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Neuromyelitis Optica Spectrum Disorders – NMO
Devic’s Disease – NMO Related Optic Neuritis – Acute Myelitis – Area Postrema Syndrome – Symptomatic Narcolepsy – Treatment of NMO
Neuromyelitis Optica Spectrum Disorders
The cardinal symptoms of neuromyelitis optica are vision loss due to bilateral optic neuritis and severe myelitis. Myelitis is an inflammation in the spinal cord with resulting loss of multiple functions in the body anywhere below the neck.
NMO has been known for more than a century. Until recently, it was believed to be some version of multiple sclerosis. Neuromyelitis optica is different from MS in many respects. It has statistically worse prognosis, has almost exclusively relapsing-remitting course, and spares of the brain in most cases (only spinal cord and optic nerves are affected).
Devic’s disease (which is another name of NMO) starts later than multiple sclerosis. A median age of onset is about 40 years. It is even more common in females than MS with female-to-male ratio of 9:1. Myelin is not attacked directly in NMO. It is rather a subject to collateral damage. Neuromyelitis optica has specific immunological markers.
Symptoms of Neuromyelitis Optica
It is hard to suspect neuromyelitis optica on its first attack. There are four types of clinical presentation which may occur in any order or in any combination. They include optic neuritis; acute myelitis; intractable hiccups, nausea and vomiting; brainstem syndrome; and narcolepsy. This is why NMO is often called neuromyelitis optica spectrum disorders.
Isolated brain lesions in NMO are rare (5%). About 4% have optic neuritis and myelitis simultaneously. The rest 7% have an atypical combination, such as brain lesion together with optic neuritis.
Optic neuritis in Neuromyelitis Optica
Classical presentation starts with visual symptoms in one or both eyes which occasionally might be followed by transverse myelitis shortly thereafter.
Severe loss of vision in both eyes is very suspicious for NMO. Typical complaints are blurred vision, decreased contrast sensitivity, black spot in central vision, loss of color vision and pain on eye movements. Optic neuritis is hard to distinguish from the one in MS. However, if both optic nerves and chiasm involvement are seen on the contrast MRI, it is likely neuromyelitis optica.
Optic neuritis presents in 41% of confirmed NMO cases and usually involves both eyes. Severity of vision loss is variable, but it is worse than in MS on average.
Transverse Myelitis in Neuromyelitis Optica
Transverse myelitis in neuromyelitis optica is statistically more severe than in MS. It occurs in 43% at onset.
In untreated cases, it extends 3 or more segments of the spinal cord. It is not uncommon to see a very long portion of the spinal cord involved in the disease process. Cervical spinal cord is typically affected the most. The extent of the spinal cord damage is variable. Either one or both sides may be involved. Spectrum of neurological symptoms is defined by the level of spinal cord lesions.
Most of the spinal cord tissue bulk consists of long nerve tracts connecting the upper part of the cord and the brain to the rest of the body. Basically, spinal cord is like a cable, which is made up of millions of wires with multiple relay stations along the way. Nerve fibers within the spinal cord carry sensation to the brain and motor commands from the brain.
Symptoms of myelitis include numbness, or loss of sensation, lack of balance, weakness in the leg(s), arm(s), or one side of the body. A complete involvement of the whole widths of the spinal cord will produce a loss of all functions below the lesion, which include lack sensation, voluntary movements, and ability to control urination, and bowel. The most common symptom is weakness in both legs. The vast majority of patients with weakness in the legs develop bowel and urine control problems. Numbness and tingling in the legs are very common. Unlike NMO, a severe transverse myelitis is uncommon in MS.
Area Postrema Syndrome
Intractable vomiting and hiccup are typical for neuromyelitis optica. They may be the first symptoms and affect about 20% to 30% of NMO patients. These patients are usually evaluated by gastroenterologists, but nothing wrong is found on the GI work up. The correct diagnosis is rarely made until some NMO symptoms pops up.
Vomiting and hiccup are generated by area postrema. It is a small region in the lower portion of the brainstem. Its primary function is a detection of toxins in the blood and an induction of vomiting. Brain is isolated from many blood components by so called blood-brain barrier. Blood-brain barrier is meant to protect the brain from unwanted chemicals, including antibodies. Area postrema lacks blood-brain barrier because it has to analyze the blood constituents. Antibodies targeting brain cells enter though this region and the subsequent inflammation irritates area postrema. The result is a severe vomiting. Further spread of toxic antibodies throughout the brain tissue leads to the rest of NMO symptoms.
Area postrema syndrome responds well to corticosteroid treatment.
Besides area postrema syndrome (vomiting in 33%, hiccups in 23%), other symptoms of brainstem involvement might include eye movement abnormalities (20%), itching (12%), yawning, trigeminal neuralgia, Bell’s palsy, vertigo, and other cranial nerves symptoms.
