Stoyan Popkirov

Involvement of the Metabotropic Glutamate Receptor mGluR5 in NMDA Receptor-Dependent, Learning-Facilitated Long-Term Depression in CA1 Synapses

Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with persistent synaptic plasticity to the coupling of weak afferent stimulation, which is subthreshold for the induction of plasticity, with a spatial learning experience. The metabotropic glutamate receptor subtype 5 (mGluR5) is critically involved in enabling the persistency of multiple forms of hippocampal synaptic plasticity. We compared the effects of pharmacological allosteric antagonism of mGluR5 in learning-facilitated plasticity with plasticity that had been induced solely by patterned afferent stimulation of the Schaffer collateral pathway to the CA1 stratum radiatum of adult freely behaving rats. Intracerebroventricular injection of the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) had no effect on basal synaptic transmission but significantly prevented both long-term depression (LTD) elicited by electrical stimulation and LTD facilitated by novel object-place configuration learning. NMDA receptor antagonism also prevented learning-facilitated LTD. Habituation to the objects was prevented by MPEP application. Whereas reexposure to the object-place configuration (after 7 days) failed to facilitate LTD in control animals, those who had been treated previously with MPEP expressed LTD, suggesting that inhibition of learning contributed to the initial prevention of LTD. These data support a pivotal role for mGluR5 in both hippocampal LTD and the acquisition of object-place configurations.

Lesion guided stereotactic radiofrequency thermocoagulation for palliative, in selected cases curative epilepsy surgery

INTRODUCTION Resective epilepsy surgery is an established treatment option in patients with pharmacoresistant, lesion related epilepsy. Yet, if the presurgical work-up proves multi-focal organization of the epileptogenic zone, or the area of intended resection is close to eloquent brain areas, patients may decide against resections because of an unfavorable risk-benefit-ratio. We assess if lesion guided cortical stereotactic radiofrequency thermocoagulation (L-RFTC) is a potential surgical alternative in these patients. METHODS We performed seven procedures of L-RFTC. Three patients had monofocal epilepsy arising close to eloquent structures; in four, invasive pre-surgical workup documented monofocal seizure onset but strong interictal epileptic activity also independent and distant from the seizure onset zone. L-RFTC was restricted to the lesional area (=seizure onset site). RESULTS 12 to 37 months after RFTC worthwhile seizure improvement was achieved in 6 patients. One patient became seizure free following complete coagulation of a focal cortical dysplasia, two had had 1-2 auras under tapered but not under continued medication. In one patient only subclinical seizures persisted. In one patient hypermotor seizures were transformed into milder short tonic seizures and another one had a seizure reduction by 50%. Only one patient did not profit at all. One patient developed a persisting neurological deficit. SIGNIFICANCE In patients with complex epileptogenic zones L-RFTC can lead to worthwhile seizure reduction. This qualifies this procedure as a palliative surgical technique with potential good risk-benefit ratio. In patients with small focal cortical dysplasias L-RFTC may even allow minimal-invasive surgery with curative intention.

A systematic review of suggestive seizure induction for the diagnosis of psychogenic nonepileptic seizures

Suggestive seizure induction is a widely used method for diagnosing psychogenic nonepileptic seizures (PNES). Despite seven decades of multidisciplinary research, however, there is still no unified protocol, no definitive agreement on the ethical framework and no consensus on diagnostic utility. This systematic review surveys the evidence at hand and addresses clinically relevant aspects of suggestive seizure induction. In addition to its use for facilitating the diagnostic process, its mechanism of action and utility in elucidating the psychopathology of PNES will be discussed.

