Information Obtained from the Walton Centre-Medical Services Neurology and Long Term Conditions in England
The Walton Centre for Neurology and Neurosurgery NHS Trust
Lower Lane
Fazakerley
Liverpool
L9 7LJ
Devic's Disease is also Known as Neuromyelitis Optica
1. What is NMO?
Neuromyelitis Optica (NMO) as the name implies (‘neuros’-to do with the nervous system, ‘myelos’- spinal cord, ‘optica’- related to vision) is a disease of the nervous system, which affects mainly the spinal cord and the optic nerves (the nerves that connect the eye to the brain). It is a type of demyelinating disease.
2. Who is Devic?
Eugene Devic was a French neurologist who summarized the features of the condition in 1894. It had been described earlier by Albutt (1870) and Erb (1880).
3. What does ‘demyelinating’ mean?
Myelin is the protective covering of nerves, like the insulation on an electric wire. The cells of the body’s immune system sometimes attacks myelin covering the nerves of the central nervous system (CNS). The CNS includes the brain – including the optic nerves – and spinal cord, but not peripheral nerves (like those in the arms and legs). The extent and type of damage and where in the CNS this takes place determines the type of demyelinating disease. In demyelinating disease, symptoms develop from lack of flow of electrical signals through the nerve fiber that is stripped of its myelin- for example lack of sensation, or weakness. Some times electrical "short circuits" through the bare wires cause attacks of muscle spasm or tingling sensations.
Some other examples of other demyelinating conditions are multiple Sclerosis, ADEM (acute demyelinating encephalomyelitis, which can affect the brain and spinal cord) and transverse myelitis (TM, which affects only spinal cord).
4. What are the symptoms of NMO?
The most common symptoms are:
a. Optic neuritis (ON)
b. Transverse Myelitis (TM)
ON - is the inflammation of the optic nerve. It causes visual loss, typically in one eye at a time, but can occasionally affect both eyes simultaneously. It may be associated with eye pain on movement. Opthalmoscopy (looking at the back of the eye with an ophthalmoscope) may show swelling of the optic disc. Often swelling is not seen, as the demyelination can be further away from the eye (retro bulbar neuritis). It can be demonstrated by a test called VEP or VER (Visual Evoked Potentials or Visual evoked response), which shows a ‘delay’ in transmitting the signals from the eye to the brain.
Transverse myelitis – is inflammation of the spinal cord, which causes weakness, numbness or other sensory disturbances. It can also cause disturbances of bladder and bowel function. The degree of weakness or numbness depends on the location and severity of the inflammation of the spinal cord. When the spinal cord in the neck is affected, all 4 limbs may be affected (as the nerves to the arms branch off from the spinal cord at the neck). When the lower spinal cord is affected, only the legs and trunk may be affected.
Though NMO classically affects the optic nerve and spinal cord, other parts of the brain may be affected.
5. How is NMO different from Transverse Myelitis (TM) and ADEM?
a. NMO can affect both the optic nerves and spinal cord. TM affects only the spinal cord.
b. ADEM affects multiple parts of the brain and spinal cord (not restricted to optic nerves and cord) at the same time and usually does not recur.
6. What are the main differences between Multiple Sclerosis and NMO?
a. NMO usually affects only the optic nerves and spinal cord. MS can affect any part of the brain and spinal cord
b. Relapsing Remitting MS (RRMS) tends to change to a gradually progressive stage but this is very rare in NMO
c. Attacks of NMO are usually more severe with lasting disability, while initial attacks of RRMS recover almost fully.
7. Are there any more differences between NMO and MS?
Yes. See sections 25, 26, 29 42 below.
8. Why do individuals develop NMO?
We don’t know.
It is an autoimmune disorder in which the body’s own defense mechanisms damage the optic nerve and spinal cord. Why this is predominantly restricted to these two locations is a mystery. Possibly a unique protein in these structures or the blood vessels in these regions, makes them vulnerable7.
9. Does an infection, either a virus or bacteria, cause this disease?
No specific organism has been identified in the optic nerves and spinal cords of people who had NMO. But it’s possible that like in other demyelinating illnesses, infections could ‘trigger’ the attack (rather than causing it)
10. Are there any genetic factors or families with more than one person with NMO?
Familiar cases have been reported but the vast majority of NMO cases have no affected relatives and it is generally regarded as a sporadic (non-familial) condition8-11.
