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NMDA receptor antibodies associated with distinct white matter syndromes.

Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin JP, Pike M, Pullaperuma S, Siddiqui A, Wassmer E, Waters P, Irani SR, Buckley C, Vincent A, Lim M - Neurol Neuroimmunol Neuroinflamm (2014)

Bottom Line: Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers.When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences (Y.H., L.J., P.W., S.R.I., C.B., A.V., M.L.) and Department of Pediatric Neurology (M.P.), John Radcliffe Hospital, University of Oxford; Children's Neurosciences (M.A., J.-P.L., M.L.), Evelina Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London; Department of Pediatric Neurology (C.H.), Great Ormond Street Hospital for Children, London; Department of Pediatrics (S.P.), St Mary's Hospital, Imperial College Academic Health Science Centre, London; Department of Neuroradiology (A.S.), Kings College Hospital, King's Health Partners Academic Health Science Centre, London; and Department of Pediatric Neurology (E.W.), Birmingham Children's Hospital, Birmingham, UK.

ABSTRACT

Objective: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders.

Method: Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.

Results: THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers.

Conclusion: Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.

No MeSH data available.


Related in: MedlinePlus

NMDAR-Ab levels, clinical syndromes, and therapy in 8 informative patients with white matter syndromes in association with NMDAR-Ab(A–C) Cases 1–3 presented initially with brainstem encephalitis; Cases 1 and 2 relapsed with encephalopathy, psychiatric features, movement disorder, and dysautonomia. Case 2 had additional seizures. In both, the diagnosis of NMDAR-Ab encephalitis was made at the time of relapse. Case 3 had a monophasic illness and did not have any of the clinical characteristics of NMDAR-Ab encephalitis. (D, E) Cases 4 and 5 presented with herpes simplex virus encephalitis (HSVE) and then had a neurologic relapse, which correlated with raised NMDAR-Abs in both serum and CSF and demonstrated a clinical response to immunotherapy with reduction of antibody levels. (F) Case 8 presented with optic neuritis and poor visual recovery, which prompted a neuroinflammatory screen and the identification of the antibody positivity. She only received a course of steroids 1 year into her illness and 3 years later had a neurologic relapse. (G) Case 9 presented initially with 2 episodes of acute disseminated encephalomyelitis (ADEM) and relapsed at 1 year with optic neuritis. He was also MOG-Ab positive, which remain detectable even when NMDAR-Abs are no longer detectable and when the patient had clinically recovered. (H) Case 10 had recurrent episodes of hyperventilation, dizziness, and double vision; did not receive any treatment; and both her clinical and radiologic features remained unchanged. Ab = antibody; CSF Ab × 10 = NMDAR antibody titers in CSF (all between 1:20 and 1:50) multiplied by 10 to provide visibility in comparison to serum levels; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LeukoE = radiologic leukoencephalopathy; Lt = left; MMF = mycophenolate mofetil; NMDAR = NMDA receptor; ON = optic neuritis; PLEX = plasma exchange; Rt = right; Serum Ab titer = titer measured by endpoint dilution.
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Figure 2: NMDAR-Ab levels, clinical syndromes, and therapy in 8 informative patients with white matter syndromes in association with NMDAR-Ab(A–C) Cases 1–3 presented initially with brainstem encephalitis; Cases 1 and 2 relapsed with encephalopathy, psychiatric features, movement disorder, and dysautonomia. Case 2 had additional seizures. In both, the diagnosis of NMDAR-Ab encephalitis was made at the time of relapse. Case 3 had a monophasic illness and did not have any of the clinical characteristics of NMDAR-Ab encephalitis. (D, E) Cases 4 and 5 presented with herpes simplex virus encephalitis (HSVE) and then had a neurologic relapse, which correlated with raised NMDAR-Abs in both serum and CSF and demonstrated a clinical response to immunotherapy with reduction of antibody levels. (F) Case 8 presented with optic neuritis and poor visual recovery, which prompted a neuroinflammatory screen and the identification of the antibody positivity. She only received a course of steroids 1 year into her illness and 3 years later had a neurologic relapse. (G) Case 9 presented initially with 2 episodes of acute disseminated encephalomyelitis (ADEM) and relapsed at 1 year with optic neuritis. He was also MOG-Ab positive, which remain detectable even when NMDAR-Abs are no longer detectable and when the patient had clinically recovered. (H) Case 10 had recurrent episodes of hyperventilation, dizziness, and double vision; did not receive any treatment; and both her clinical and radiologic features remained unchanged. Ab = antibody; CSF Ab × 10 = NMDAR antibody titers in CSF (all between 1:20 and 1:50) multiplied by 10 to provide visibility in comparison to serum levels; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LeukoE = radiologic leukoencephalopathy; Lt = left; MMF = mycophenolate mofetil; NMDAR = NMDA receptor; ON = optic neuritis; PLEX = plasma exchange; Rt = right; Serum Ab titer = titer measured by endpoint dilution.

Mentions: Three patients had encephalopathy, predominant brainstem signs (cranial neuropathies and ataxia), and neuroimaging findings of brainstem abnormalities, or a clinical syndrome unequivocally localized to the brainstem.13 Case 1 (M, age 18) had brainstem changes at presentation (figure 1A) but evolved to a polysymptomatic encephalopathy, with resolution of the brainstem changes (figure 1B). NMDAR-Abs were only detected a year later after a relapse but fell with immunotherapies with a good clinical response (figure 2A). Case 2 (F, age 10) presented 3 weeks after first symptoms when her encephalopathy worsened with intractable seizures, movement disorder, and hyperpyrexia. She had recurrent periods of encephalopathy (figure 2B) associated with radiologic features of a leukoencephalopathy (figure 1D) that progressed over the following 5 years (figure 2B), when serum and CSF NMDAR-Abs were first identified. She was not given immunotherapies and is substantially impaired (table 1). Case 3 (M, age 5), the most recent patient, presented with brainstem signs and cranial nerve enhancement; NMDAR-Abs were identified within a few weeks of onset. He made a full recovery with steroids and plasma exchange (PLEX) (figure 2C). All 3 patients were negative for GQ1b antibodies.


NMDA receptor antibodies associated with distinct white matter syndromes.

Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin JP, Pike M, Pullaperuma S, Siddiqui A, Wassmer E, Waters P, Irani SR, Buckley C, Vincent A, Lim M - Neurol Neuroimmunol Neuroinflamm (2014)

