Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) that primarily involves the optic nerve and spinal cord. NMO has long been considered a subtype of multiple sclerosis (MS), but numerous lines of evidence suggest that it has many clinical and pathological manifestations distinct from MS and, therefore, may be a separate disease unit.
1. Clinical manifestations
NMO predominantly affects women, with more than three times as many women as men in relapsed cases, and the average age of onset is nearly 40 years, 10 years later than in classic MS. Japanese survey data show that 7.6% of demyelinating diseases are NMO, while more than 6% of demyelinating diseases in India are NMO.
The first episode of optic neuritis (ON) in NMO peaks with near blindness in about 40% of affected eyes. The ON may be unilateral or bilateral. The acute optic nerve symptoms of NMO are severe, with or without retrobulbar pain. There may be different forms of visual field defects. Recurrent ON often leaves some visual impairment. Some patients may have chronic demyelinating changes in the optic nerve and optic cross on autopsy.
Classic acute myelitis may manifest as a complete transection of the spinal cord, with severe impairment of motor, sensory, and sphincter function on both sides of the spinal cord from hours to days, while similar presentations are rare in classic MS. Lhermitte’s sign, episodic painful muscle spasms, and radicular pain are relatively common in those with relapses.
The current clinical diagnostic criteria for NMO have improved the differential diagnosis with MS. In patients with classic MS, ON and spinal cord symptoms may occur during the course of the disease, but they are not the same as in NMO. Nystagmus, headache, etc. Very few cases of NMO have extraocular muscle paralysis, epilepsy, ataxia, dysarthria, encephalopathy, autonomic dysfunction, and peripheral neuropathy. The diagnosis of most NMO should be made with caution if there are clinical signs of involvement of the brain and brainstem.
Visual impairment in NMO is severe and recovery is poor, whereas MS is relatively less severe, rarely involves both sides, and recovers well. Spinal cord lesions are often unilateral in MS, and symptoms are often asymmetric. In contrast, NMO is often bilateral and the symptoms are relatively symmetrical, but rarely the brainstem and brain are involved.
2. Natural history and course of NMO
NMO has different clinical and imaging features and laboratory findings from typical MS, so these characteristics of the disease determine that NMO has its own independent diagnostic criteria. Patients who meet the diagnosis of NMO may present with a monochronic or multitemporal course. After several years of follow-up, it has been found that less than 25% of NMO cases presenting with unilateral or bilateral ON and myelitis have a monochronic course with no further clinical deterioration. The vast majority of patients had a relapsing course, with the first occurrence of ON and myelitis occurring weeks or even years apart, but within a few months to a few years ON, myelitis, or both recurred. In most cases, the relapsing course occurs earlier. Based on the NMO diagnostic criteria, the percentage of patients with a recurrent course in clinical practice is 55% at 1 year, 78% at 3 years, and 90% at 5 years.
The so-called opticospinal type MS or Asian type MS in Japan has the same clinical presentation, neuroimaging and pathological features as the cases of multiphasic NMO reported in North America. Therefore, it is actually NMO. “Pure” opticospinal MS (defined as clinical follow-up for more than 5 years, showing only optic nerve and spinal cord involvement, with normal cranial MRI except for optic nerve abnormalities) has the same essential features as relapsed NMO. Moreover, the serum autoantibodies used to differentiate NMO from MS were also positive in most Japanese patients with opticospinal MS.
Characteristic clinical manifestations and laboratory tests in the early stages of the disease help to distinguish monochronic from multitemporal NMO and are useful for both diagnosis and prognosis. Initially, MRI and CSF were not considered to be predictive of disease course and severity. Recent studies have confirmed that patients with almost simultaneous bilateral ON and myelitis are more likely to have a monochronic course. Other independent risk factors for a polyphasic course include being female (female:male RR = 10) and having a less severe motor impairment at the time of the first episode of myelitis (RR = 0.48 for every 1-point reduction on the motor impairment scale). The severity of the first episode of ON was not an independent risk factor predicting the course of the disease. These prognostic parameters help to decide whether to apply immunosuppressive therapy prophylactically early in the course of the disease and are a guide to disease course trends and treatment strategies.
