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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

Radiologic features of patients with white matter syndromes in association with NMDA receptor antibodies(A, B) Case 1, who presented with a brainstem syndrome. Axial T2 fluid-attenuated inversion recovery (FLAIR) images showing hyperintensity in the midbrain and mesial temporal lobe (arrows in A), which subsequently resolved on follow-up imaging performed at 2 months when the patient had relapsed with a polysymptomatic encephalopathy (B). (C, D) Case 2, who presented initially with a brainstem syndrome followed by periods of recurrent encephalopathy. Axial T2-weighted images 6 months after her initial brainstem syndrome revealed diffuse global cortical atrophy (C). Imaging during an encephalopathic episode 5 years later revealed new white matter changes (arrow in D) and further atrophy. This radiologic feature of leukoencephalopathy progressed on subsequent imaging (not shown). (E–H) Two patients with neurologic syndromes following herpes simplex virus encephalitis (HSVE). Serial axial T2 FLAIR images of case 4 (E–G) showing localized cortical changes in the left thalamus and occipital lobe (arrows in E) on initial imaging that progressed, demonstrating significant bilateral white matter signal changes in the parieto-occipital region 2 months later (arrows in F) when the patient presented with significant worsening of cognitive, behavioral, and motor regression. Following treatment and improvement of symptoms, follow-up neuroimaging 2 months later demonstrated a significant resolution of this white matter change (G). Axial T2-weighted image of case 5 at relapse 2 months after HSVE showing extensive bilateral but asymmetrical cystic encephalomalacia centered on the temporo-insular regions (only parietal changes shown) characteristic of HSVE, but in addition demonstrating the characteristic leukoencephalopathic changes seen globally (arrows in H). (I–L) Patients presenting with acquired demyelinating syndrome (ADS). At time of relapse with left optic neuritis, brain imaging in case 8 showed subtle periventricular white matter signal change on a T2-weighted image (arrow demonstrating one periventricular lesion in I). Imaging of case 9 showing midbrain (arrow in J), capsular (arrow in K), and thalamic changes (not shown) on axial T2 FLAIR. Axial T2 FLAIR image of case 10 demonstrating patchy subcortical white matter changes (L).
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Figure 1: Radiologic features of patients with white matter syndromes in association with NMDA receptor antibodies(A, B) Case 1, who presented with a brainstem syndrome. Axial T2 fluid-attenuated inversion recovery (FLAIR) images showing hyperintensity in the midbrain and mesial temporal lobe (arrows in A), which subsequently resolved on follow-up imaging performed at 2 months when the patient had relapsed with a polysymptomatic encephalopathy (B). (C, D) Case 2, who presented initially with a brainstem syndrome followed by periods of recurrent encephalopathy. Axial T2-weighted images 6 months after her initial brainstem syndrome revealed diffuse global cortical atrophy (C). Imaging during an encephalopathic episode 5 years later revealed new white matter changes (arrow in D) and further atrophy. This radiologic feature of leukoencephalopathy progressed on subsequent imaging (not shown). (E–H) Two patients with neurologic syndromes following herpes simplex virus encephalitis (HSVE). Serial axial T2 FLAIR images of case 4 (E–G) showing localized cortical changes in the left thalamus and occipital lobe (arrows in E) on initial imaging that progressed, demonstrating significant bilateral white matter signal changes in the parieto-occipital region 2 months later (arrows in F) when the patient presented with significant worsening of cognitive, behavioral, and motor regression. Following treatment and improvement of symptoms, follow-up neuroimaging 2 months later demonstrated a significant resolution of this white matter change (G). Axial T2-weighted image of case 5 at relapse 2 months after HSVE showing extensive bilateral but asymmetrical cystic encephalomalacia centered on the temporo-insular regions (only parietal changes shown) characteristic of HSVE, but in addition demonstrating the characteristic leukoencephalopathic changes seen globally (arrows in H). (I–L) Patients presenting with acquired demyelinating syndrome (ADS). At time of relapse with left optic neuritis, brain imaging in case 8 showed subtle periventricular white matter signal change on a T2-weighted image (arrow demonstrating one periventricular lesion in I). Imaging of case 9 showing midbrain (arrow in J), capsular (arrow in K), and thalamic changes (not shown) on axial T2 FLAIR. Axial T2 FLAIR image of case 10 demonstrating patchy subcortical white matter changes (L).

