Simone Baiardi

High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions

An early and accurate in vivo diagnosis of rapidly progressive dementia remains challenging, despite its critical importance for the outcome of treatable forms, and the formulation of prognosis. Real-Time Quaking-Induced Conversion (RT-QuIC) is an in vitro assay that, for the first time, specifically discriminates patients with prion disease. Here, using cerebrospinal fluid (CSF) samples from 239 patients with definite or probable prion disease and 100 patients with a definite alternative diagnosis, we compared the performance of the first (PQ-CSF) and second generation (IQ-CSF) RT-QuIC assays, and investigated the diagnostic value of IQ-CSF across the broad spectrum of human prions. Our results confirm the high sensitivity of IQ-CSF for detecting human prions with a sub-optimal sensitivity for the sporadic CJD subtypes MM2C and MM2T, and a low sensitivity limited to variant CJD, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. While we found no difference in specificity between PQ-CSF and IQ-CSF, the latter showed a significant improvement in sensitivity, allowing prion detection in about 80% of PQ-CSF negative CJD samples. Our results strongly support the implementation of IQ-CSF in clinical practice. By rapidly confirming or excluding CJD with high accuracy the assay is expected to improve the outcome for patients and their enrollment in therapeutic trials.

Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

Towards an early clinical diagnosis of sporadic CJD VV2 (ataxic type)

Introduction Sporadic Creutzfeldt-Jakob disease (sCJD) includes a broad spectrum of clinical–pathological subtypes, which complicates the clinical differential diagnosis with other rapidly progressive neurological syndromes. Aim To provide a better characterisation of clinical features and results of diagnostic investigations, especially at an early disease stage, in patients with sCJDVV2, the second most common sCJD subtype. Methods We evaluated neurological symptoms/signs, and results of brain diffusion-weighted resonance imaging (DW-MRI), electroencephalographic recordings (EEG) and cerebrospinal fluid (CSF) biomarker studies in 120 patients with a definite (n=93) or probable (n=27) diagnosis of sCJDVV2. Results All patients presented with prominent cerebellar signs, which were often associated with memory loss and/or oculomotor, visual or peripheral/spinal cord signs. In contrast, dementia was invariably a late finding. All CSF samples were positive for the 14-3-3 protein assay and had total-tau protein levels above 1250 pg/mL. Brain DW-MRI showed hyperintensity of basal ganglia, thalamus and cerebral cortex, respectively in 91.5%, 57.4% and 19.1% of cases. EEG revealed periodic sharp-wave complexes in only 17.8% of cases. Conclusions sCJDVV2 should be considered in any patient presenting with a rapidly progressive ataxia, especially when associated with oculomotor, visual or peripheral/spinal cord signs, even in the absence of dementia or myoclonus. CSF assays and brain DW-MRI represent sensitive diagnostic tests, even at an early stage. These data strongly suggest that sCJDVV2 can be clinically diagnosed early and accurately based on clinical data, DW-MRI, CSF assays and codon 129 genotyping and provide the basis for improved and subtype-specific diagnostic criteria of sCJD.

Technique and Preliminary Analysis of Drug-Induced Sleep Endoscopy With Online Polygraphic Cardiorespiratory Monitoring in Patients With Obstructive Sleep Apnea Syndrome.

Importance Drug-induced sleep endoscopy is a diagnostic technique that allows dynamic evaluation of the upper airway during artificial sleep. The lack of a standardized procedure and the difficulties associated with direct visual detection of obstructive events result in poor intraobserver and interobserver reliability, especially when otolaryngology surgeons not experienced in the technique are involved. Objectives To describe a drug-induced sleep endoscopy technique implemented with simultaneous polygraphic monitoring of cardiorespiratory parameters (DISE-PG) in patients with a diagnosis of obstructive sleep apnea syndrome and discuss the technique’s possible advantages compared with the standard procedure. Design, Setting, and Participants This prospective cohort study included 50 consecutive patients with obstructive sleep apnea syndrome who underwent DISE-PG from March 1, 2013, to June 30, 2014. A standard protocol was adopted, and all the procedures were carried out in an operation room by an experienced otolaryngology surgeon under the supervision of an anesthesiologist. Endoscopic and polygraphic obstructive respiratory events were analyzed offline in a double-blind setting and randomized order. Main Outcomes and Measures The feasibility and safety of the DISE-PG technique, as well as its sensitivity in detecting respiratory events compared with that of the standard drug-induced sleep endoscopy procedure. Results All 50 patients (43 men and 7 women; mean [SD] age, 51.1 [12.1] years) underwent DISE-PG without technical problems or patient difficulties regarding the procedure. As expected, polygraphic scoring was more sensitive than endoscopic scoring in identifying obstructive events (mean [SD] total events, 13.3 [6.8] vs 5.3 [3.6]; mean [SD] difference, 8.8 [5.6]; 95% CI, 7.3 to 10.4; Cohen d, –1.5). This difference was most pronounced in patients with a higher apnea-hypopnea index (AHI) at baseline (mean [SD] difference for AHI >30, 27.1% [31.0%]; 95% CI, –36.2% to 90.4%; Cohen d, 0.2; for AH I >40, 76.0% [35.5%]; 95% CI, 4.6% to 147.4%; Cohen d, 0.5; for AHI >50, 92.2% [37.2%]; 95% CI, 17.3% to 167.1%; Cohen d, 0.6) and a high percentage of hypopneas (≥75% of all obstructive events) at baseline (mean [SD] difference, 20.2% [5.4%]; 95% CI, 9.2% to 31.3%; Cohen d, 1.1). No other anthropomorphic or polygraphic features at baseline were associated with the differences between the DISE-PG and baseline home sleep apnea test. Conclusions and Relevance The DISE-PG technique is feasible, safe, and more sensitive at detecting an obstructed breathing pattern than is drug-induced sleep endoscopy alone. The DISE-PG technique could be helpful for accurate comprehension of upper airway obstructive dynamics (ie, degree of obstruction and multilevel pattern) and a nonobstructive breathing pattern (ie, central apneas).