11. Are women more likely to get NMO?
Yes 80-90% of people with NMO are women. (In fact most autoimmune disorders are commoner in women.)
12. Is there any specific part of the world that’s more involved? NMO seems to be present across the world unlike MS, which has a higher incidence in temperate climates and white races. Africans and Asians especially in Far East may have a higher risk of NMO, although the exact incidence of this disease is unknown, making specific conclusions difficult
13. How common is it in Europe and Americas?
NMO is an uncommon disorder. Though the exact incidence is not known it is far less common than epilepsy and MS (Epilepsy affects 6 in 1,000 people and MS affects roughly about 1 in 800 people).
14. Is optico-spinal MS (OSMS) the same as NMO?
Optico-spinal MS is considered a type of MS that presents with transverse myelitis and optic neuritis. It was the dominant type of MS in Japan and thought distinct from western MS. There are lots of similarities between NMO and OSMS. In fact some authors think both are the same. A recent study looking for the NMO-IgG in Japanese patients suggests that optico-spinal MS is the same as NMO in the western World14 See section 29 for NMO-IgG
15. Are there different types of NMO?
Two types are recognized based on whether there is recurrence of symptom.
a. Monophasic Type -in less than 20% of cases only one episode of optic neuritis and one episode of myelitis occurs. This can happen sequentially (either can occur first) or simultaneously. After this no further attacks occur.
b. Relapsing Type –most patients with NMO will get further recurrences.
16. How many attacks can a person with relapsing NMO get?
The number is highly variable, ranging from 10 attacks per year to 1 attack every 10 years; in general, attacks are more frequent in NMO than in MS, and they tend to occur in clusters.
17. When will the recurrences / relapses occur?
It is estimated that if a person with NMO has the relapsing type, then he or she will experience a relapse within 5 years of the onse.
Roughly about 50% will have a relapse in 1st year, 75% by 3rd year and, 90% by 5th year
18. Can doctors predict who will get relapses and who won’t?
It’s quite difficult. However, some studies suggest that women and those with a less severe initial attack of myelitis may be more prone to relapses. Also a longer time interval between initial ON and myelitis may indicate more future relapses.
19. Generally at 5 years after being diagnosed with NMO how are people affected?
About half the patients with relapsing NMO have significant visual loss (less than 20/200 or 6/60) in at least one eye and/or cannot walk due to leg weakness and is reliant on a walking aid such as a walking stick, frame or wheelchair15.
However this information is a generalisation drawn from an early study based on patients referred to a major hospital (i.e: they may already have been significantly impaired or had severe disease, which was why they were referred in the first place) and may not be representative of all patients. Furthermore, some patients were not treated. Early treatment may lead to better outcomes.
20. How severe can NMO be?
Some may have only a mild attack of ON, and myelitis with near complete recovery and no further relapses with or without treatment. Some people with NMO may lose vision in both eyes and be paralysed in all 4 limbs due to damage to the spinal cord in the neck. Breathing difficulties and death can occur due to muscle weakness or involvement of the brainstem. Severely affected persons may need artificial ventilation. Most people with NMO have disabilities between these two extremes
21. Are there criteria to diagnose NMO?
The pragmatic criteria that we follow at present are listed below, although each case must be individually analyzed, as some patients who are exceptions to the criteria below may still have NMO:
a. Optic Neuritis
b. Transverse myelitis with a long cord lesion (usually spinal cord MRI signal intensity in more than > 3 vertebral segments) ,when done during an acute attack
(Modified from Wingerchuk et al Neurology, 1999 and 200615 17).
The presence of NMO IgG helps confirm diagnosis of NMO, but is not mandatory for diagnosis. An abnormal MRI of the brain does not exclude NMO. It’s important to understand that criteria are generalisations and for guidance only. Each case has to be assessed separately. Also criteria change with time to incorporate new scientific information.
Also certain other diseases have to be excluded. A MRI of the brain and spinal cord is required. Often a lumbar puncture too is required.
The pragmatic criteria that we follow at present are listed below, although each case must be individually analyzed, as some patients who are exceptions to the criteria below may still have NMO:-
22. So if a person has optic neuritis and myelitis does he have NMO?
Not necessarily. MS may cause identical symptoms, but the myelitis is not accompanied by the long spinal cord lesion on MRI that is typically seen in NMO.