Immunoglobulin-G4-related hypertrophic pachymeningitis with antineutrophil cytoplasmatic antibodies effectively treated with rituximab

We describe a 52-year-old man with hypertrophic pachymeningitis (HP) who was both seropositive for antineutrophil cytoplasmatic antibodies (ANCA) against myeloperoxidase, and had an immunoglobulin G4 (IgG4) positive fibroinflammatory response in meningeal biopsy. HP is a chronic inflammatory thickening of the dura mater which typically presents with headache, cranial nerve dysfunction and other neurological deficits. While first-line treatment with corticosteroids is recommended, many patients relapse and need additional immunosuppression. One recently described etiology is IgG4-related disease and in a subgroup of idiopathic patients, evidence suggests a crucial role of ANCA. To our knowledge, the simultaneous occurrence of IgG4-related disease and ANCA has not been reported so far. This man suffered life-threatening disease progression despite the administration of high dose steroids, cyclophosphamide and azathioprine. Treatment with rituximab was initiated which led to disappearance of clinical symptoms and decrease of dural thickening within weeks. This patient presents a possible disease overlap of IgG4-related and ANCA-associated HP and illustrates the effectiveness of rituximab in refractory IgG4-related HP.

Hyperventilation and photic stimulation are useful additions to a placebo-based suggestive seizure induction protocol in patients with psychogenic nonepileptic seizures

The early and definitive diagnosis of psychogenic nonepileptic seizures is a common challenge in epileptology practice. Suggestive seizure induction is a valuable tool to aid the differentiation between epileptic and psychogenic nonepileptic seizures, especially when long-term video-EEG monitoring is inconclusive or unavailable. In this retrospective analysis, we compared the diagnostic yield of a classical, placebo-based induction protocol with that of an extended protocol that includes hyperventilation and photic stimulation as means of suggestion while also implementing more open, standardized patient information. We investigated whether the diversification of suggestive seizure induction has an effect on diagnostic yield and whether it preempts the administration of placebo. Data from 52 patients with confirmed psychogenic nonepileptic seizures were analyzed. While suggestive seizure induction using only placebo-based suggestion provoked a typical event in 13 of 20 patients (65%), the extended protocol was positive in 27 of 34 cases (84%); this improvement was not significant (p=0.11). Noninvasive suggestion techniques accounted for 78% of inductions, avoiding placebo administration in a majority of patients. Still, placebo remains an important part of suggestive seizure induction, responsible for 22% (6 out of 27) of successful inductions using our extended protocol. Our study demonstrates that the diversification of suggestive seizure induction is feasible and beneficial for both patients and diagnosticians.

Persistent postural-perceptual dizziness (PPPD): a common, characteristic and treatable cause of chronic dizziness

Persistent postural-perceptual dizziness (PPPD) is a newly defined diagnostic syndrome that unifies key features of chronic subjective dizziness, phobic postural vertigo and related disorders. It describes a common chronic dysfunction of the vestibular system and brain that produces persistent dizziness, non-spinning vertigo and/or unsteadiness. The disorder constitutes a long-term maladaptation to a neuro-otological, medical or psychological event that triggered vestibular symptoms, and is usefully considered within the spectrum of other functional neurological disorders. While diagnostic tests and conventional imaging usually remain negative, patients with PPPD present in a characteristic way that maps on to positive diagnostic criteria. Patients often develop secondary functional gait disorder, anxiety, avoidance behaviour and severe disability. Once recognised, PPPD can be managed with effective communication and tailored treatment strategies, including specialised physical therapy (vestibular rehabilitation), serotonergic medications and cognitive-behavioural therapy.

Faciobrachio-crural dystonic seizures in LGI1 limbic encephalitis: A treatable cause of falls

Faciobrachial dystonic seizures (FBDS) are closely associated with antibodies (Ab) to the leucine-rich glioma inactivated-1 protein (LGI1) component of the voltage-gated potassium channel (VGKC) complex. They precede or indicate the onset of limbic encephalitis (LE).1 Immunotherapy can prevent the development of LE and cognitive impairment.1,2

Frontal EEG asymmetry in borderline personality disorder is associated with alexithymia

