide.
  • Always search for underlying malignancy.

Myasthenia Gravis

Symptomatic

  • Pyridostigmine: 30-60 mg q4-6h.
  • Side effects: SLUDGE; muscle fasciculations.

Immunosuppressive

  • Prednisone: induction 60-80 mg/day; taper over months; long-term low-dose maintenance.
  • Azathioprine, mycophenolate: steroid-sparing agents; weeks to months for onset.
  • Methotrexate, cyclosporine, tacrolimus: alternatives.
  • IVIG, plasmapheresis: acute exacerbation; pre-surgical preparation.

Newer Biologics

  • Eculizumab (Soliris): terminal complement inhibitor; FDA-approved for refractory MG.
  • Ravulizumab (Ultomiris): longer-acting complement inhibitor.
  • Rozanolixizumab (Rystiggo): anti-FcRn; reduces pathogenic IgG; SC.
  • Efgartigimod (Vyvgart): anti-FcRn; IV; reduces total IgG.
  • Rituximab (off-label): anti-CD20; especially effective in MuSK-positive MG.
  • Zilucoplan: small-molecule complement C5 inhibitor.

Myasthenic Crisis

  • Respiratory failure; ICU.
  • IVIG or plasmapheresis.
  • Avoid muscle-weakening drugs: aminoglycosides, fluoroquinolones, magnesium, succinylcholine careful use, certain anesthetics.

Inflammatory Demyelinating Neuropathies

Guillain-Barré Syndrome (GBS)

  • IVIG (0.4 g/kg/day × 5 days) or plasmapheresis: standard.
  • Steroids ineffective (do not use).
  • Supportive care (respiratory monitoring, autonomic).

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

  • IVIG, steroids, plasmapheresis: first-line.
  • Maintenance: SC IG (Hizentra, Hyqvia); IVIG every 3-6 weeks; corticosteroids; immunosuppressants.
  • Rituximab: off-label for refractory.

Stiff-Person Syndrome / Stiff-Person Spectrum

  • Anti-GAD antibodies often.
  • Diazepam, baclofen: symptomatic.
  • IVIG: helpful in many.
  • Rituximab: emerging.
  • Plasmapheresis: severe.

Autoimmune Dementias

  • Anti-LGI1, anti-CASPR2 limbic encephalitis can present with rapid cognitive decline; treatable with immunotherapy.
  • Hashimoto encephalopathy: anti-thyroid antibodies; responds to steroids.
  • Suspect autoimmune in: rapid cognitive decline, fluctuating symptoms, MRI abnormalities, abnormal CSF, seizures.

IgG4-Related Disease

  • Pachymeningitis, orbital pseudotumor, hypophysitis.
  • Steroids first-line.
  • Rituximab effective.

Neurosarcoidosis

  • Steroids: induction and maintenance.
  • Methotrexate, mycophenolate: steroid-sparing.
  • Anti-TNF (infliximab): refractory.
  • Cyclophosphamide: severe.

Vasculitis

Primary CNS Vasculitis

  • Steroids + cyclophosphamide induction; mycophenolate or rituximab maintenance.

Giant Cell Arteritis

  • High-dose steroids urgently to prevent blindness.
  • Tocilizumab (anti-IL-6R): steroid-sparing.

🔍 Did You Know?

The recognition that some MS DMTs can dramatically worsen NMOSD is one of the most important diagnostic-therapeutic principles in neuroimmunology. Interferon-β, fingolimod, and natalizumab — all effective MS therapies — can cause serious NMOSD relapses, sometimes irreversible. This is particularly critical because NMOSD and MS can look clinically similar early on — both can present with optic neuritis, transverse myelitis, and brain lesions. The clinical implication is profound: testing for AQP4-IgG (and MOG-IgG) before starting any MS DMT is now standard of care for patients with atypical features. Atypical features that should prompt testing include: severe optic neuritis (especially bilateral), longitudinally extensive transverse myelitis (≥3 vertebral segments), area postrema syndrome, intractable nausea/vomiting/hiccups, severe brainstem syndromes, or onset after age 50 with atypical MRI. The 2015 IPND diagnostic criteria for NMOSD now standardize this. The lesson generalizes: pre-treatment diagnostic certainty is essential for any potentially harmful therapy, and the cost of an AQP4-IgG test ($100-500) is trivial compared to the cost of a misdirected DMT (causing permanent disability). For practicing neurologists, the take-home: any new “MS” diagnosis with atypical features deserves AQP4-IgG testing, and any catastrophic worsening on MS DMT should prompt urgent re-evaluation for NMOSD.

Pitfalls and Pearls

  • NMOSD: AQP4-IgG+; severe; complement-mediated.
  • Avoid in NMOSD: interferon-β, fingolimod, natalizumab — worsen disease.
  • NMOSD biologics: eculizumab, ravulizumab, inebilizumab, satralizumab.
  • Rituximab: off-label NMOSD use; cost-effective.
  • MOGAD: distinct from NMOSD; may respond to immunotherapy.
  • Autoimmune encephalitis: first-line steroids + IVIG/plasmapheresis; second-line rituximab/cyclophosphamide.
  • Anti-NMDA receptor encephalitis: search for ovarian teratoma; tumor removal helps.
  • Paraneoplastic: intracellular antigens (anti-Hu, anti-Yo) often refractory; tumor treatment mainstay.
  • MG newer biologics: eculizumab, ravulizumab, rozanolixizumab, efgartigimod, zilucoplan.
  • FcRn inhibitors (efgartigimod, rozanolixizumab): reduce pathogenic IgG.
  • MuSK MG: rituximab particularly effective.
  • GBS: IVIG or plasmapheresis; steroids NOT effective.
  • CIDP: IVIG, steroids, plasmapheresis; maintenance SCIG (Hizentra).
  • Stiff-person syndrome: anti-GAD; IVIG, rituximab, diazepam.
  • Neurosarcoidosis: steroids + methotrexate or anti-TNF.
  • GCA: urgent steroids; tocilizumab steroid-sparing.
  • Eculizumab/ravulizumab: meningococcal vaccination required.

References

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  2. Marignier R, Hacohen Y, Cobo-Calvo A, et al. Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol. 2021;20(9):762-772.
  3. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
  4. Howard JF Jr, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT). Lancet Neurol. 2021;20(7):526-536.
  5. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.
  6. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625.