Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of CNS that preferentially affects the optic nerves and spinal cord. It was formerly known as Devic’s disease, an severe variant of multiple sclerosis (MS) and now no longer considered.
It has distinctive and specific clinical, radiological and pathological features.(1) NMO & it’s limited forms are known as NMO spectrum disorders (NMOSD). Most NMOSD are associated with an antibodies to Aquaporin-4 channel ( AQ-4 IgG). In fewer percentages of AQ-4 seronegative cases, it is associated with Myelin oligodendrocytic antibody ( MOG Ab).(2,5,6)2. Epidemiology NMO occurs in all major ethnic groups, with prevalence of 0.
5 and 10 per 100,000.(3,4) It has a strong female predilection as in other autoimmune disorders with female to male ratios range from 2:1 to 10:1.(5) The median age of onset is 39 years, but the disease also occurs in children and elderly. (6) Its prevalence is high in Asia & West Indies and low in Caucasians, North America & Australia. (6,7)Neuromyelitis optica is a sporadic disease, but familial cases can also occur. (3% of patients).
(7,8) Human leukocyte antigens (HLAs) associated with high risk includes DRB1*0301 in white people and DP B1*0501 in Asians. (6)3. Clinical presentationThe classic clinical manifestation of NMO is recurrent acute attacks of unilateral or bilateral ON and/or transverse myelitis with incomplete recovery between attacks.(1,6,9) Relapsing course is seen in 90% of patients & remaining 10% have monophasic course. 60% of the patients experience a relapse within one year and 90% within three years after the first attack. (5,6) Particularly, patients who are AQ-4 seropositive with recurrent optic neuritis (ON) are or the first episode of LETM are at high risk of relapse. (5)Various limited forms have been recently included which are described below(6)3.1 Optic Neuritis (ON) It typically presents with reduced visual acuity and eye pain aggravated by eye movements.
Patients of simultaneously bilateral ON or severe ON with poor recovery despite treatment & noncentral scotoma deficits such as altitudinal field defects should raise suspicion.(1,10) The lesions are typically longer involving more than half the length of optic nerve and involve the posterior aspect of the nerve or the chiasm.MRI may show increased signal on fat suppressed T2-weighted sequences or T1 gadolinium enhancement in the optic nerve or optic chiasm.(9,11)3.2 Transverse Myelitis (TM)TM is characterised by severe spinal cord dysfunction which often results in complete spinal cord syndrome (c.f.
with MS) with paraparesis or quadriparesis, bladder dysfunction, and sensory loss caudal to the level of the cord lesion. Pain is particulary prominent. Recovery may be poor despite treatment.MRI shows “longitudinally extensive transverse myelitis” (LETM), lesions extending over 3 or more spinal cord segments, involving the cervical or thoracic cord.fig2 Cervical lesions extending into the medulla has high predictive value for NMOSD. Lesions preferentially involves the central grey matter which usually show enhancement with gadolinium ( c.f.
with MS) fig 1 Fig 1 T2 MRI of NMOSD patient showing central hyperintensity extending from C1 to D43.3 Acute brainstem syndromeThis occurs frequently (34%). (23) The common symptoms are vomiting (33%), hiccups (22%), oculomotor dysfunction (20%), and pruritus (12%). Less common symptoms include hearing loss, facial palsy, vertigo, vestibular ataxia, and trigeminal neuralgia.
Lesions are typically peri-ependymal. 3.4 Area postrema syndromeIt is characterized by intractable hiccups and/or nausea and vomiting(43%).
(13) It may be the presenting manifestation in upto 10% of the cases. MRI shows lesions involving dorsal medulla (especially area postrema). It shows good response to steroids.3.
5 Acute diencephalic syndrome It may manifest with various endocrinopathies like SIADH, narcolepsy, hypo- or hyperthermia, anorexia or obesity, hyperprolactinemia. MRI shows lesions in hypothalamus & areas adjacent to basilar cistern or the third ventricle.3.6 Symptomatic cerebral syndromeIt may present in the form of encephalopathy (large hemispheric lesions), PRES or focal neurological deficits. 4. DIAGNOSTIC EVALUATIONThe initial diagnostic evaluation should include serologic testing for AQP4-IgG,CSF analysis and neuroimaging of the brain and spine with MRI.4.1 Serum Aquaporin 4–Immunoglobulin G TestingIt is a specific NMO biomarker and play an essential role in the disease pathogenesis.