23. What are the other diseases to be excluded? a. Multiple Sclerosis
b. ADEM (acute demyelinating encephalomyelitis)
c. Sjogren’s syndrome, SLE (systemic lupus erythematosis) and such connective tissue diseases, may have spinal cord inflammation. But if they have long spinal cord MRI abnormalities or NMO-IgG, they may have both NMO and SLE/Sjogren’s.
d. Virus induced inflammation example – acute chicken pox myelitis
e. Cancer associated inflammation affecting eyes and spinal cord
f. Incidental conditions affecting vision and spinal cord example: stroke to eye and spondylosis of the neck
24. Can a person have only relapsing optic neuritis or relapsing myelitis?
Yes. It is quite likely that these disorders are closely related to NMO. Hence they are called NMO spectrum disorders. Many have positive NMO IgG too making this hypothesis likely.
25. What will the MRI scan of the brain show?
Usually the brain MRI is normal.
But recent studies have shown that a wide variety of abnormalities can be present in NMO. Their presence doesn’t make NMO diagnosis incorrect. However MRI appearances typical for MS are present in only 10% people.
26. What will the MRI scan of the spinal cord show?
The most typical abnormality is seen during an acute relapse, during which a part of the cord spanning more than 3 vertebral segments is swollen and "hyper-intense" (looks white on a T2 type MRI scan). In MS a much smaller section of the cord is often asymmetrically involved.
The most typical abnormality is seen during an acute relapse, during which a part of the cord spanning more than 3 vertebral segments is swollen and "hyper-intense" (looks white on a T2 type MRI scan). In MS a much smaller section of the cord is often asymmetrically involved.
27. What is a Lumbar puncture?
Cerebral Spinal Fluid (CSF) is the watery liquid that surrounds and protects the brain and spinal cord. With many neurological conditions, the components of CSF, like proteins may change in quality or quantity. Traces of other substances may appear. A lumbar puncture (LP) requires a small amount of CSF to be drawn from the spinal cord with a needle. This only takes a few minutes and hurts a little and so is normally done under a local anaesthetic. Some people can get a headache after the procedure (due to leak of fluid). It can be avoided by lying flat for a few hours after the test.
28.What will the Lumbar Puncture test (CSF Study) show?
If done during an acute attack of TM there may be increased white cells and raised proteins. A special pattern of antibody proteins called oligoclonal bands (OCBs) is usually present in MS but absent in NMO. But it can be present in about 20% patients with NMO.
29. What is NMO IgG?
In 2003 doctors from the Mayo Clinic USA reported presence of an antibody (a kind of protein) in the blood of patients with NMO. It has been named NMO-IgG (NMO Immunoglobulin G)14
This antibody seems to be present in about 70% of people with NMO. It’s not present in people with MS or other conditions that can present with NMO like illnesses. Doctors can now diagnose very early (probably after the first attack of ON or myelitis) people who are at risk to develop further symptoms that would lead to a later clinical diagnosis of NMO and consider preventive measures, to reduce the chance of relapse or severity of a second neurological attack.
30. What is an antibody?
An antibody is a protein produced by the body’s defence cells (Plasma cells that are in turn formed from B cells) against other proteins (antigens). These proteins can be foreign like viruses and bacteria, which is a normal response. But sometimes the defence cells mistake one’s own tissues to be foreign and produce antibodies against it (autoantibodies). Such illnesses are called autoimmune illnesses. Examples are lupus (SLE), rheumatoid arthritis, thyroiditis, pernicious anaemia. In many conditions, such as multiple sclerosis that are presumed autoimmune, a specific antibody has not been found.
31. Is the NMO IgG necessary for diagnosis of NMO?
No it is not. Thirty percent of individuals with NMO, for reasons currently not understood; do not have this antibody when tested. When present, however, it helps in making a more confident diagnosis. It’s possible that there are currently undetetectable antibodies like NMO IgG or the testing methods are not perfect yet.
32. Is NMO IgG present in other conditions?
Yes .It can be present in longitudinally extensive transverse myelitis (LETM). 40% patients in whom it is detected after the first attack of myelitis will go on to have more events. 25% of patients with relapsing optic neuritis have the NMO IgG.
The presence of NMO-IgG in these conditions strengthens the view that these are NMO spectrum disorders.
NMO-IgG has been found in less than 2 percent patients with multiple sclerosis and therefore is an important differentiating tool14 21.
