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 controversial 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
(i) 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.
Eighty to 90% of NMO patients present with a recurrent disease course, with 60% of patients reported to have relapses 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 the most common form of monochronic NMO.
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 cannot 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 (e.g., SLE-induced) optic nerve spinal cord injury.
(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. Classical 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 autoimmune antibody positivity, with poor prognosis. 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, relapsing 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.
(C) Ancillary tests
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). 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, mostly expressed at the astrocyte peduncle of the blood-brain barrier; NMO serum AQP4 antibody is mostly positive, MS serum AQP4 antibody is mostly negative; therefore, NMO-IgG positivity is one of the reference bases to distinguish 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 given immunosuppressive prophylaxis. there are various methods for 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 NMO patients is inflammatory demyelinating lesions in long segments of the spinal cord, with a continuous length of ≥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. The 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 from MS. GFAP is often significantly elevated in the acute phase of NMO, while it is mostly normal in the acute phase of MS.
6. Increased serum autoimmune antibodies. Studies have shown that the positive rate of serum ANAs in NMO patients is 44.4% (36/81), among which the positive rates of ANA, anti-dsDNA, anti-adherent antibody (ACA), anti-SSA antibody and anti-SSB antibody are 35.8% (29/81), 6.2% (5/81), 1.2% (1/81), 24.7% (20/81), 1.2% (1/81), 1.2% (1/81) and 1.2% (1/81), respectively. 24.7% (20/81), 8.6% (7/81), and only one case of positive ANAs in the MS group (1/49).
(iii) Diagnostic criteria
The diagnosis of NMO is recommended by the 2006 Wingerchuk revised diagnostic criteria for NMO: (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.
Differential diagnosis of optic neuromyelitis optica
1, mainly should be differentiated from MS: mainly based on their different clinical manifestations, imaging changes, serum NMO-IgG and the corresponding clinical diagnostic criteria (Table 1).
2. 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 multinucleated cells, oligoclonal zone band, IgG index, positive serum NMO-IgG, recurrence rate, etc. to differentiate. Among them, long spinal cord lesions and NMO-IgG, the severity has important reference significance
3. 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)
5-10:1
2:1
Severity of morbidity
Moderately severe prevalence
Mild to moderate prevalence
Legacy of the disease
May cause blindness or severe visual impairment
Non-blind
Clinical course
>85% relapsing, less often secondary progressive, few monochromatic
85% relapsing-remitting, mostly secondary progressive, 15% primary progressive
Serum NMO-IgG
Mostly positive
Mostly negative
Cerebrospinal fluid cells
Leukocytes >5×106/ L in most patients
Leukocytes >50×106/ L 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)
IgG index
Mostly normal
Mostly elevated
MRI of spinal cord
Long spinal cord lesions >3 vertebral segments, axial images mostly in the central part of the spinal cord, reinforcing
Spinal cord lesions <2 vertebral segments, mostly in the white matter, reinforcing
Brain MRI
None, or punctate, subcortical, hypothalamus, thalamus, peri-catheter, no significant enhancement
Lateral paraventricular white matter, subcortical white matter, cerebellum and brainstem, can be strengthened.
Treatment of optic neuromyelitis optica
The treatment of NMO should be different from MS, and it is not appropriate to copy the treatment method of MS.
(i) Acute treatment
1.Glucocorticoid
The use of high-dose methylprednisolone shock therapy can accelerate the remission of the disease, and is 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.
The specific method: 1g of methylprednisolone, 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 for a certain period of 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 high dose of hormone should be paid attention to the slow pace of hormone shock and must be closely monitored. 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.
2.Plasma replacement
Some NMO patients have poor response to methylprednisolone shock therapy, plasma replacement therapy can be tried and may be effective. Especially in the early application, some of them showed significant improvement after 2 times of plasma replacement. This further confirms the humoral immune mechanism present in NMO. Some clinical trials have shown that about 50% of NMO patients whose treatment with hormone shock is ineffective are still effective when treated with plasma exchange, and it is generally recommended to exchange plasma 3~5 times, with the volume of plasma exchange at 2~3 L each time, and most of them are effective after 1~2 times.