Symptomatic Narcolepsy and Other Brain Involvement Symptoms of NMO
Occasional patients develop narcolepsy symptoms due to autoimmune damage to the hypothalamus. Even less frequently NMO may cause a wide spread brain damage similar to ADEM (Acute Disseminated Encephalomyelitis). Cases of dysregulation of the body temperature and endocrinological abnormalities also reported as a part of neuromyelitis optica spectrum disorders
Pathophysiology of Neuromyelitis Optica (Cause and Mechanism of Tissue Damage)
Relatively recently, a specific type of autoantibodies associated with NMO was discovered. Antibodies are special proteins produced by the immune system. Antibodies attach to foreign objects in the body. Once attached, they tag the object as foreign, which sets off a chain of events intended for the invader destruction. Under normal circumstances, the immune system attacks bacteria, viruses, fungi, and cancer cells.
Erroneous creation of antibodies targeting normal body tissues is one of the mechanisms of autoimmune diseases. In case of neuromyelitis optica, the antibodies are targeting Aquaporin-4 (AQP4) in the cells, called astrocytes. Aquaporin is a protein in the cell membrane that regulates water transport across cell the membrane.
Astrocytes have “legs” with large “feet”. These feet wrap around tiny blood vessels of the brain. The astrocyte feet are essential for creation of the blood brain barrier mentioned above. Aquaporin is highly concentrated in these feet. Astrocytes have nothing to do with myelin, but the immune attack against astrocytes destroys myelin and nerve fibers as innocent bystanders.
There are a few different versions of this protein. Antibodies, however, are very specific. They target only a particular type of protein. This is a good explanation of selective damage to specific areas of the nervous system in neuromyelitis optica. It all depends on distribution of specific types of aquaporin-4.
Presence of high concentration of aquaporin-4 in the feet of astrocytes explains a specific distribution of inflammation in the brain. Most destruction destruction is observed around tiny flood vessels.
In one-third of cases, patients who are positive for aquaporin-4 antibodies, have associated infections (tuberculosis, hepatitis, Lyme disease or syphilis).
As in any autoimmune disorder, presence of NMO increases the chance of other autoimmune conditions, such as lupus, myasthenia gravis, Sjogren syndrome, thyroid disorders, and celiac disease.
Diagnosis of Neuromyelitis Optica
As much as 43% of NMO cases are initially misdiagnosed as MS and 53% were initially treated with interferon-beta, which may be harmful in neuromyelitis optica. The diagnosis of NMO is delayed for as long as 16 months if it presents with myelitis and for 55 months with optic neuritis onset.
Blood Test for NMO
Blood aquaporin-4 antibodies are detectable in up to 90% of patients with neuromyelitis optica. This test is very specific for this condition (>90%). The antibody level decreases after the acute attack is over and after treatment, so a blood work has to be repeated in recurrent attacks. Spinal tap is only rarely positive for NMO-specific antibodies in seronegative cases.
There are multiple methods of AQP4 antibody detection. Cell-based method offers the highest sensitivity. This method utilizes special cells carrying human APQ-4 protein in their cell membranes.
Diagnostic Criteria in NMO
Suspicious clinical picture in combination with Aquaporin-4 antibodies in the blood makes the diagnosis of NMO spectrum disorder certain. Lack of such antibodies requires presence of a combination of symptoms for the right diagnosis. It requires at least 2 core features:
- At least one of the following: optic neuritis, acute myelitis affecting at least 3 spinal cord segments, area postrema syndrome, acute brainstem syndrome, or symptomatic narcolepsy
- Dissemination in space, or recurrent attacks
- Specific findings on the MRI consistent with patient symptoms
Biopsy in Neuromyelitis Optica
Spinal cord biopsy is only rarely performed for the diagnosis of demyelinating disorders and is not generally recommended. Biopsy in NMO reveals a striking difference from multiple sclerosis. NMO plaques demonstrate loss of cells with AQP-4 protein. In MS, there is an increased amount of AQP-4 within the plaques. Special staining reveals deposition of immunoglobulin (antibodies) around the blood vessels.
Magnetic Resonance Imaging (MRI)
Brain MRI reveals nothing specific in 90% of patients shortly after the disease onset, besides contrast enhancing lesion of the optic nerves (if optic neuritis symptoms are present). Subsequent brain imaging reveals some nonspecific abnormalities on the brain MRIs. There are white matter changes similar to the ones that are seen in microvascular disease caused by diabetes or hypertension. Those white matter abnormalities are not associated with any particular symptoms.
Contrast MRI brain studies may reveal large areas of the white matter enhanced in cloud-like pattern. Considering the fact that autoantibodies in NMO attack the building blocks of the blood-brain barrier (see above), this pattern is not surprising.