Although monochronic NMO patients have more severe episodes, the long-term prognosis is better than that of polychronic patients, with no relapse and no further progression of residual neurological deficits. 22% of monochronic ON patients have residual visual impairment in at least one eye, and more than 50% have recovered. However, the majority of patients with myelitis have permanent residual moderate weakness in at least one limb and sphincter dysfunction, with a 31% incidence of monoplegia or paraplegia. The 5-year survival rate for patients with monochronic NMO is approximately 90%, and the cause of death is not directly related to NMO or to complications arising from bed rest.
Similar to typical MS, the course of relapsing NMO consists of multiple unpredictable, single episodes separated by months or years. Although NMO can be severe with accumulating neurological deficits, the natural history of relapsing NMO is markedly different from that of classic MS. More than half of patients with relapsing NMO have severe visual impairment permanently remaining in at least one eye or are unable to walk due to paraplegia or monoplegia within 5 years of onset. This differs from MS, in which most patients recover better (or heal) after the first episode and have relatively mild impairment until the secondary progressive phase. nmo infrequently presents with a progressive course.
The frequency of recurrence of NMO varies widely. The remission period may last only a few weeks or may be as long as 10 years or more. The 5-year survival rate for recurrent NMO is approximately 68%, and all deaths are due to respiratory failure due to myelitis. The actual incidence of respiratory failure associated with myelitis may be lower because some milder cases that were actually NMO were diagnosed as MS based on the diagnostic criteria prior to the revision. The symptoms of NMO relapse are heavier than those of MS relapse, and a long-term treatment plan should be developed in the early stage of NMO.
3. Laboratory tests
The cerebrospinal fluid examination also plays an auxiliary role. In 30% of patients with acute myelitis in NMO, the cerebrospinal fluid cell count increases and the WBC exceeds 50 cells/mm3, which is rarely seen in typical MS. The CSF cell classification is predominantly neutrophilic, which is also rarely seen in MS.
Electrophoresis and immunofixation techniques showed that approximately 85% of MS patients had at least one oligoclonal band. In contrast, in NMO, the rate of positive CSF oligoclonal bands (20-40%) and other abnormal immunoglobulins (IgG), such as the rate of IgG synthesis, are rare.
Electrophysiology has some diagnostic value for NMO, and visual evoked potentials are diagnostic aids for patients with subclinical lesions of the optic nerve that present only as recurrent myelitis.
One or more autoantibodies, such as antinuclear antibodies, anti-double-stranded DNA antibodies, extractable nuclear antigen antibodies (ENA), and antithyroid antibodies, are often detected in the sera of NMO patients.
The Mayo Clinic group reported the identification of a novel serum autoantibody that can be used to differentiate NMO from classical MS. application of indirect immunofluorescence can reveal this specific marker (called NMO-IgG), which selectively binds to the CNS microvascular, perichondrial, subchondrial and perivascular (Virchow-Robin) gaps. NMO-IgG is the first specific biological marker of NMO and, if proven effective, may also be a strong diagnostic basis in the early stages of pathogenesis.
4.MRI
MRI of the head is useful for the diagnosis of NMO. In patients with clinical manifestations of recurrent optic neuritis and myelitis, the diagnosis of NMO is better supported if the cranial MRI findings are normal, or if there are only nonspecific white matter lesions that do not meet the diagnostic imaging criteria for MS. Patients with a history of relapses with white matter lesions that accumulate over time but present as nonspecific patchy lesions also do not meet the diagnostic criteria for MS imaging. As with all primary demyelinating diseases, there are clinical exceptions that can present very much like NMO but with MS-like brain and brainstem lesions. Therefore, cases such as these should negate the possibility of NMO.
Most NMO patients have spinal cord lesions in 3 or more vertebral segments, with lesions adjacent to each other and significant gadolinium enhancement. In contrast, spinal cord lesions in MS patients rarely exceed 2 vertebrae and are mostly located at the periphery of the spinal cord. With time, the lesions at the NMO spinal cord changed from edema and obvious enhancement to persistent intramedullary T2 abnormal signal with segmental spinal cord atrophy.
5. Pathological manifestations and immune mechanisms
The NMO optic neuropathy showed myelin loss and mild inflammatory cell infiltration. The brain tissue is approximately normal, or there is small patchy myelin loss, glial cell hyperplasia, and peritubular inflammatory cell infiltration.