BackgroundFrontal EEG asymmetry is a widely studied correlate of emotion processing and psychopathology. Recent research suggests that frontal EEG asymmetry during resting state is related to approach/withdrawal motivation and is also found in affective disorders such as major depressive disorder. Patients with borderline personality disorder (BPD) show aberrant behavior in relation to both approach and withdrawal motivation, which may arguably be associated with their difficulties in emotion processing. The occurrence and significance of frontal EEG asymmetry in BPD, however, has received little attention.ResultsThirty-seven BPD patients and 39 controls underwent resting EEG and completed several psychometric questionnaires. While there were no between-group differences in frontal EEG asymmetry, in BPD frontal EEG asymmetry scores correlated significantly with alexithymia. That is, higher alexithymia scores were associated with relatively lower right-frontal activity. A subsequent analysis corroborated the significant interaction between frontal EEG asymmetry and alexithymia, which was moderated by group.ConclusionsOur findings reveal that lower right frontal EEG asymmetry is associated with alexithymia in patients with BPD. This finding is in accordance with neurophysiological models of alexithymia that implicate a right hemisphere impairment in emotion processing, and could suggest frontal EEG asymmetry as a potential biomarker of relevant psychopathology in these patients.

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.

Recurrent loss of consciousness despite DDD pacing: psychogenic pseudosyncope in a 19-year-old man.

Unexplained recurrent syncope requires interdisciplinary assessment. Paroxysmal bradyand tachycardias can mimic psychiatric conditions [1, 2] and, on the other hand, epileptic seizures, panic attacks and psychogenic phenomena can be mistaken for dysrhythmias. While the former misdiagnosis can be avoided by structured cardiological workup, the latter requires neurological assessment considering the differential diagnosis psychogenic pseudosyncope [3]. A 19-year-old man with recurrent syncope of unknown origin was referred to our epilepsy center for neurological assessment. Attacks with transient loss of consciousness first occurred 2 years previously. A typical event would often be preceded by a rising sensation of pressure and pulsation in the neck and head, followed by a (usually backwards) fall. The ensuing unconsciousness usually lasted 4–5 min with reorientation afterwards lasting several minutes. No motor activity, tongue bite or enuresis during the events was reported. Within 3 months prior to neurological assessment, 1–2 events per week were noted. Previous medical history included autonomic dysfunction, arterial hypertension, nicotine addiction, obesity (135 kg) and obstructive sleep apnea; he was diagnosed in other institutions as having ‘‘Tourette’s syndrome, social phobia, Asperger syndrome’’ and ‘‘attention deficit disorder’’. Multiple cardiological investigations had led to implantation of an event recorder, which registered eventcorrelated narrow complex tachycardias of up to 187 bpm as well as bradycardias of 40 bpm. An electrophysiological study revealed no sign of habitual arrhythmia and no inducible tachycardias. ‘‘Sick sinus syndrome’’ was diagnosed and a DDD pacemaker was implanted. However, the attacks persisted with unaltered frequency. On repeated cardiological assessment, pacemaker function was intact and no signs of autonomic dysfunction or dysrhythmia were found. A neurological investigation was recommended. During 2 days of continuous electroencephalography(EEG-)video monitoring, no interictal epileptic discharges were recorded and no transient loss of consciousness occurred. Tilt-table test was impossible due to weight restrictions of the equipment; Schellong testing was normal with no sign of autonomic dysfunction. The patient was then subjected to suggestive ‘‘seizure’’ provocation through postural maneuvers (sitting down and standing up swiftly) and intravenous administration of saline (mixed with Vitamin B12 for pink coloring); he was informed that these techniques induced fits in some patients. Mattresses were placed on the floor to avoid injury. Rapid postural changes akin to Schellong testing did not elicit loss of consciousness or any significant changes in blood pressure. After three consecutive injections, however, the patient suddenly fell to the ground and was unresponsive for 92 s. Before, during and after the event Electronic supplementary material The online version of this article (doi:10.1007/s00392-014-0711-5) contains supplementary material, which is available to authorized users.