Electroencephalography (EEG) for neurological prognostication after cardiac arrest and targeted temperature management; rationale and study design.

BACKGROUND: Electroencephalography (EEG) is widely used to assess neurological prognosis in patients who are comatose after cardiac arrest, but its value is limited by varying definitions of pathological patterns and by inter-rater variability. The American Clinical Neurophysiology Society (ACNS) has recently proposed a standardized EEG-terminology for critical care to address these limitations. METHODS/DESIGN: In the TTM-trial, 399 post cardiac arrest patients who remained comatose after rewarming underwent a routine EEG. The presence of clinical seizures, use of sedatives and antiepileptic drugs during the EEG-registration were prospectively documented. DISCUSSION: A well-defined terminology for interpreting post cardiac arrest EEGs is critical for the use of EEG as a prognostic tool. TRIAL REGISTRATION: The TTM-trial is registered at ClinicalTrials.gov (NCT01020916).

Musculoskeletal manifestations in polymyalgia rheumatica and temporal arteritis.

To evaluate the incidence and characteristics of musculoskeletal manifestations in polymyalgia rheumatica (PMR) and temporal arteritis (TA). METHODS The records of 163 cases of PMR or TA diagnosed over a 15 year period in one area of Spain were reviewed for the presence and type of musculoskeletal manifestations. RESULTS Of 163 patients, 90 had isolated PMR and 73 had TA. Eighteen of the 90 patients (20%) with isolated PMR developed distal peripheral arthritis either at diagnosis or during the course of the disease. When it occurred, synovitis was mild, monoarticular or pauci-articular, asymmetrical, transient, and not destructive. Other distal manifestations observed in these patients were carpal tunnel syndrome and distal extremity swelling with pitting oedema. In all cases these manifestations occurred in conjunction with active PMR. As expected, PMR was the most frequent musculoskeletal manifestation in patients with TA, occurring in 56% of cases. On the contrary, only 11% of patients with TA developed peripheral arthritis. An important finding was that peripheral arthritis in these patients appears to be linked only temporally to the presence of simultaneous PMR and is not observed in its absence. Distal extremity swelling or defined polyarthritis were not observed. CONCLUSION The spectrum of distal musculoskeletal manifestations of PMR in our series is similar to that reported in other populations. By contrast, distal musculoskeletal symptoms are uncommon in TA. The almost complete absence of distal musculoskeletal manifestations in patients with pure TA suggests different mechanisms of disease in PMR and TA, supporting the view of two separate conditions or one common disease in which host susceptibility influences the clinical expression.

Common Variable Immunodeficiency: molecular pathways and clinical manifestations

Common variable immunodeficiency (CVID), is a disease that is characterized by hypogammaglobulinemia as well as a defect in T, B and dendritic cells. This leads to recurrent bacterial infection mainly caused by Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, as well as inflammatory manifestations, i.e. granulomateous disease, gastro-intestinal disorders and chronic lung disease. Intravenous Immunoglobulin (IVIg) therapy reduces CVID susceptibility to bacterial infections to some extend. We analyzed clinical aspects of patients from our database. We recently showed that bacteria-specific CD4 T cells of CVID patients were impaired. We therefor postulated that CVID patients may harbor an acquired T-cell deficiency also called exhaustion. To test this hypothesis, we performed a comprehensive investigation of the functional profiles of bacteria-specific CD4 T cells isolated from 31 healthy individuals and 30 CVID patients. In the present study, we demonstrated that bacteria-specific but not virus-specific CD4 T cells in CVID patients harbored reduced proliferation capacity and expressed high level of PD-1. Interestingly, the blockade of PD-1/PD-1 ligands interactions restored partially bacteria but not virus-specific CD4 T-cell proliferation. Finally, we showed that 1) the level of endotoxins inversely correlates with IgG concentration, 2) IVIG treated CVID patients harbored reduced endotoxemia and 3) IgG concentration exceeding 7 mg/mL strongly reduces both the proportion of CVID patients with detectable endotoxemia and the concentration of endotoxins in plasma. Taken together our observations, suggest that primary B-cell defect(s) in CVID patients leads to recurrent bacterial infections that are associated to an acquired (secondary) impairment of CD4 T cells which may in turn exacerbate the lack of protection against extracellular bacteria.

Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia.

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization. © 2012 Wiley Periodicals, Inc.

Seizure semiology: an overview of the 'inverse problem'.

In clinical practice, a classification of seizures based on clinical signs and symptoms leads to an improved understanding of epilepsy-related issues and therefore strongly contributes to a better patient care. The inverse problem involves inferring the anatomical brain localization of a seizure from the scalp surface EEG, a concept we apply here to correlate seizure origin with seizure semiology. The spheres of sensorium, motor features, consciousness changes and autonomic alterations during ictal and postictal manifestations are reviewed, including several subdivisions used to better categorize particular features. Particular attention is given to behavioral features, as well as to features occurring in idiopathic generalized epileptic syndromes and psychogenic nonepileptic spells.

Vascularite rhumatoïde et autres complications systémiques: aspects diagnostique et thérapeutique [Diagnosis and treatment of rheumatoid vasculitis and other systemic complications of rheumatoid arthritis]

Rheumatoid arthritis is a systemic disease that can potentially affect any organ. If the articular manifestations are central to the disease; skin, ophthalmic, neurological, cardiac, pulmonary as well as renal manifestations are well recognized, the latter particularly in the context of a secondary amyloidosis. Although incidence of extraarticular manifestations appears to decrease, likely a result from our more aggressive and early management of rheumatoid arthritis, their consequences remain severe in terms of morbidity and mortality, and their treatments complicated. The new biological therapies seem to be a promising alternative to current therapies, such as cyclophosphamide and high dose prednisone, even if evidences are still limited.

Neurological Prognostication after Cardiac Arrest and Therapeutic Hypothermia: a Prospective Validation Study

Introduction: Clinical examination and electroencephalography study (EEG) have been recommended to predict functional recovery in comatose survivors of cardiac arrest (CA), however their prognostic value in patients treated with induced hypothermia (IH) has not been evaluated. Hypothesis: We aimed to validate the prognostic ability of clinical examination and EEG in predicting outcome of patients with coma after CA treated with IH and sought to derive a score with high predictive value for poor functional outcome in this setting. Methods: We prospectively studied 100 consecutive comatose survivors of CA treated with IH. Repeated neurological examination and EEG were performed early after passive rewarming and off sedation. Mortality was assessed at hospital discharge, and functional outcome at 3 to 6 months with Cerebral Performance Categories (CPC), and was dichotomized as good (CPC 1-2) vs. poor (CPC 3-5). Independent predictors of outcome were identified by multivariable logistic regression and used to assess the prognostic value of a Reproducible Electro-clinical Prognosticators of Outcome Score (REPOS). Results: Patients (20/100) with good outcome had all a reactive EEG background. Incomplete recovery of brainstem reflexes, myoclonus, time to return of spontaneous circulation (ROSC) > 25 min, and unreactive EEG background were all independent predictors of death and severe disability, and were added to construct the REPOS. Using a cut-off of 0 or 1 variables for good vs. 2 to 4 for poor outcome, the REPOS had a positive predictive value of 1.00 (95% CI: 0.92-1.00), a negative predictive value of 0.43 (95% CI: 0.29-0.58) and an accuracy of 0.81 for poor functional recovery at 3 to 6 months. Conclusions: In comatose survivors of CA treated with IH, a prognostic score, including clinical and EEG examination, was highly predictive of death and poor functional outcome at 3 to 6 months. Lack of EEG background reactivity strongly predicted poor neurological recovery after CA. Our findings show that clinical and electrophysiological studies are effective in predicting long-term outcome of comatose survivors after CA and IH, and suggest that EEG improves early prognostic assessment in the setting of therapeutic cooling.

International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.

OBJECTIVES: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. METHODS: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. RESULTS: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. CONCLUSION: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology

Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated. Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences.

Parésie trochléaire transitoire comme signe neurologique inaugural d'une panartérite noueuse [Transient trochlear nerve palsy as the presenting neurological sign of panarteritis nodosa]

INTRODUCTION: Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. OBSERVATION: A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. CONCLUSIONS: Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms.