Optic neuromyelitis optica (NMO), also known as Devic’s disease, is an immune-mediated primary central nervous system (CNS) inflammatory demyelinating disease that primarily involves the optic nerve and spinal cord. Optic neuromyelitis optica is more common in CNS inflammatory demyelinating disease in Asian populations such as China and Japan, and less common in Western populations in Europe and the United States.
It has long been debated whether NMO is a separate disease entity or a subtype of multiple sclerosis (MS), but recent studies have found that NMO-IgG is a more specific immunomarker for NMO, and NMO-IgG is an antibody to CNS aquaporin-4 (AQP4). AQP4 is distributed in the astrocyte peduncle, which is involved in the composition of the blood-brain barrier. Unlike MS, NMO is an inflammatory demyelinating disease of the CNS in which humoral immunity is predominant and cellular immunity is supplementary. Because NMO differs from MS in terms of immune mechanisms, pathological changes, clinical and imaging changes, treatment and prognosis, NMO is considered a different disease entity from MS. Therefore, early identification of NMO and MS should be based on the corresponding clinical symptoms, imaging features and serum AQP4 antibodies, and the treatment should be differentiated accordingly.
I. Diagnosis of optic neuromyelitis optica
(a) Clinical manifestations
Optic neuromyelitis optica is much more common in women than in men, with a female:male ratio of 5 to 10:1, much higher than the female:male ratio in MS patients (2:1). Optic neuritis can occur unilaterally, bilaterally or simultaneously. The onset and progression of the disease is rapid, and the loss of vision can lead to blindness. In particular, dysfunction such as bilateral lower extremity paralysis, bilateral sensory disturbances and urinary retention are significantly worse than in MS, and more likely to have radicular neuralgia, painful muscle spasms and Lhermitte’s sign. Symptoms often worsen or peak within a few days in most patients. Recovery of visual impairment is worse in NMO patients than in MS, and visual impairment in NMO patients is less effective than in MS with high-dose methylprednisolone shock therapy. Some NMO may involve the brainstem and manifest as vertigo, nystagmus, diplopia, intractable eructation and vomiting, choking on water, and dysphagia. Some NMO is purely an injury to the optic nerve and spinal cord without accompanying lesions in the brain, and some NMO can find a few demyelinating lesions in the brain without meeting the diagnostic imaging criteria for MS.
Between % and 90% of NMO patients show a recurrent disease course, with 60% of patients reported to relapse within 1 year and 90% within 3 years. The annual recurrence rate of most NMOs is higher than that of MS, and a small proportion of Western NMOs have a monochronic course, with bilateral optic neuritis and myelitis occurring simultaneously or in close proximity (within 1 month) being more common in monochronic NMOs.
Overall, the prognosis of NMO is worse than that of MS. About half of the patients have severe monocular visual impairment or blindness within 5 years, and about 50% of patients with recurrent NMO are unable to walk independently 5 years after onset. Unlike MS, NMO is less likely to develop into a secondary progressive form.
Some patients with NMO may have other autoimmune diseases, such as systemic lupus erythematosus, dry syndrome, mixed connective tissue disease, myasthenia gravis, hyperthyroidism, Hashimoto’s thyroiditis, polyarteritis nodosa, etc. Other autoimmune antibodies, such as antinuclear antibodies, anti-SSA/SSB antibodies, anticardiolipin antibodies, etc., may also be detected in the serum. However, care should be taken to distinguish between primary NMO and secondary optic nerve spinal cord injury (e.g., caused by SLE).
(b) Optic neuromyelitis optica spectrum disorders (NMOSDs) refers to NMO and related diseases, most patients are serum NMO-IgG positive, but the clinical manifestations are different.
1. Classic Devic’s NMO is a monochronic course of acute optic neuritis and myelitis, in which bilateral optic neuritis and myelitis occur simultaneously or in close proximity, and the lesions are limited to the optic nerve and spinal cord. This monochronic NMO has been reported in the West, but is rare in Asia, and Chinese NMO cases are basically recurrent.