There are many characteristic changes in the acute phase of the spinal cord lesion. Gross view of the spinal cord reveals swelling, softening, and cavity formation. Microscopic changes ranging from mild inflammatory demyelination to complete hemorrhage and necrosis in the gray and white matter peritubular areas are seen. In most cases there is a heavy infiltration of leukocytes including neutrophils and eosinophils. This heavier inflammatory cell infiltration pattern is completely different from the lymphocyte-dominated mild infiltration of classic MS. The role of eosinophils in the pathogenesis of NMO is unclear and may be either the initial response or secondary to the activation of complement C5a fragments. Recent immunopathological studies on biopsies and autopsies of spinal cord specimens support the association of NMO with humoral immunity, with deposits of IgG and C9 neoantigens (markers of complement activation) found in areas of active myelin destruction, also seen in vessel walls with vascular hyperplasia and fibrotic changes.
6. Diagnostic criteria
Wingerchuck et al. proposed new diagnostic criteria for NMO in 1999, which were
Necessary conditions.
(1) optic neuritis.
(2) acute myelitis.
(3) No involvement outside the optic nerve and spinal cord.
Major supporting conditions.
(1) Negative cranial MRI at presentation (normal or not meeting diagnostic imaging criteria for MS).
(2) Abnormal T2 signal in ≥3 vertebrae on MRI of the spinal cord.
(3) Increased CSF cell count (WBC/mm3>50) or neutrophils/mm3>5.
Secondary supporting conditions.
(1) Bilateral optic neuritis.
(2) Persistent visual acuity below 20/200 in at least one eye.
(3) Persistent weakness in one or more limbs associated with the disease (MRC grade 2 or less).
NMO may be considered if all of the above criteria and one primary or two secondary supporting conditions are met, and if the possibility of optic nerve spinal cord injury due to other autoimmune diseases is excluded.
In 2006, Wingerchuck et al. combined immunoassays and found that serum NMO-IgG antibody positivity was 76% and specificity was 94% in NMO patients. Thus, the diagnostic criteria were modified by removing the secondary supporting conditions, retaining the first two of the mandatory and primary supporting conditions, and replacing the third CSF cell count change with a positive serum NMO-IgG antibody.
7. Treatment
All currently recommended treatment regimens are separate treatment experiences and small, uncontrolled case studies. Treatment includes mono- and multi-temporal NMO acute exacerbation treatment, prevention of complications and rehabilitation exercises. Long-term immunotherapy should only be used in patients with relapsing NMO.
Intravenous corticosteroids, commonly methylprednisolone 1000 mg/d, or dexamethasone 200 mg/d for 5 days, are an option when the acute phase of optic neuritis and myelitis progresses and worsens. The change to oral prednisone after the end of injectable corticosteroids is often used as part of the measures to prevent recurrent NMO attacks. Patients who do not improve or further worsen with high-dose corticosteroid therapy should be intervened with plasma exchange therapy within a few days.
Patients with relapsing NMO have a steady accumulation of corresponding symptoms due to a stepwise neurological impairment. Therefore, effective prophylactic measures are needed for these patients to protect neurological function from impairment in the long term.The secondary progressive course of NMO is rarely seen clinically, so it becomes relevant to prolong the remission period and thus modify the natural course of the disease. Unfortunately, there are no randomized controlled studies on this aspect of treatment to date. A combination of azathioprine and prednisone has been used as first-line prophylaxis in patients with relapsing NMO.
Small doses of prednisone (5-15 mg/d or every other day) can be effective in controlling symptoms, but are often ineffective with attempted dose reductions. Sometimes new-onset optic neuritis and myelitis are apparent, while other cases present with increased lower extremity dysfunction without clinical or imaging evidence of new lesions.
Initial success has been reported with the monoclonal antibody Rituximab (trade name Meroval) against CD20+ immune cells for the treatment of NMO. the rationale for Rituximab treatment is that it clears B cells, which produce antibodies in response to humoral immune disorders. rituximab is well tolerated. Rituximab is well tolerated and may be used as a second-line agent in patients with NMO who feel that their disease is still progressing. Because of its rapid onset of action, it may also be used as a first-line agent in patients with severe active disease, but data from this study are very limited.
In conclusion, through modern immunopathology and careful clinical observation, it is not difficult to find that Asian optic chiasm MS and NMO may be the same disease and different from MS. Of course, it is still debated whether NMO is a subtype of MS, and many questions regarding the distribution of the respective specific sites of involvement, humoral and cellular immune pathogenesis, and diagnostic and therapeutic aspects need to be answered by clinical studies with large samples.