(6,7) S AQ-4 abs have 73% sensitivity and 91% specificity for clinically defined NMO (6) Sensitivity depends on analytical methods used for the detection of AQP-4-IgG and is highest for cell-based assays. Around 10%–25% of NMO patients are seronegative for AQP4-IgG 6. Antibodies against myelin oligodendrocyticglycoprotein (MOG) are found in fraction of AQP4-seronegative patients. In contrast with AQ-4 positive patients, MOG positive patients have higher frequency of simultaneous ON, milder TM of cervical or lumbosacral cord, and better prognosis.(14)4.2 Cerebrospinal fluid (CSF) examinationCSF studies should include cell count, cytology, protein, albumin CSF–serum ratio,immunoglobulin (IgG, IgA, IgM) CSF–serum ratios, and oligoclonal bands (OCBs). It is helpful in distinguishing NMOSD from MS.Significant pleocytosis (>50 cells/mm3) with a high proportion of neutrophils and high protein level (100 to 500 mg/dL) is common in NMO, unlike in MS 1,6,8.
Oligoclonal IgG bands are present in 85%–90% of patients with MS, but are uncommon in patients with NMO (15%–30%).(1,6,8) The albumin quotient may be elevated, particularly during a relapse, indicating blood-brain barrier disruption. Glial fibrillary acidic protein (GFAP)is significantly elevated which reflects prominent astrocyte damage unique of NMOSD.(15) CSF IL-6 is elevated which is not observed in MS.4.
3 NeuroimagingPatients should undergo MRI with and without gadolinium enhancement of the brain and spine, as well as optic nerve MRI in cases suspicious of ON. Imaging features associated with the most common clinical syndromes are described in the ‘clinical presentation’ section. Brain MRI may reveal nonspecific deep WM lesions which are typically extensive with irregular & indistinct borders and clinically silent. Acute brain lesions may enhance with gadolinium with different patterns like “cloudlike”, “pencil thin ” and rarely meningeal enhancement. (16)5. DIAGNOSTIC CRITERIAThe International Panel for Neuromyelitis Optica Diagnosis (IPND) revised diagnostic criteria and published in 2015.
(11) The new criteria unify the concepts of NMO & NMOSD and stratify it further into seropositive and seronegative by serological testing. Diagnosis is based on the presence of “six core clinical characteristics”, AQ-4 antibody status, & MRI imaging features. More stringent clinical criteria with additional neuroimaging features are required for seronegative NMO diagnosis . These criteria are highlighted in box1.According to IPND, NMOsd diagnosis can be made only when the patient hasexperienced at least one clinical attack. Asymptomatic seropositivity for AQP4-IgG or asymptomatic MRI lesions characteristic for NMOsd are insufficient for the diagnosis. Presence of some clinical features indicate alternative diagnosis (Red flags) which are shown in Table 1.
Table 1 :Findings Atypical for Neuromyelitis Optica Spectrum Disorder ( a,b)6. TREATMENT Treatment recommendations are based upon data from observational studies and by the consensus from clinical experience of experts.6.1 Acute attacks :NMOSD patients with acute attacks, both initial and recurrent should be treated as soon as possible. Initial treatment with high-dose intravenous methylprednisolone (1 gram daily for three to five consecutive days) is usually given.Plasma exchange is indicated in patients with severe symptoms unresponsive to steroids.
usually done on alternative days up to a total of seven exchanges.6.2 Maintenance therapy:There is no well-established or optimal therapy for the maintenance of remission and prevention of relapse. Observational studies show improved outcomes with several immunosuppressive agents, including rituximab, mycophenolatemofetil (MMF), azathioprine (AZA), and mitaxantrone. . Initial and maintenance treatment of seronegative disease is similar to the seropositive disease 17.For further details, see chapter 13 Immunotherapy ?