An antibody is a protein produced by the body’s defence cells (Plasma cells that are in turn formed from B cells) against other proteins (antigens). These proteins can be foreign like viruses and bacteria, which is a normal response. But sometimes the defence cells mistake one’s own tissues to be foreign and produce antibodies against it (autoantibodies). Such illnesses are called autoimmune illnesses. Examples are lupus (SLE), rheumatoid arthritis, thyroiditis, pernicious anaemia. In many conditions, such as multiple sclerosis that are presumed autoimmune, a specific antibody has not been found.
33. What is Aquaporin?
Aquaporin is a protein water channel on the surface of certain cells that allow water to move in and out of the cell. There are many types of aquaporins scattered across the body tissues and in many other living organisms22. It has recently been found that Aquaporin 4 is the target of NMO-IgG23. How damage to aquaporin 4 by NMO IgG causes NMO is being studied.
34. How is NMO treated?
There are 4 aspects to treatment in NMO 24 25
a. Treating the acute attack
b. Preventing relapses
c. Treating the residual symptoms of the relapse
d. Rehabilitation
35. Are these evidence based (proven to be effective) treatments?
No. Most recommendations about treatment are based on experience of doctors rather than on scientifically conducted clinical trials. This is mainly because NMO is an uncommon and under-diagnosed disease that sufficient numbers of patients aren’t there to conduct a scientifically valid trial. Also trials are very expensive and it often doesn’t make ‘business sense’ to pharmaceutical companies to spend huge amounts on relatively rare illnesses.
36. How are acute attacks treated?
Intravenous methyl prednisone (solumedrol) is usually given .The idea is to dampen the immune attack. The dosage might normally be 1 gram given for 3 to 5 days followed by a tapering dose of oral steroids for about 8 weeks. In many patients relapses may occur even on gradual reduction of the steroids and many may need to continue on a low dose of steroids for longer periods.
37. If steroids don’t help, what next?
Plasma exchange (a technique in which the blood is drawn out of the body and the plasma (which contains the antibodies) is separated with the help of a machine .The blood is then returned back into the body. However this will remove only the antibody from the blood – the cells that make the antibody (B cells) are still present in the blood. There is some evidence from controlled clinical trials that this helps patients with NMO, as well as those with other demyelinating diseases, such as MS, who have acute, severe attacks26.
38. Can relapses be prevented?
Since we believe that the body’s immune system is the culprit we try to suppress the immune system with various drugs. Azathioprine (AZT, Imuran) is what is commonly used27. Many doctors begin AZT along with the steroids in the acute attack stage. The dose can be build up to about 2-3 mg/kg of bodyweight /day over a few months. The usual, long term, maintenance doses are between 100 to 200 mg/day. Once AZT is effective in the body and patients are clinically stable the dose of steroids is gradually tapered down .
39. Are there any side effects for AZT?
Azathioprine like most immunosuppressants has a variety of possible side effects including liver dysfunction, low blood counts, stomach upsets, and future risk of cancers. Pregnancy is unsafe while on AZT as there is a risk of malformations in the unborn child. Malaise, rash, and allergic reactions can occur
40. What happens if relapses occur frequently despite AZT?
When relapses occur despite being on AZT, steroids may need to be continued on the lowest possible doses to maintain remission or to try another drug. (Section 41)
Steroid (glucocorticoid) side-effects include infection, glaucoma, diabetes, osteoporosis, mental disturbances, muscle wasting, stomach ulcers and weight gain. In children, corticosteroids may result in suppression of growth. There are some side effects in pregnancy too.
41. What if relapses occur despite AZT and steroids?
This is a difficult but common situation. A variety of other drugs have been found to be useful in NMO and related disorders. Other immunosuppressants -Mycophenolate28 ( Cellcept)
Mitoxantrone( Novantrone)29 –a widely used chemotherapy drug.
Rituximab- (Rituxan) a monoclonal antibody against the B cells has been recently shown to be very effective in preventing relapses 30. Some other drugs that have been tried are: Methotrexate20, cyclosporine, cyclophosphamide31, intravenous immunoglobulins32
All of these drugs have side effects. They have been used only in small number of patients and neurologists can’t say much about effectiveness or long-term side effects yet. Larger trials are needed to find definitive answers.
