Bruno Giometto

Recommended diagnostic criteria for paraneoplastic neurological syndromes

Background: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate “true” PNS from neurological syndromes that are coincidental with a cancer. Objective: To provide more rigorous diagnostic criteria for PNS. Methods: An international panel of neurologists interested in PNS identified those defined as “classical” in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as “well characterised”. The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. Results: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: “definite” and “possible”. Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of “classical” syndrome and “well characterised” onconeural antibody. Conclusions: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force

Background:  Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus‐myoclonus, Lambert–Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence‐based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG‐PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions

B7 is a constimulatory molecule which is expressed on antigen-presenting cells and which plays a pivotal role in T cell activation and proliferation. To elucidate mechanisms regulating intracerebral immune responses, expression of B7 was examined in cultured microglial cells and in brain tissue from control and multiple sclerosis patients. Using immunocytochemical and polymerase chain reaction techniques, we show that B7 was expressed in cultured microglial cells from the human embryonic brain. Microglia also bound the soluble form of the B7 receptor CTLA-4 (CTLA-4-Ig). B7 gene expression and binding of anti-B7 antibodies and CTLA-4-Ig increased after treatment with interferom B7 was not inducible in human astrocytes. Human microglia expressed other costimulatory molecules, such as intercellular adhesion molecule-I, LFA-I and LFA-3. In sections of multiple sclerosis brains, B7 immunoreactivity was detected on activated microglia and infiltrating macrophages within active lesions. In chronic lesions, only perivascular cells were stained. B7 immunoreactivity was undetectable in sections from Alzheimers disease or normal brain tissue. These data suggest that B7 may be involved in T cell activation and lesion development in multiple sclerosis and that the regulated expression of B7 on microglia may contribute to the local stimulation of T cell proliferation and effector functions.

Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition

The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.

Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers.

BACKGROUND Paraneoplastic neurologic syndrome (PNS) represents the remote effects of cancer on the nervous system. Diagnostic criteria for the syndrome were published by the PNS Euronetwork and form the basis of a database to collect standardized clinical data from patients with PNS. OBJECTIVES To analyze various types of PNS, frequent tumor and antibody associations, clinical characteristics of individual syndromes, and possible therapeutic and prognostic strategies. DESIGN Prospective case series and database study. SETTING Twenty European centers. Patients Patients were recruited from January 1, 2000, to December 31, 2008. MAIN OUTCOME MEASURES Based on diagnostic criteria published by the PNS Euronetwork consortium, clinical characteristics of classic PNS and several other less well-characterized syndromes associated with cancer were assessed. RESULTS Data from 979 patients were analyzed, representing the largest PNS investigation to date. The findings elucidate the clinical evolution of paraneoplastic cerebellar syndrome according to the onconeural antibodies present, the heterogeneity and prognosis of dysautonomic disorders, and the clinical variability of paraneoplastic limbic encephalitis. CONCLUSION The study results confirm that PNS influences oncologic patient survival. Tumors are the main cause of death, but some types of PNS (such as dysautonomia) have a poorer prognosis than malignant neoplasms.

A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study

BACKGROUND Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen. METHODS In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples. FINDINGS All eight patients (five women; median age at disease onset 59 years [range 52-76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2-12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied. INTERPRETATION IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. FUNDING Fondo de Investigaciones Sanitarias, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3, and the National Institutes of Health.

Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique

Abstract In the brain of patients with AIDS, HIV-1 is localised in a productive form in mononuclear cells. One issue that still needs clarification is whether HIV is localised in cells other than those of mononuclear lineage. Gene amplification by polymerase chain reaction/in situ hybridisation (PCR-IS) could shed light on it. In this study, formalin-fixed, paraffin-embedded brain tissue from ten adult AIDS sufferers was used. Five of them showed evidence of HIV encephalitis (HIVE), five did not show any abnormality. Nested PCR revealed HIV-1 DNA in all HIVE cases and in three of the group without HIVE. HIV-1 DNA and RNA were also detected in situ in seven cases (all seven were also HIV-1 DNA positive in tube). A higher signal was located in the white than in the grey matter. HIV-1 DNA was found in microglia, macrophages, perivascular cells, multinucleated gaint cells (MGC) and in CD68-negative cells. Some of them were identified as endothelial cells, astrocytes and oligodendrocytes. Reverse transcriptase-PCR-IS was positive in macrophages, MGC, endothelial and glial cells. These results confirm infection of endothelial cells and other glial cells and give clues about the route of entry of virus into the central nervous system and the pathogenesis of the disease. This study did not give any convincing evidence supporting an infection of neurons by HIV-1.

Revised diagnostic criteria for neuromyelitis optica (NMO) : Application in a series of suspected patients

We analyzed neuromyelitis optica (NMO) IgG in the serum or CSF samples from 46 patients with suspected NMO (28) and limited forms of NMO (18). One hundred and fifteen samples from multiple sclerosis (MS) patients were included as controls. The final clinical diagnosis after follow-up was 16 NMO, 12 MS, 11 transverse myelitis (TM) and seven recurrent optic neuritis (RON). NMO-IgG was detected in 62.5% of NMO, 50% of the recurrent longitudinally extensive TM, 14.3% of the RON but in none of the MS patients. The authors then compared the newly revised diagnostic criteria for NMO with the criteria published in 1999, in the 28 patients with suspected NMO. The revised criteria had higher specificity, and positive and negative predictive value (83.3% vs. 25%; 87.5% vs. 62.5; 83.3% vs. 75%), but slightly lower sensitivity (87.5% vs. 93.7%). Our study confirms NMO-IgG as a highly specific marker of NMO, and the usefulness of the revised diagnostic criteria in predicting a diagnosis of NMO.

Axonal damage revealed by accumulation of β-APP in HIV-positive individuals without AIDS

The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to β-amyIoid precursor protein (β-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of β-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of β-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.