Compared with monochronic NMO, recurrent NMO is more common in women, with a female to male ratio of up to 10:1. The age of onset is older than MS, and it can be associated with other autoimmune diseases or positive autoimmune antibodies. Relapsing NMO may have mild signs of brainstem, such as nystagmus, diplopia, nausea, dysarthria and dysphagia. In Asian patients, some NMO-type MS belong to this type. For patients with demyelinating lesions always involving only the optic nerve and spinal cord, spinal cord lesions longer than 3 vertebral segments, and positive serum NMO-IgG, recurrent NMO should be considered, and if the lesions involve the optic nerve and spinal cord, and there are multiple demyelinating lesions in the brain consistent with MS changes, MS should be diagnosed.
Recurrent NMO with atypical intracerebral lesions. MRI of NMO brain is mostly normal at the first onset, but MRI may show non-specific and atypical lesions in the brain in the course of later disease. These lesions are usually non-enhancing, and the most common type is the periventricular-ductal-central canal type. Most patients are serum NMO-IgG positive.
4. Recurrent optic neuritis or recurrent acute myelitis (high-risk syndromes for NMO), recurrent optic neuritis or recurrent myelitis, has a high rate of serum NMO-IgG positivity. This type may be an early manifestation of NMO.
(iii) Auxiliary examination
1, cerebrospinal fluid examination: some NMO patients have abnormal cerebrospinal fluid (CSF) examination, such as slightly increased leukocyte count, a few even above 50×106/L, neutrophils are common, and even eosinophils can be seen; while the CSF leukocytes in MS relapse are mostly normal, the highest is usually below 50×106/L. The rate of positive CSF oligoclonal zone in NMO patients (<20%) is significantly lower than that in MS patients (about 85% in the West). The rate of positive CSF oligoclonal zone in NMO patients (<20%) was significantly lower than that in MS patients (approximately 85% in the West). These changes in CSF have some reference significance in differentiating MS.
2, serum NMO-IgG (AQP4 antibody) test: NMO-IgG is a relatively specific autoantibody marker for NMO, which is mostly expressed at the astrocyte peduncle of the blood-brain barrier. serum AQP4 antibody is mostly positive in NMO and negative in MS; therefore, NMO-IgG positivity is one of the reference bases for differentiating NMO from MS. In addition, NMO patients with strong positive NMO-IgG have a higher possibility of recurrence, and patients with positive NMO-IgG should be actively treated with immunosuppressive prophylaxis. there are various methods of NMO-IgG detection, and the sensitivity and specificity of the detection by cell transfection indirect immunofluorescence method are higher.
3.MRI examination
The characteristic manifestation of MRI in patients is long segmental inflammatory demyelinating lesions in the spinal cord, with a continuous length of generally ≥3 vertebral segments, and the lesions are mostly located in the central part of the spinal cord on axial images, involving most of the gray matter and part of the white matter. The lesions are mainly found in the cervical and thoracic segments. In the acute stage, the spinal cord is swollen, and in severe cases, cavity-like changes can be seen, and the lesions can be enhanced after enhancement scans. In patients with MS, the spinal cord lesions are ≤2 consecutive vertebral segments in length, and the lesions are mainly located in the white matter, often on one side, with little swelling of the spinal cord in the acute phase and no significant spinal cord atrophy in the remission phase. Therefore, long spinal cord demyelinating lesions have an important reference value for differentiating MS from NMO.
The affected optic nerve showed swelling and thickening, and the optic nerve sheath showed long T1 and long T2 signals. Pathology demonstrates that the inflammatory response of the optic nerve causes local obstruction of cerebrospinal fluid circulation, resulting in a T2-weighted image with “track-like” high signal. In some patients without hypermetropia, a similar presentation is still present. As the disease progresses, some patients may see punctate high signal changes in the optic nerve. Enhancement scans show small striations of enhancement in the affected optic nerve.
More than half of the patients initially have normal brain MRI examinations, but abnormal nonspecific lesions can be found on subsequent MRI reviews. Most of these lesions are small and nonspecific and do not meet the diagnostic imaging criteria for MS, a few are in the subcortical region, and some are located in the hypothalamus, thalamus, triventricular, periventricular, and pedunculopontine areas.
4. The visual evoked potential P100 latency is significantly prolonged, and some waveforms are reduced in amplitude or cannot be elicited. Prolonged P100 is also seen in a few patients without visual impairment.
5.Serum GFAP test: It is meaningful to distinguish NMO and MS. GFAP is often significantly elevated in the acute phase of NMO, while it is mostly normal in the acute phase of MS.
The rate of positive serum ANAs in NMO patients was 44.4% (36/81), among which the positive rates of ANA, anti-dsDNA, anti-adherent antibody (ACA), anti-SSA antibody and anti-SSB antibody were 35.8% (29/81), 6.2% (5/81), 1.2% (1/81), 24.7 (20/81), 8.6% (7/81), and only one case of positive ANAs in the MS group (1/49).
(iii) Diagnostic criteria
(1) Necessary conditions: (1) optic neuritis; (2) acute myelitis. (2) Supporting conditions: ① abnormal spinal MRI lesions ≥ 3 vertebral segments; ② cranial MRI does not meet the diagnostic criteria for MS; ③ positive serum NMO-IgG. The diagnosis of NMO can be made if all the necessary conditions and two of the supporting conditions are present.
II. Differential diagnosis of optic neuromyelitis optica
It should be differentiated mainly from MS: mainly based on their different clinical manifestations, imaging changes, serum NMO-IgG and the corresponding clinical diagnostic criteria (Table 1).
First-onset optic neuritis or acute myelitis should be differentiated from clinically isolated syndrome (CIS) based on age of onset, male to female ratio, length of optic nerve lesion and whether it is thickened, length of spinal cord lesion, severity and prognosis, cerebrospinal fluid leukocytes and polymorphonuclear cells, oligoclonal bands, IgG index, serum NMO-IgG positivity, and recurrence rate. Among them, long spinal cord lesions and NMO-IgG, the severity has important reference significance
Differentiate from Leber optic neuropathy, transverse myelitis, subacute necrotizing myelopathy, subacute joint degeneration, spinal dural arteriovenous fistula, syphilitic optic neuromyelopathy, spinal cerebellar ataxia, hereditary spastic paraplegia, spinal cord tumor, spinal vascular disease, tropical spastic paralysis, hepatic myelopathy, etc. Certain connective tissue diseases, such as systemic lupus erythematosus, leukoencephalopathy, dry syndrome, and systemic vasculitis with spinal cord injury should also be distinguished from NMO.
Table 1: Differentiation of optic neuromyelitis optica from multiple sclerosis by clinical and ancillary tests
Optic neuromyelitis optica
Multiple sclerosis
Race
History of antecedent infection or vaccination
More frequent in Asians
Mostly absent
Westerners more often
Can be triggered
Age of onset
Any age, median 39 years
Rare in children and over 50 years old, median 29 years
Sex (female: male)
:
: : : :
Severity of morbidity
Moderately severe prevalence
Mild and moderate prevalence
Legacy of the disease
Blind or severely visually impaired
Non-blind
Clinical course
Relapsing, less often secondary progressive, rarely monochromatic
Relapsing-remitting type in %, eventually progressing to secondary progressive type in most cases, primary progressive type in 15%
Serum
Mostly positive
Mostly negative
Cerebrospinal fluid cells
Leukocytes >5× in most patients
Leukocytes >50× in a few patients
Neutrophils are more common, even eosinophils are seen
Most normal, leukocytes <50×106/ L, predominantly lymphocytes
Positive cerebrospinal fluid oligoclonal zone
Less common (about 20%)
Common (~85% abroad)
index
Mostly normal
Mostly elevated
Spinal cord
Long spinal cord lesions >3 vertebral segments, axial images mostly in the center of the spinal cord, reinforcing
Spinal cord lesions <2 vertebral segments, mostly in the white matter, reinforcing
Brain
None, or punctate, subcortical, hypothalamic, thalamic, peri-ductal, no significant enhancement
Lateral paraventricular white matter, subcortical white matter, cerebellum and brainstem, can be strengthened
Treatment of optic neuromyelitis optica
The treatment should be different from that of MS and should not be copied from MS.