NMDAR-Ab levels, clinical syndromes, and therapy in 8 informative patients with white matter syndromes in association with NMDAR-Ab(A–C) Cases 1–3 presented initially with brainstem encephalitis; Cases 1 and 2 relapsed with encephalopathy, psychiatric features, movement disorder, and dysautonomia. Case 2 had additional seizures. In both, the diagnosis of NMDAR-Ab encephalitis was made at the time of relapse. Case 3 had a monophasic illness and did not have any of the clinical characteristics of NMDAR-Ab encephalitis. (D, E) Cases 4 and 5 presented with herpes simplex virus encephalitis (HSVE) and then had a neurologic relapse, which correlated with raised NMDAR-Abs in both serum and CSF and demonstrated a clinical response to immunotherapy with reduction of antibody levels. (F) Case 8 presented with optic neuritis and poor visual recovery, which prompted a neuroinflammatory screen and the identification of the antibody positivity. She only received a course of steroids 1 year into her illness and 3 years later had a neurologic relapse. (G) Case 9 presented initially with 2 episodes of acute disseminated encephalomyelitis (ADEM) and relapsed at 1 year with optic neuritis. He was also MOG-Ab positive, which remain detectable even when NMDAR-Abs are no longer detectable and when the patient had clinically recovered. (H) Case 10 had recurrent episodes of hyperventilation, dizziness, and double vision; did not receive any treatment; and both her clinical and radiologic features remained unchanged. Ab = antibody; CSF Ab × 10 = NMDAR antibody titers in CSF (all between 1:20 and 1:50) multiplied by 10 to provide visibility in comparison to serum levels; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LeukoE = radiologic leukoencephalopathy; Lt = left; MMF = mycophenolate mofetil; NMDAR = NMDA receptor; ON = optic neuritis; PLEX = plasma exchange; Rt = right; Serum Ab titer = titer measured by endpoint dilution.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: NMDAR-Ab levels, clinical syndromes, and therapy in 8 informative patients with white matter syndromes in association with NMDAR-Ab(A–C) Cases 1–3 presented initially with brainstem encephalitis; Cases 1 and 2 relapsed with encephalopathy, psychiatric features, movement disorder, and dysautonomia. Case 2 had additional seizures. In both, the diagnosis of NMDAR-Ab encephalitis was made at the time of relapse. Case 3 had a monophasic illness and did not have any of the clinical characteristics of NMDAR-Ab encephalitis. (D, E) Cases 4 and 5 presented with herpes simplex virus encephalitis (HSVE) and then had a neurologic relapse, which correlated with raised NMDAR-Abs in both serum and CSF and demonstrated a clinical response to immunotherapy with reduction of antibody levels. (F) Case 8 presented with optic neuritis and poor visual recovery, which prompted a neuroinflammatory screen and the identification of the antibody positivity. She only received a course of steroids 1 year into her illness and 3 years later had a neurologic relapse. (G) Case 9 presented initially with 2 episodes of acute disseminated encephalomyelitis (ADEM) and relapsed at 1 year with optic neuritis. He was also MOG-Ab positive, which remain detectable even when NMDAR-Abs are no longer detectable and when the patient had clinically recovered. (H) Case 10 had recurrent episodes of hyperventilation, dizziness, and double vision; did not receive any treatment; and both her clinical and radiologic features remained unchanged. Ab = antibody; CSF Ab × 10 = NMDAR antibody titers in CSF (all between 1:20 and 1:50) multiplied by 10 to provide visibility in comparison to serum levels; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LeukoE = radiologic leukoencephalopathy; Lt = left; MMF = mycophenolate mofetil; NMDAR = NMDA receptor; ON = optic neuritis; PLEX = plasma exchange; Rt = right; Serum Ab titer = titer measured by endpoint dilution.
Mentions: Three patients had encephalopathy, predominant brainstem signs (cranial neuropathies and ataxia), and neuroimaging findings of brainstem abnormalities, or a clinical syndrome unequivocally localized to the brainstem.13 Case 1 (M, age 18) had brainstem changes at presentation (figure 1A) but evolved to a polysymptomatic encephalopathy, with resolution of the brainstem changes (figure 1B). NMDAR-Abs were only detected a year later after a relapse but fell with immunotherapies with a good clinical response (figure 2A). Case 2 (F, age 10) presented 3 weeks after first symptoms when her encephalopathy worsened with intractable seizures, movement disorder, and hyperpyrexia. She had recurrent periods of encephalopathy (figure 2B) associated with radiologic features of a leukoencephalopathy (figure 1D) that progressed over the following 5 years (figure 2B), when serum and CSF NMDAR-Abs were first identified. She was not given immunotherapies and is substantially impaired (table 1). Case 3 (M, age 5), the most recent patient, presented with brainstem signs and cranial nerve enhancement; NMDAR-Abs were identified within a few weeks of onset. He made a full recovery with steroids and plasma exchange (PLEX) (figure 2C). All 3 patients were negative for GQ1b antibodies.

Bottom Line: Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers.When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences (Y.H., L.J., P.W., S.R.I., C.B., A.V., M.L.) and Department of Pediatric Neurology (M.P.), John Radcliffe Hospital, University of Oxford; Children's Neurosciences (M.A., J.-P.L., M.L.), Evelina Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London; Department of Pediatric Neurology (C.H.), Great Ormond Street Hospital for Children, London; Department of Pediatrics (S.P.), St Mary's Hospital, Imperial College Academic Health Science Centre, London; Department of Neuroradiology (A.S.), Kings College Hospital, King's Health Partners Academic Health Science Centre, London; and Department of Pediatric Neurology (E.W.), Birmingham Children's Hospital, Birmingham, UK.

ABSTRACT

Objective: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders.

Method: Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.

Results: THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers.

Conclusion: Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.

No MeSH data available.


Related in: MedlinePlus