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)

Radiologic features of patients with white matter syndromes in association with NMDA receptor antibodies(A, B) Case 1, who presented with a brainstem syndrome. Axial T2 fluid-attenuated inversion recovery (FLAIR) images showing hyperintensity in the midbrain and mesial temporal lobe (arrows in A), which subsequently resolved on follow-up imaging performed at 2 months when the patient had relapsed with a polysymptomatic encephalopathy (B). (C, D) Case 2, who presented initially with a brainstem syndrome followed by periods of recurrent encephalopathy. Axial T2-weighted images 6 months after her initial brainstem syndrome revealed diffuse global cortical atrophy (C). Imaging during an encephalopathic episode 5 years later revealed new white matter changes (arrow in D) and further atrophy. This radiologic feature of leukoencephalopathy progressed on subsequent imaging (not shown). (E–H) Two patients with neurologic syndromes following herpes simplex virus encephalitis (HSVE). Serial axial T2 FLAIR images of case 4 (E–G) showing localized cortical changes in the left thalamus and occipital lobe (arrows in E) on initial imaging that progressed, demonstrating significant bilateral white matter signal changes in the parieto-occipital region 2 months later (arrows in F) when the patient presented with significant worsening of cognitive, behavioral, and motor regression. Following treatment and improvement of symptoms, follow-up neuroimaging 2 months later demonstrated a significant resolution of this white matter change (G). Axial T2-weighted image of case 5 at relapse 2 months after HSVE showing extensive bilateral but asymmetrical cystic encephalomalacia centered on the temporo-insular regions (only parietal changes shown) characteristic of HSVE, but in addition demonstrating the characteristic leukoencephalopathic changes seen globally (arrows in H). (I–L) Patients presenting with acquired demyelinating syndrome (ADS). At time of relapse with left optic neuritis, brain imaging in case 8 showed subtle periventricular white matter signal change on a T2-weighted image (arrow demonstrating one periventricular lesion in I). Imaging of case 9 showing midbrain (arrow in J), capsular (arrow in K), and thalamic changes (not shown) on axial T2 FLAIR. Axial T2 FLAIR image of case 10 demonstrating patchy subcortical white matter changes (L).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Radiologic features of patients with white matter syndromes in association with NMDA receptor antibodies(A, B) Case 1, who presented with a brainstem syndrome. Axial T2 fluid-attenuated inversion recovery (FLAIR) images showing hyperintensity in the midbrain and mesial temporal lobe (arrows in A), which subsequently resolved on follow-up imaging performed at 2 months when the patient had relapsed with a polysymptomatic encephalopathy (B). (C, D) Case 2, who presented initially with a brainstem syndrome followed by periods of recurrent encephalopathy. Axial T2-weighted images 6 months after her initial brainstem syndrome revealed diffuse global cortical atrophy (C). Imaging during an encephalopathic episode 5 years later revealed new white matter changes (arrow in D) and further atrophy. This radiologic feature of leukoencephalopathy progressed on subsequent imaging (not shown). (E–H) Two patients with neurologic syndromes following herpes simplex virus encephalitis (HSVE). Serial axial T2 FLAIR images of case 4 (E–G) showing localized cortical changes in the left thalamus and occipital lobe (arrows in E) on initial imaging that progressed, demonstrating significant bilateral white matter signal changes in the parieto-occipital region 2 months later (arrows in F) when the patient presented with significant worsening of cognitive, behavioral, and motor regression. Following treatment and improvement of symptoms, follow-up neuroimaging 2 months later demonstrated a significant resolution of this white matter change (G). Axial T2-weighted image of case 5 at relapse 2 months after HSVE showing extensive bilateral but asymmetrical cystic encephalomalacia centered on the temporo-insular regions (only parietal changes shown) characteristic of HSVE, but in addition demonstrating the characteristic leukoencephalopathic changes seen globally (arrows in H). (I–L) Patients presenting with acquired demyelinating syndrome (ADS). At time of relapse with left optic neuritis, brain imaging in case 8 showed subtle periventricular white matter signal change on a T2-weighted image (arrow demonstrating one periventricular lesion in I). Imaging of case 9 showing midbrain (arrow in J), capsular (arrow in K), and thalamic changes (not shown) on axial T2 FLAIR. Axial T2 FLAIR image of case 10 demonstrating patchy subcortical white matter changes (L).
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