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A case of inflammatory peripheral nerve destruction antedating anti-NMDA receptor encephalitis.

Prüss H, Hoffmann C, Stenzel W, Saschenbrecker S, Ebinger M - Neurol Neuroimmunol Neuroinflamm (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Experimental Neurology (H.P., C.H., M.E.) and Department of Pathology (W.S.), Charité-Universitätsmedizin Berlin; German Center for Neurodegenerative Diseases (DZNE) Berlin (H.P.); and Institute for Experimental Immunology (S.S.), affiliated with Euroimmun, Lübeck, Germany.

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NMDA receptor (NMDAR) antibody encephalitis is the second most common autoimmune encephalitis after acute disseminated encephalomyelitis, presenting with a multistage clinical progression with prodromal signs, psychiatric abnormalities, reduced levels of consciousness, epileptic seizures, dyskinesias, and autonomic dysfunction... Causal factors in tumor-negative patients are largely unknown... Recent studies showed that infectious encephalitides with herpes simplex virus (HSE) are associated with the generation of NMDAR antibodies and that antibodies cause immunotherapy-responsive relapsing symptoms post-HSE... It is unknown, however, whether further types of neuronal damage can trigger a secondary immune response leading to NMDAR encephalitis... Lumbar puncture showed normal cell count (5/µl) but high protein (>1,047 mg/L)... Viral encephalitis was suspected and acyclovir was started until PCR for herpes simplex virus (HSV) and varicella-zoster virus showed negative results... Differential diagnosis of the concomitant severe neuropathy included nerve conduction studies, which showed sensorimotor axonal and demyelinating neuropathy predominantly affecting the legs (compound muscle action potential of right tibial nerve was reduced, nerve conduction velocity was delayed, and there were no reproducible recordings from peroneal and sural nerves)... Reflexes were normal, and there were no atrophies or fasciculations... Sural nerve biopsy 3 months after referral showed severe reduction of myelinated fibers but also strong axonal degeneration and single axon regeneration clusters (figure)... Nine months after initial presentation he showed no dyskinesias, no signs of autonomic or psychiatric dysfunction, and normal consciousness and attention... Motor function and leg pain were markedly improved whereas electrophysiology was unchanged... We hypothesize that NMDAR antibodies represent a secondary immune response to massive destruction of peripheral nerve proteins as shown in sural nerve biopsy, also supported by the temporal relationship between neuritis onset and NMDAR antibodies... The present case suggests that inflammatory neuropathies may also trigger a secondary autoimmune response leading to severe encephalitis... Whether less obvious damage to peripheral neuronal tissue can under certain conditions trigger an immune response with formation of pathogenic autoantibodies and NMDAR encephalitis is an intriguing question.

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Related in: MedlinePlus

Clinical course of acute neuritis and NMDA receptor (NMDAR) encephalitis, sural nerve biopsy, and detection of NMDAR antibodies(A) Approximately 3–4 weeks after onset of peripheral neuropathy, NMDAR antibody (ab) titers started to appear in CSF (red) and serum (blue). NMDAR encephalitis showed response to immunotherapy with methylprednisolone (MP), IV immunoglobulin (IVIg), plasma exchange (PE), and rituximab. Curves for neuropathy and encephalitis demonstrate global clinical impression (arbitrary units) to visualize the sequence of clinical symptoms. mRS = modified Rankin Scale. (B–D) Patient's serum (green, Alexa Fluor 488, Jackson ImmunoResearch, Suffolk, UK) showed the typical pattern in rat hippocampus (dilution 1:400, B) and NMDAR-transfected HEK293 cells (C) but not control-transfected cells (D). Red nuclear stain was performed with TO-PRO-3 iodide (Invitrogen, Karlsruhe, Germany). (E.a) Semithin section stained by methylene blue illustrates severe reduction of myelinated fibers, affecting both thin and thickly myelinated fibers. Also, profound axonal loss (asterisks), acute axonal degeneration (arrows), and single axon regeneration clusters are visible (box E.b: higher magnification). (F) Teased fibers show short internodal segments (arrows). (G) Higher magnification demonstrates hypomyelinated and shortened segments (sign of demyelination) and alignment of ovoids (sign of acute axonal degeneration).
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Figure 1: Clinical course of acute neuritis and NMDA receptor (NMDAR) encephalitis, sural nerve biopsy, and detection of NMDAR antibodies(A) Approximately 3–4 weeks after onset of peripheral neuropathy, NMDAR antibody (ab) titers started to appear in CSF (red) and serum (blue). NMDAR encephalitis showed response to immunotherapy with methylprednisolone (MP), IV immunoglobulin (IVIg), plasma exchange (PE), and rituximab. Curves for neuropathy and encephalitis demonstrate global clinical impression (arbitrary units) to visualize the sequence of clinical symptoms. mRS = modified Rankin Scale. (B–D) Patient's serum (green, Alexa Fluor 488, Jackson ImmunoResearch, Suffolk, UK) showed the typical pattern in rat hippocampus (dilution 1:400, B) and NMDAR-transfected HEK293 cells (C) but not control-transfected cells (D). Red nuclear stain was performed with TO-PRO-3 iodide (Invitrogen, Karlsruhe, Germany). (E.a) Semithin section stained by methylene blue illustrates severe reduction of myelinated fibers, affecting both thin and thickly myelinated fibers. Also, profound axonal loss (asterisks), acute axonal degeneration (arrows), and single axon regeneration clusters are visible (box E.b: higher magnification). (F) Teased fibers show short internodal segments (arrows). (G) Higher magnification demonstrates hypomyelinated and shortened segments (sign of demyelination) and alignment of ovoids (sign of acute axonal degeneration).

