Neuromyelitis Optica Spectrum Disorder Presents Diagnostic and Treatment Challenges

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall

BARCELONA—Revised consensus criteria have proposed that neuromyelitis optica spectrum disorder (NMOSD) become the new unifying term to replace neuromyelitis optica, and that the condition be further stratified based on serologic testing. In kind, NMOSD treatment may differ based on the goals of either relapse prevention or prevention of acute attacks. NMOSD diagnosis and treatment were discussed at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

NMOSD encompasses what previously has been diagnosed as neuromyelitis optica, an inflammatory CNS syndrome distinct from multiple sclerosis (MS), which requires clinical optic neuritis and myelitis. It also includes limited forms (eg, optic neuritis or myelitis alone) and a series of associated conditions such as area postrema syndrome and certain brain syndromes known to occur with other symptoms of neuromyelitis optica, said Brian G. Weinshenker, MD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the international panel that developed the NMOSD consensus criteria. The criteria were published in the July 14 issue of Neurology. The criteria also include patients who are aquaporin 4 (AQP4) seronegative but have otherwise typical clinical presentations.

Patients who are AQP4 antibody sero­positive should have at least one core clinical characteristic for a diagnosis of NMOSD, according to the criteria. The core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome (ie, otherwise unexplained hiccups or nausea), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with diencephalic lesions typical of NMOSD on MRI, and symptomatic cerebral syndrome.

“There are no exclusionary criteria, but our caveat is that there should be no better explanation for the symptoms,” Dr. Weinshenker noted. “Comorbidities such as lupus or Sjögren’s syndrome do not exclude NMOSD, but some syndromes or comorbidities raise red flags. These red flags are clinical and MRI features that might suggest a diagnosis of MS instead of NMOSD, as well as sarcoidosis, which can cause optic neuritis or myelitis.” Other red flags, according to the criteria, include cancer and chronic infection (eg, HIV or syphilis).

For patients who are AQP4 seronegative or those for whom serologic testing is unavailable, the criteria are similar, but more rigorous. Specifically, at least two core clinical characteristics are required, and one of them must be optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM) lesions, or area postrema syndrome.

“There must be evidence of dissemination in space, and we require additional MRI features to be present,” said Dr. Weinshenker. “For example, in patients with intractable vomiting, we require that they also have associated dorsal medulla/area postrema lesions.” Those with myelitis must have a long spinal cord lesion and those with acute optic neuritis must have a long optic nerve lesion that takes up half or more of the length of the optic nerve or affects the optic chiasm. “Again, there should be no better explanation for the findings,” he said.

The revised criteria align “with our contemporary view of what NMOSD is and captures current expert practice,” Dr. Weinshenker said. “It should facilitate clinical research by allowing for early diagnosis in a larger pool of patients who might be eligible for clinical trials.”

However, as is true for any set of diagnostic criteria, physicians will still need to exercise individual judgment, he said. He noted that despite the high accuracy of enzyme-linked immunosorbent assay (ELISA) testing, the most widely used serologic test in the United States for AQP4 antibodies, there is still about a 5% chance of false positives, particularly among patients with a low pretest probability of NMOSD. In addition, patients who are AQP4 seronegative, who make up approximately 30% of the total NMOSD population, are poorly characterized.

Among the AQP4 seropositive patients are those who have detectable serum myelin oligodendrocyte glycoprotein (MOG) antibodies. They tend to be younger, male, and less likely to relapse than those with AQP4 antibodies “Maybe MOG syndrome will ultimately be considered separately, but currently we consider it to be a form of NMOSD, and future versions of the diagnostic criteria will probably incorporate other biomarkers,” Dr. Weinshenker said.

NMOSD therapy can be stratified into two types: treatment of acute (ie, monophasic) attack and relapse prevention, said Jacqueline Palace, BM, DM, Consultant Neurologist at the University of Oxford, United Kingdom. She noted that her classifications for treatment purposes are not based on the newly revised NMOSD diagnostic criteria, but rather are slightly broader. She pointed out that her treatment recommendations are in line with 2010 guidelines by the European Federation of Neurological Societies.

“AQP4 antibody disease is a relapsing condition when untreated,” said Dr. Palace. “On the other hand, many MOG antibody seropositive patients have monophasic phenotypes.” Other monophasic conditions include LETM or idiopathic transverse myelitis, Devic’s disease, and severe or bilateral optic neuritis.

Patients in the monophasic group may go on to develop relapsing disease (ie, relapsing NMOSD, relapsing optic neuritis, and relapsing LETM), Dr. Palace noted. Among the difficult-to-treat patients are those who have overlap between MS and antibody-negative NMOSD.

Management of an acute attack across all of these monophasic syndromes is similar because the attacks tend to present with more severe relapses than patients with MS, and some patients are left with severe residual disability, said Dr. Palace. “We treat these patients urgently with IV methylprednisolone for three to five days to try to restore function. If there is poor response or significant disability, we follow with plasma exchange.” If plasma exchange is not feasible, patients may be given IV immunoglobulin (IVIG), she suggested. “There is a small proportion of patients who develop severe paraplegia that don’t appear to respond at all to treatment, even if given urgently. In my experience, these patients are monophasic and they are antibody negative for both MOG and AQP4.”

Patients with acute disseminated encephalomyelitis can rebound if given a short course of IV methylprednisolone. Dr. Palace recommended follow-on prednisolone for two months for patients who have such monophasic MOG and AQP4 antibody disorders to prevent rebound, and for longer (ie, six to 12 months) for monophasic patients with MOG antibodies.

Preventing relapse is probably the most important aspect of managing NMOSD. “AQP4 antibody disease is a relapsing condition, and there is no progressive phase as there is in MS,” Dr. Palace said. “There is a high morbidity and mortality associated with relapse.”

In a 2012 review of AQP4 antibody-seropositive patients—many of whom were on corticosteroids or other immunosuppression—researchers found that, among 59 patients in the UK with a median follow-up of five years, 22% had permanent bilateral visual loss with visual acuity of less than 6/36 in the better eye, and nearly 30% were wheelchair-dependent.

Prednisolone cover alone or in conjunction with a steroid-sparing drug (ie, azathioprine, mycophenolate, methotrexate, or rituximab) is the recommended first-line treatment for relapse prevention. “If patients have a relapse on an adequate dose tried for three to six months, then you might consider an alternative first-line drug or other less commonly used immunosuppressive agents such as ciclosporin/tacrolimus, cyclophosphamide, or mitoxantrone. Regular plasma exchange or IVIG is also an option,” said Dr. Palace. “We note that our patients appear less likely to relapse if they are kept on a low background dose of prednisolone when on other immunosuppressants. If they have a relapse, we may increase the background prednisolone dose rather than switch treatments.”

Some MS disease-modifying drugs have been reported to exacerbate NMOSD, including beta-interferon, natalizumab, and fingolimod. In addition, there is a theoretical risk of alemtuzumab being harmful because it is known to precipitate antibody-mediated disease, Dr. Palace said.

—Adriene Marshall