42. Are drugs for preventing attacks of MS, such as interferons and glatiramer acetate (copaxone), useful in NMO?
As MS and NMO seem to be different but related diseases with different pathologic mechanisms, they may not be useful. There are reports of benefit with Copaxone33. In our experience they are not useful. A recent French study supports this view.
43. How do we treat NMO spectrum disorders?
Since NMO spectrum disorders have recurrences and may evolve into NMO, we believe that treatment should probably be similar .This may be especially true if the NMO-IgG is positive. However this is a controversial topic.
44. Are there any trials in NMO being planned?
There are discussions of possible trials in NMO
45. How does one get involved in a trial?
You could contact the investigators and will need to be assessed for eligibility. There might be specific criteria to enrol in a study.
In some trials, not all the participants of the trial will get the new treatment being tested; some will get a pseudo-drug (placebo, which has no real effect). There is no way of knowing who is receiving the treatment drug and who is on a placebo (blinded trial) till the trial is over. These strict methods are to see if there is a treatment effect from the drug. Errors in trial methods have led to ineffective drugs being ‘considered effective’ and prescribed world over.
Rehabilitation and symptomatic Management
46. What does symptomatic management mean?
This means managing the symptoms caused by underlying disease process without having any effect on the condition itself. This is usually managed by drugs or physical therapy. There is no ‘right’ drug. Only by trial and error will your doctor be able to reach the right drug at the right dose.
a. Pain: E.g. amitryptiline, gabapentin, pregabalin and carbamazepine.
b. Stiffness: E.g. baclofen, tizanidine, dantrolene
c. Bladder symptoms: learning self catheterisation, (a very simple technique) or medicines like oxybutinin, tolterodine
d. Tonic Spasms: this a painful spasm of the muscles that lasts seconds to minutes. Often it’s controlled by carbamazepine at fairly low doses.
e. Male Sexual dysfunction: E.g sildenafil( Viagra) or vardenafil( levitra)
f. Constipation: laxatives, high fibre diet
47. Can deficits that are present for many years be reversed?
It is rare for this to happen. So physical adaptations (modifications in house, wheel chair etc) and life style modifications (change of job, moving to single floor house) should be planned in advance and money spend wisely rather than waiting for ‘miracles to happen’ or trying out costly alternative medicines or exotic cures. There is promising research on remyelination going on in various centres.
48. What about managing permanent disability?
Combined efforts by doctors, nurses, occupational therapists, physiotherapists, and social services will help the complex requirements of the individual patient. Visual aids, walking aids, motorised wheelchairs, and home adaptations can improve quality of life remarkably and many patients live an active life.
49. Is exercise good?
Yes. Regular moderate exercise is very important. Stretching and swimming are easy to do and very useful.
50. Are there special diets?
No. But a healthy diet with adequate vegetables, fruits, calcium and vitamin D (remember steroids can cause bones to weaken) vitamins and proteins is needed to keep the body fit. Excess weight should be avoided .It is often very easy to put on too much weight –with the steroids, lack of exercise and simply overeating –and this should be avoided.
51. Are Vaccines like ‘flu shots’ to be avoided in NMO?
There is no evidence (no articles published in medical journals) yet to suggest this.
52. What about NMO and pregnancy?
We are not certain if pregnancy has an effect – good or bad – on NMO. Azathioprine and other drugs are potentially harmful to the unborn child.
53. Are alternative medicines useful in NMO?
There is no evidence for this.
54.What about stem cells?
Stem cells are still largely experimental only. No studies have been done in NMO.
55. What does the future hold for NMO?
NMO is an uncommon disease. In most such diseases clinical studies and trials take a long time. (See section for researchers and collaborators) Such diseases normally go through the stages of:
a. Characterisation of features, identifying natural history and risk factorsThen tests that support the diagnosis evolve – like MRIand tests that actually diagnose the condition evolve like NMO IgGStudies on patients and biopsy materials will need to be done. When a good number of motivated patients and researchers are available, trials that test the effectiveness of the current and new, medications should be undertaken. Ultimately we hope that rapid, definitive and easily available diagnostic tests and potent drugs with few side effects will develop and early effective treatment will allow a normal life for people with NMO.
56. Is there a lot of research going on in NMO across the world?
Yes. There are groups in many countries doing excellent work. But the rarity of patients (and hence the need to identify as many as possible) and absence of a unified diagnostic criterion makes studies difficult. Clearly the way forward would be a global collaboration amongst researchers.
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