Mentions: A previously healthy 75-year-old man was referred with confusion, disorientation, and agitation. History revealed signs of neuropathy with ascending pain and numbness in his legs starting at least 3–4 weeks (but not >8 weeks) prior to referral; a friend reported progressive difficulties in walking and frequent falls during this time. Lumbar puncture showed normal cell count (5/µl) but high protein (>1,047 mg/L). Viral encephalitis was suspected and acyclovir was started until PCR for herpes simplex virus (HSV) and varicella-zoster virus showed negative results. Head MRI was unremarkable, showing mild generalized atrophy. No infectious agents were detected in serum and CSF, and NMDAR antibodies were below detection threshold (figure).


A case of inflammatory peripheral nerve destruction antedating anti-NMDA receptor encephalitis.

Prüss H, Hoffmann C, Stenzel W, Saschenbrecker S, Ebinger M - Neurol Neuroimmunol Neuroinflamm (2014)

Clinical course of acute neuritis and NMDA receptor (NMDAR) encephalitis, sural nerve biopsy, and detection of NMDAR antibodies(A) Approximately 3–4 weeks after onset of peripheral neuropathy, NMDAR antibody (ab) titers started to appear in CSF (red) and serum (blue). NMDAR encephalitis showed response to immunotherapy with methylprednisolone (MP), IV immunoglobulin (IVIg), plasma exchange (PE), and rituximab. Curves for neuropathy and encephalitis demonstrate global clinical impression (arbitrary units) to visualize the sequence of clinical symptoms. mRS = modified Rankin Scale. (B–D) Patient's serum (green, Alexa Fluor 488, Jackson ImmunoResearch, Suffolk, UK) showed the typical pattern in rat hippocampus (dilution 1:400, B) and NMDAR-transfected HEK293 cells (C) but not control-transfected cells (D). Red nuclear stain was performed with TO-PRO-3 iodide (Invitrogen, Karlsruhe, Germany). (E.a) Semithin section stained by methylene blue illustrates severe reduction of myelinated fibers, affecting both thin and thickly myelinated fibers. Also, profound axonal loss (asterisks), acute axonal degeneration (arrows), and single axon regeneration clusters are visible (box E.b: higher magnification). (F) Teased fibers show short internodal segments (arrows). (G) Higher magnification demonstrates hypomyelinated and shortened segments (sign of demyelination) and alignment of ovoids (sign of acute axonal degeneration).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Clinical course of acute neuritis and NMDA receptor (NMDAR) encephalitis, sural nerve biopsy, and detection of NMDAR antibodies(A) Approximately 3–4 weeks after onset of peripheral neuropathy, NMDAR antibody (ab) titers started to appear in CSF (red) and serum (blue). NMDAR encephalitis showed response to immunotherapy with methylprednisolone (MP), IV immunoglobulin (IVIg), plasma exchange (PE), and rituximab. Curves for neuropathy and encephalitis demonstrate global clinical impression (arbitrary units) to visualize the sequence of clinical symptoms. mRS = modified Rankin Scale. (B–D) Patient's serum (green, Alexa Fluor 488, Jackson ImmunoResearch, Suffolk, UK) showed the typical pattern in rat hippocampus (dilution 1:400, B) and NMDAR-transfected HEK293 cells (C) but not control-transfected cells (D). Red nuclear stain was performed with TO-PRO-3 iodide (Invitrogen, Karlsruhe, Germany). (E.a) Semithin section stained by methylene blue illustrates severe reduction of myelinated fibers, affecting both thin and thickly myelinated fibers. Also, profound axonal loss (asterisks), acute axonal degeneration (arrows), and single axon regeneration clusters are visible (box E.b: higher magnification). (F) Teased fibers show short internodal segments (arrows). (G) Higher magnification demonstrates hypomyelinated and shortened segments (sign of demyelination) and alignment of ovoids (sign of acute axonal degeneration).