3.Intravenous immunoglobulin (IVIg)
For patients with poor response to methylprednisolone shock therapy, IVIg can be used. From clinical experience, the treatment of NMO with IVIg is more effective than the treatment of MS. The dosage of immunoglobulin is 0.4g/kg/d, IVIg is used for 5 consecutive days as a course of treatment.
4.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. Such as combined with cyclophosphamide treatment, which terminates the progression of the disease.
(ii) Treatment in remission
The aim is to prevent relapse, and early prophylactic treatment 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 (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-β 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 after the effect of azathioprine (2-3 months) the prednisone will be tapered, long-term use of hormones should prevent osteoporosis or even femoral head necrosis. Long-term immunosuppression should be applied in AQP4 antibody-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. The side effects are mainly gastrointestinal symptoms and increased chance of infection.
3.Rituximab Rituximab is a monoclonal antibody against CD20 on the surface of B cells, which is commonly used in the targeted treatment of B-cell lymphoma in China, and the drug also has good effect on 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. Usage: 375 mg/m2 intravenous drip by body surface area, once a week for 4 weeks; or 1000 mg intravenous drip, twice a week (2 weeks apart).
4.Cyclophosphamide: 7-25 mg/kg intravenous drip by body mass, once a month for 6 months. It can be used in conjunction with uromitexan injection to prevent hemorrhagic cystitis.
5. 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.
6.Natalizumab This drug is a recombinant α4-integrin monoclonal antibody, which may be effective in NMO patients who are not treated with interferon-β, but its long-term application should be noted for its possible side effects. So far, among 67,700 patients treated with natalizumab, 55 patients have been reported with progressive multifocal leukoencephalopathy, of which about 20% died and the rest were left with varying degrees of functional impairment .
Some NMO patients have a certain dependence on glucocorticoids, and the reduction of hormone dosage for these patients should be slower than that for MS. It has been reported that low-dose prednisone maintenance therapy can reduce NMO relapse, especially for NMO with increased serum autoimmune antibodies. It is especially suitable for NMO with elevated serum autoimmune antibodies. It has also been reported that regular hormone shock, such as shock once every 3 months, can reduce NMO relapse, but there are no results of multicenter randomized controlled trials with large samples.
8.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
IVIg has better efficacy than MS.
(C) Symptomatic treatment
1. painful spasm Drugs such as carbamazepine, gabapentin and baclofen can be applied. For more intense trigeminal neuralgia and neuralgia, pregabalin can also be applied.
2, chronic pain, abnormal sensation, etc. Amitriptyline, SNRI, NaSSA, pregabalin and other drugs can be applied.
3, depression and anxiety SSRI, SNRI, NaSSA and psychological counseling can be applied.
4.Lethargy and fatigue Modafinil and Amantadine are available.
5.Tremor Benzhexol hydrochloride, Aurolol hydrochloride and other drugs can be applied.
6.Bladder and rectal dysfunction Promethazine, oxybutynin, prazosin, etc. can be used for urinary incontinence; urinary retention should be catheterized, constipation can be used for laxatives, and enemas can be used for heavy cases.
7, sexual dysfunction can be applied to improve sexual function drugs, etc.
8, cognitive impairment can be applied cholinesterase inhibitors, etc.
9.Walking difficulties Dalfampridine (Ampyra™), a central potassium channel antagonist, can be used.
10.Spastic hypertonia of the lower limbs Baclofen can be administered orally, and in severe cases, intravertebral administration or botulinum toxin A can be used.
11.Limb function training When applying high-dose glucocortisol hormone, excessive activities 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, activities can be encouraged and corresponding rehabilitation training can be carried out.