(A) Acute treatment
Glucocorticoid
The use of high-dose methylprednisolone shock therapy can accelerate the remission of the disease, which is also generally in accordance with the three-day decreasing method. The current principle of hormone therapy in the acute phase is: high dose, short course of treatment.
Specific method: Methylprednisolone 1g, IV 1/day x 3 days, 500mg IV 1/day x 3 days, 240mg IV 1/day x 3 days, 120mg IV 1/day x 3 days, 60mg orally x 3 days, 20mg orally 1/day x 3 days, 16mg orally 1/day to maintain a certain time. It should be noted that high-dose shocks should be continued for 3-4 hours per IV drip to avoid cardiac side effects. Another method is: methylprednisolone 1g IV 1/day x 3-5 days, then change to prednisone 60mg orally 1/day x 14 days, later taper to 3-4 tablets per day, or 3-4 tablets every other day to maintain a certain time.
Unlike MS, some NMO patients are hormone-dependent and have recurrent disease during the dose reduction process. For hormone-dependent patients, the hormone reduction process should be slow and can be reduced by 5mg per week to maintenance dose (3-4 tablets per day), and the maintenance time of small dose hormone should be longer than MS.
Most of the side effects of hormone therapy, such as electrolyte disorders, blood sugar, blood pressure, lipid abnormalities, upper gastrointestinal bleeding, etc., can be prevented, but the arrhythmia that can be caused by large doses of hormone should be slowed down and close attention must be paid to hormone shock. Once the arrhythmia occurs, it should be dealt with in time, or even discontinued. In hormone therapy, attention should be paid to calcium supplementation and application of acid-suppressing drugs. In addition, the amount and course of hormone should be controlled as much as possible to prevent hormone-induced complications such as osteoporosis, femoral head necrosis and serious fractures.
Plasma replacement
Some patients with NMO respond poorly to methylprednisolone shock therapy, plasma replacement therapy can be tried and may be effective. Especially in early applications, some have shown significant improvement after 2 plasma replacements. This further confirms the humoral immune mechanism present in NMO. Some clinical trials have shown that about 50% of NMO patients who have failed to respond to hormone shock therapy are still effective when treated with plasma exchange, and it is generally recommended to exchange plasma 3-5 times, with 2-3 L of plasma exchange each time, and most of them are effective after 1 or 2 times.
Intravenous high-dose immunoglobulin
For patients who respond poorly to methylprednisolone shock therapy, IVIg can be used. Clinical experience shows that treating NMO with IVIg is more effective than treating MS. The dosage of immunoglobulin is 0.4g/kg/d, IVIg is usually used for 5 consecutive days as a course of treatment.
Hormone combined with other immunosuppressants
When hormone shock therapy is not effective, especially in patients with other autoimmune diseases, hormone combined with other immunosuppressive therapy can be chosen. For example, the combination of cyclophosphamide treatment terminates the progression of the disease.
(ii) Treatment in remission
The aim is to prevent relapse, and early prophylaxis should be given to those with NMO, NMO high-risk syndrome and serum NMO-IgG positivity after acute exacerbation. First-line drugs include azathioprine, mescaline mofetil, and rituximab if available; second-line drugs include cyclophosphamide, methotrexate, natalizumab (natalizumab, tysabri) and mitoxantrone, etc. Regular IVIG therapy can also be used for NMO treatment. Other immunosuppressive agents such as cyclosporine A, FK506, and leflunomide may also be tried.
