Progressive encephalomyelitis with rigidity and myoclonus

Balint, Bettina; Jarius, Sven; Nagel, Simon; Haberkorn, Uwe; Probst, Christian; Blöcker, Inga Madeleine; Bahtz, Ramona; Komorowski, Lars; Stöcker, W.; Kastrup, Andreas; Kuthe, Martin; Meinck, H.-M.

doi:10.1212/wnl.0000000000000372

Cited by 183 publications

(141 citation statements)

References 15 publications

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“…DISCUSSION The clinical findings of our newly identified patient with anti-DPPX encephalitis are reminiscent of those reported in the original series 1 rather than the PERM-like presentation described in 3 patients with anti-DPPX antibodies. 2 A noteworthy feature was transient hypersomnia, consistent with the recent observation of sleep disturbances in 9 of 20 patients with anti-DPPX encephalitis.…”

supporting

confidence: 83%

“…[1][2][3] DPPX is a membrane glycoprotein involved in increasing the surface expression and channel conductance of Kv4.2 channels. [4][5][6] Although its function and the expression of DPPX in *These authors contributed equally to this work.…”

Section: Resultsmentioning

confidence: 99%

“…1 An additional 3 patients with anti-DPPX antibodies and a distinct syndrome resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) were subsequently described. 2 Recently, clinical features and outcomes were characterized in 20 patients with anti-DPPX encephalitis. 3 Remarkably, 14 of the 27 patients with anti-DPPX encephalitis reported so far had pronounced gastrointestinal symptoms, including severe diarrhea in 10 and constipation in 4 patients.…”

mentioning

confidence: 99%

“…3 Remarkably, 14 of the 27 patients with anti-DPPX encephalitis reported so far had pronounced gastrointestinal symptoms, including severe diarrhea in 10 and constipation in 4 patients. [1][2][3] DPPX is a membrane glycoprotein involved in increasing the surface expression and channel conductance of Kv4.2 channels. [4][5][6] Although its function and the expression of DPPX in hippocampus, cerebellum, striatum, and myenteric plexus 1,7 are compatible with the clinical symptoms of anti-DPPX encephalitis, the pathogenic mechanisms of anti-DPPX antibodies have not been characterized.…”

mentioning

confidence: 99%

“…It thus seems conceivable that the initial severe diarrhea of patients with anti-DPPX encephalitis is related to anti-DPPX-antibody-induced hyperexcitability of enteric neurons, leading to gastrointestinal hyperactivity. Nevertheless, the occasional occurrence of gastrointestinal hypomotility 2,3 suggests that in certain instances anti-DPPX antibodies could also lead to loss Figure 4 Binding of anti-dipeptidyl-peptidase-like protein 6 serum to excitatory and inhibitory synapses and association with Kv4.2…”

mentioning

confidence: 99%

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Anti-DPPX encephalitis

Piepgras¹,

Höltje²,

Michel³

et al. 2015

Neurology

109

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Objective: To characterize pathogenic effects of antibodies to dipeptidyl-peptidase-like protein 6 (DPPX), a subunit of Kv4.2 potassium channels, on gut and brain neurons. Methods:We identified a new patient with anti-DPPX encephalitis and analyzed the effects of the patient's serum and purified immunoglobulin G (IgG), and of serum of a previous patient with anti-DPPX encephalitis, on the activity of enteric neurons by voltage-sensitive dye imaging in guinea pig myenteric and human submucous plexus preparations. We studied the subcellular localization of DPPX by immunocytochemistry in cultured murine hippocampal neurons using sera of 4 patients with anti-DPPX encephalitis. We investigated the influence of anti-DPPX-containing serum and purified IgG on neuronal surface expression of DPPX and Kv4.2 by immunoblots of purified murine hippocampal neuron membranes. Results:The new patient with anti-DPPX encephalitis presented with a 2-month episode of diarrhea, which was followed by tremor, disorientation, and mild memory impairment. Anti-DPPX-IgGcontaining sera and purified IgG increased the excitability and action potential frequency of guinea pig and human enteric nervous system neurons. Patient sera revealed a somatodendritic and perisynaptic neuronal surface staining that colocalized with the signal of commercial anti-DPPX and Kv4.2 antibodies. Incubation of hippocampal neurons with patient serum and purified IgG resulted in a decreased expression of DPPX and Kv4.2 in neuronal membranes. In 2013, a novel autoimmune encephalitis associated with antibodies to dipeptidyl-peptidaselike protein 6 (DPPX), an auxiliary subunit of Kv4.2 potassium channels, was identified in 4 patients whose clinical presentation included agitation, hallucinations, confusion, myoclonus, tremor, and seizures.1 An additional 3 patients with anti-DPPX antibodies and a distinct syndrome resembling progressive encephalomyelitis with rigidity and myoclonus (PERM) were subsequently described.2 Recently, clinical features and outcomes were characterized in 20 patients with anti-DPPX encephalitis.3 Remarkably, 14 of the 27 patients with anti-DPPX encephalitis reported so far had pronounced gastrointestinal symptoms, including severe diarrhea in 10 and constipation in 4 patients. [1][2][3] DPPX is a membrane glycoprotein involved in increasing the surface expression and channel conductance of Kv4.2 channels. [4][5][6] Although its function and the expression of DPPX in *These authors contributed equally to this work.

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supporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Anti-DPPX encephalitis

Piepgras¹,

Höltje²,

Michel³

et al. 2015

Neurology

109

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Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

et al. 2016

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Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

Chia

McKeon

Dalakas

et al. 2023

Ann Clin Transl Neurol

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Background: Stiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging. Methods: Patients referred for diagnosis/ suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high-titer GAD65-IgG (>20.0 nmol/L), glycinereceptor-IgG or amphiphysin-IgG, and/or confirmatory electrodiagnostic studies (essential if seronegative). Clinical presentation, examination, and ancillary testing were compared to differentiate SPSD from non-SPSD. Results: Of 173 cases, 48 (28%) were diagnosed with SPSD and 125 (72%) with non-SPSD. Most SPSD were seropositive (41/48: GAD65-IgG 28/41, glycine-receptor-IgG 12/41, amphiphysin-IgG 2/41). Pain syndromes or functional neurologic disorder were the most common non-SPSD diagnoses (81/125, 65%). SPSD patients more commonly reported exaggerated startle (81% vs. 56%, p = 0.02), unexplained falls (76% vs. 46%, p = 0.001), and other associated autoimmunity (50% vs. 27%, p = 0.005). SPSD more often had hypertonia (60% vs. 24%, p < 0.001), hyperreflexia (71% vs. 43%, p = 0.001), and lumbar hyperlordosis (67% vs. 9%, p < 0.001) and less likely functional neurologic signs (6% vs. 33%, p = 0.001). SPSD patients more frequently had electrodiagnostic abnormalities (74% vs. 17%, p < 0.001), and at least moderate symptomatic improvement with benzodiazepines (51% vs. 16%, p < 0.001) or immunotherapy (45% vs. 13% p < 0.001). Only 4/78 non-SPSD patients who received immunotherapy had alternative neurologic autoimmunity. Interpretation: Misdiagnosis was threefold more common than confirmed SPSD. Functional or non-neurologic disorders accounted for most misdiagnoses. Clinical and ancillary testing factors can reduce misdiagnosis and exposure to unnecessary treatments. SPSD diagnostic criteria are suggested.

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Progressive encephalomyelitis with rigidity and myoclonus

Cited by 183 publications

References 15 publications

Anti-DPPX encephalitis

Anti-DPPX encephalitis

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder

Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

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