Patients with vomiting and hiccup will have abnormal MRI signal in area postrema region. Lesions in diencephalon and around the aqueduct in the midbrain are typical for neuromyelitis optica.
In contrast to MS, there are no corpus callosum specific lesions (“Dawson fingers”). The corpus callosum lesions look like blocks of abnormal signal.
In acute phase, Cervical (less commonly thoracic and lumbar) Spine MRI demonstrate evidence of transverse myelitis. The lesions typically extend 3 or more segments of the spinal cord and may reach the brainstem (lower part of the brain). These lesions are better seen on contrast enhances studies.
Over months, these MRI findings will fade and only a few small patches will stay permanently. Years down the road it is impossible to say if it was transverse myelitis due to NMO or spinal cord plaques due to MS.
Prognosis in Neuromyelitis Optica
NMO is believed to be more severe than MS. Considering recent improvement in diagnostic criteria it might be not exactly true. There are milder forms of NMO. On average, the level of mild disability is 2 times less than in MS after 10 years (12% vs. 22%).
Residual disability after individual attacks is much more severe than in relapsing remitting form of MS. About half of patients are blind at least in one eye, or require a walking aid after 5 years. NMO attacks are more frequent than in MS. Transverse myelitis relapse rate in NMO is about 60% after 1 year.
Gradual progression of disability (like in secondary progressive MS) is not typical. Predicting factors of unfavorable prognosis are the number of relapses during the first 2 years, severity of the first attack, and presence other autoimmune conditions, such as lupus.
First attack in NMO may occur in children as young as 4 years, but it is less common in pediatric population.
Considering high probability of severe disability, attack prevention in neuromyelitis optica is of great importance.
Treatment of Neuromyelitis Optica
Accurate diagnosis and differentiation from multiple sclerosis are very important, because some of medications employed for MS attack prevention aggravate NMO. Interferon-β, natalizumab, and possibly fingolimod worsen neuromyelitis optica.
Acute attacks are managed with intravenous corticosteroids or, in some severe cases, with plasma exchange. Some experts believe that plasma exchange has to be a first line treatment whenever available. Both types of treatment may be combined and have to be followed by prolonged oral treatment with corticosteroids. Intravenous Immunoglobulin is proven to be effective in a small retrospective study.
Preventive immunosuppressive treatment is recommended for patients with a well-established diagnosis (positive blood test, known relapses, and those with classical picture of NMO). The treatment is long term. Discontinuation of the treatment often precipitates relapses. Most common immunosuppressive drugs for NMO in the US are azathioprine, mycophenolate mofetil, and rituximab.
Azathioprine is probably the least effective drug but it was studied the first. All studies of its efficacy in NMO are small scale and have some limitations due to study design. Nevertheless, these studies demonstrate a significant reduction in relapse rate and accumulated disability at least short term. Immunosuppressive treatment with Azathioprine reduces the relapse rate from 30% to 70%, based on retrospective studies.
Potential complications of long term Azathioprine treatment are malignancies (lymphoma), liver toxicity, infections, and PML. Common side effects, limiting its use, are stomach upset, fatigue and hair thinning. It is contraindicated in pregnancy (Category D)
About 11% of US population has decreased activity of thiopurine methyltransferase (TPMT). Limited activity of this enzyme subjects these patients to a very high level of Azathioprine in the body due to delayed elimination. Presence of this enzyme deficiency leads to severe Azathioprine related complications.
Azathioprine relapse preventive effect is delayed for 4 to 6 months, which requires a bridge therapy with oral Prednisone.
Based on the largest retrospective study in Korea, Mycophenolate Mofetil offers close to complete suppression of relapses in 60% of adequately treated patients over 20-month period.
It is generally better tolerated than Azathioprine. It is contraindicated on pregnancy (Category D).
Actual complication rate due to long term treatment with Mycophenolate Mofetil is difficult to assess, since there are too few patients treated for NMO so far. Treatment of other autoimmune conditions is usually a combination of Mycophenolate Mofetil with other drugs. The major concerns are bone marrow suppression and infections (including PML). Stomach upset may occur.
A few prospective and retrospective studies demonstrate a definite efficacy of Rituximab in NMO. In one of the studies, there was about 90% reduction of relapse rate with 70% of patients being relapse-free over 2-year period of time. Other studies demonstrate a comparable effect of relapse prevention in NMO.
Unlike other agents, Rituximab has relatively rapid onset of action.
Other Treatment Options
Since the mechanism of this disease is relatively well understood, it opens doors to specific treatments in the future – similar to the “ideal world treatments” I mentioned on Multiple Sclerosis Spectrum Disorders.
Aquaporumab, a harmless recombinant antibody to AQP-4 exists only in the lab for now. It works by means of attaching to AQP-4 on the astrocytes. Since the spot is already taken, the damaging autoantibodies are unable to express their destructive powers. There are a few similar strategies in the works right now.
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