Cataplectic attacks during rapid eye movement sleep behavior disorder episodes in a narcoleptic patient

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Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases.

see front matter 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.08.794 ⇑ Corresponding author. Address: DIBINEM, Alma Mater Studiorum, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. Tel.: +39 051 4966926. E-mail address: giuseppe.plazzi@unibo.it (G. Plazzi). This section is a new feature of Sleep Medicine allowing readers to submit unique sleep related cases with video segments as a way to enhance educational value in a manner unattainable through paper format. Please see our web site’s (http://ees.elsevier.com/sleep/) Guide for Authors for instructions. We hope this section will be enriched by the contributions of our colleagues who wish to offer stimulating opportunities for discussion and new insights into the field of sleep.

Immunotherapy of oneiric stupor in Morvan syndrome: Efficacy documented by actigraphy.

STUDY OBJECTIVES The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. METHODS AND RESULTS Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. CONCLUSIONS Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness.

A restless abdomen and propriospinal myoclonus like at sleep onset: an unusual overlap syndrome

Morvan syndrome (MoS) is a rare acquired channelopathy associated with autoantibodies against potassium channel complex and clinically characterized by the heterogeneous combination of neuromyotonia, dysautonomia, and encephalopathy.1 Peculiar CNS symptoms are organic insomnia, which ranges from mild to malignant forms characterized by complete loss of sleep, and persistent motor/autonomic hyperactivation (agrypnia excitata2). We describe a patient with MoS who developed progressive agrypnia excitata, in which IV immunoglobulin (IVIg) treatment induced a progressive recovery of the physiologic sleep-wake cycle, documented by videopolysomnography (VPSG) and actigraphic monitoring.

Identification of rare genetic variants in Italian patients with dementia by targeted gene sequencing

We report for the first time the association between restless abdomen, a phenotypic variant of restless legs syndrome in which symptoms are limited to the abdomen, and propriospinal myoclonus at sleep onset causing severe insomnia. The treatment with a low-dosage of dopaminergic drug (pramipexole) induced the immediate disappearance of both symptoms, which was documented by video-polysomnography.

Is the Epworth Sleepiness Scale a useful tool for screening excessive daytime sleepiness in commercial drivers

Genetics is intricately involved in the etiology of neurodegenerative dementias. The incidence of monogenic dementia among all neurodegenerative forms is unknown due to the lack of systematic studies and of patient/clinician access to extensive diagnostic procedures. In this study, we conducted targeted sequencing in 246 clinically heterogeneous patients, mainly with early-onset and/or familial neurodegenerative dementia, using a custom-designed next-generation sequencing panel covering 27 genes known to harbor mutations that can cause different types of dementia, in addition to the detection of C9orf72 repeat expansions. Forty-nine patients (19.9%) carried known pathogenic or novel, likely pathogenic, variants, involving both common (presenilin 1, presenilin 2, C9orf72, and granulin) and rare (optineurin, serpin family I member 1 and protein kinase cyclic adenosine monophosphate (cAMP)-dependent type I regulatory subunit beta) dementia-associated genes. Our results support the use of an extended next-generation sequencing panels as a quick, accurate, and cost-effective method for diagnosis in clinical practice. This approach could have a significant impact on the proportion of tested patients, especially among those with an early disease onset.