Mentions: A previously healthy 75-year-old man was referred with confusion, disorientation, and agitation. History revealed signs of neuropathy with ascending pain and numbness in his legs starting at least 3–4 weeks (but not >8 weeks) prior to referral; a friend reported progressive difficulties in walking and frequent falls during this time. Lumbar puncture showed normal cell count (5/µl) but high protein (>1,047 mg/L). Viral encephalitis was suspected and acyclovir was started until PCR for herpes simplex virus (HSV) and varicella-zoster virus showed negative results. Head MRI was unremarkable, showing mild generalized atrophy. No infectious agents were detected in serum and CSF, and NMDAR antibodies were below detection threshold (figure).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Experimental Neurology (H.P., C.H., M.E.) and Department of Pathology (W.S.), Charité-Universitätsmedizin Berlin; German Center for Neurodegenerative Diseases (DZNE) Berlin (H.P.); and Institute for Experimental Immunology (S.S.), affiliated with Euroimmun, Lübeck, Germany.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

NMDA receptor (NMDAR) antibody encephalitis is the second most common autoimmune encephalitis after acute disseminated encephalomyelitis, presenting with a multistage clinical progression with prodromal signs, psychiatric abnormalities, reduced levels of consciousness, epileptic seizures, dyskinesias, and autonomic dysfunction... Causal factors in tumor-negative patients are largely unknown... Recent studies showed that infectious encephalitides with herpes simplex virus (HSE) are associated with the generation of NMDAR antibodies and that antibodies cause immunotherapy-responsive relapsing symptoms post-HSE... It is unknown, however, whether further types of neuronal damage can trigger a secondary immune response leading to NMDAR encephalitis... Lumbar puncture showed normal cell count (5/µl) but high protein (>1,047 mg/L)... Viral encephalitis was suspected and acyclovir was started until PCR for herpes simplex virus (HSV) and varicella-zoster virus showed negative results... Differential diagnosis of the concomitant severe neuropathy included nerve conduction studies, which showed sensorimotor axonal and demyelinating neuropathy predominantly affecting the legs (compound muscle action potential of right tibial nerve was reduced, nerve conduction velocity was delayed, and there were no reproducible recordings from peroneal and sural nerves)... Reflexes were normal, and there were no atrophies or fasciculations... Sural nerve biopsy 3 months after referral showed severe reduction of myelinated fibers but also strong axonal degeneration and single axon regeneration clusters (figure)... Nine months after initial presentation he showed no dyskinesias, no signs of autonomic or psychiatric dysfunction, and normal consciousness and attention... Motor function and leg pain were markedly improved whereas electrophysiology was unchanged... We hypothesize that NMDAR antibodies represent a secondary immune response to massive destruction of peripheral nerve proteins as shown in sural nerve biopsy, also supported by the temporal relationship between neuritis onset and NMDAR antibodies... The present case suggests that inflammatory neuropathies may also trigger a secondary autoimmune response leading to severe encephalitis... Whether less obvious damage to peripheral neuronal tissue can under certain conditions trigger an immune response with formation of pathogenic autoantibodies and NMDAR encephalitis is an intriguing question.

No MeSH data available.


Related in: MedlinePlus