Unlike MS, the efficacy of interferon-beta in preventing NMO relapse is uncertain
1. Azathioprine 2-3 mg/(kg?d) by body mass alone or in combination with oral prednisone [1 mg/(kg?d) by body mass], usually tapering off prednisone after azathioprine has taken effect (2-3 months), long-term use of hormones should prevent osteoporosis or even femoral head necrosis. Long-term immunosuppression should be applied to AQP4-positive patients to prevent recurrence. However, some patients with azathioprine can cause side effects such as leukocyte reduction and gastrointestinal tract, so attention should be paid to regular monitoring of blood picture.
2. mescaline molinate Usually 1 to 3 g/d orally, can be used for those who are ineffective or intolerant to azathioprine. Its side effects are mainly gastrointestinal symptoms and increased chance of infection.
. Rituximab Rituximab is a monoclonal antibody against CD20 on the surface of B cells, which is commonly used in China for targeted therapy of B-cell lymphoma, and it is also effective in immune diseases such as rheumatoid arthritis. The results of clinical trials on the application of rituximab for the treatment of NMO have shown significant efficacy of B-cell ablative therapy. Dosage: 375 mg/m2 intravenously once a week for 4 weeks or 1000 mg intravenously for 2 times (2 weeks apart).
3.Cyclophosphamide: 7-25 mg/kg intravenous drip by body mass, once a month for 6 months. Sodium methotrexate (uromitexan) injection can be applied at the same time to prevent hemorrhagic cystitis.
4. Mitoxantrone 12 mg/m2 intravenous drip according to body surface area once a month for 6 months and then 3 times every 3 months. It is effective in preventing recurrence of NMO and can be used for NMO with recurrent attacks and poor results of other treatments, but the cardiotoxicity of mitoxantrone should be monitored.
5.Natalizumab This drug is a recombinant α4-integrin monoclonal antibody, which may be effective in NMO patients who have failed interferon-β treatment, but its long-term application should be noted for its possible side effects. So far, among 67,700 patients treated with natalizumab, 55 patients with progressive multifocal leukoencephalopathy have been reported, of which about 20% died and the rest were left with varying degrees of functional impairment .
Glucocorticoids are not used for MS remission treatment, and it is debatable whether they are also not used for NMO, which should be treated individually, weighing the advantages and disadvantages. It is especially suitable for NMO with high serum autoimmune antibodies. Periodic hormone shocks, such as once every 3 months, have also been reported to reduce NMO relapse, but there are no results from multicenter randomized controlled trials with large samples.
Intermittent intravenous high-dose immunoglobulin Whether intermittent intravenous high-dose immunoglobulin can prevent NMO recurrence has only been reported to be effective in small samples, and there is a lack of large-sample randomized controlled studies. Theoretically and empirically, humoral immunity-based NMO,for
the efficacy of NMO is better than that of MS.
(iii) Symptomatic treatment
Painful spasticity Drugs such as carbamazepine, gabapentin and baclofen can be applied. For more severe trigeminal neuralgia and neuralgia, pregabalin can also be applied.
Chronic pain and sensory abnormalities Amitriptyline, SNRI, NaSSA, pregabalin and other drugs can be applied.
Depression and anxiety Can be treated with SSRI, SNRI, NaSSA drugs and psychological counseling.
Weakness, fatigue Modafinil, amantadine are available.
Tremor Drugs such as benzhexol hydrochloride and aurolol hydrochloride can be applied.
Cystorectal dysfunction Promethazine, oxybutynin, prazosin, etc. may be used for urinary incontinence; urinary retention should be catheterized, and laxatives may be used for constipation, or enemas for severe cases.
Sexual dysfunction Drugs can be applied to improve sexual function, etc.
Cognitive impairment Cholinesterase inhibitors can be applied.
Difficulty in walking Dalfampridine (Ampyra?), a central potassium channel antagonist, may be used.
Spastic hypertonia of the lower extremities Baclofen can be administered orally or, in severe cases, intravertebrally, or Botulinum toxin A can be used.
. Limb function training When high-dose glucocorticoid hormone is applied, excessive activity should not be performed to avoid aggravating osteoporosis and weight-bearing of the femoral head. When the dose is reduced to a small oral dose, activity can be encouraged and appropriate rehabilitation training can be performed.