Wolfgang Grisold

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 The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study.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.

Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen

BACKGROUNDnSome encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved.nnnMETHODSn15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls.nnnFINDINGSnAll patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001).nnnINTERPRETATIONnGABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies.nnnFUNDINGnNational Institutes of Health.

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

Background:u2002 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.

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

BACKGROUNDnIncreasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients antibodies on neuronal cultures.nnnMETHODSnIn this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy.nnnFINDINGSnNeuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3-63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2-74 years, median 26.5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor).nnnINTERPRETATIONnHigh titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable.nnnFUNDINGnThe National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.

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.

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

BACKGROUNDnParaneoplastic 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.nnnOBJECTIVESnTo analyze various types of PNS, frequent tumor and antibody associations, clinical characteristics of individual syndromes, and possible therapeutic and prognostic strategies.nnnDESIGNnProspective case series and database study.nnnSETTINGnTwenty European centers. Patients Patients were recruited from January 1, 2000, to December 31, 2008.nnnMAIN OUTCOME MEASURESnBased 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.nnnRESULTSnData 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.nnnCONCLUSIONnThe 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.

The End-of-Life Hospital Setting in Patients with Glioblastoma

Despite aggressive treatment, outcome of patients with glioblastoma is poor. Several distinct clinical problems arise in the terminal stage of this disease. The purpose of this study was to evaluate the end-of-life phase in a hospital setting in patients with glioblastoma. Twenty-nine consecutive patients with glioblastoma, who died in our department, were included in this analysis regarding symptoms, medication, diagnostics, and interventional procedures. The patients were comparable with respect to age, gender, and overall survival with data from the literature. Relevant clinical symptoms, medications, diagnostics, well as interventional procedures increased continuously toward end of life. Pain, epileptic seizures, and symptoms of brain edema were the most frequent clinical symptoms. According to this, most patients were on antiepileptic drugs (AED), steroids, and analgesics. In the last phase, symptoms from brain edema, fever, decrease of vigilance, dysphagia, and pneumonia were the prominent clinical features. Our study demonstrates that the end of life in patients with glioblastoma has several periods with different clinical aspects with respect to symptoms and treatment.

Anti-Hu-associated brainstem encephalitis

Objective: A series of patients with anti-Hu-associated brainstem encephalitis is reviewed to better define the clinical presentation and to improve its recognition. Methods: Data were collected from 14 patients diagnosed by members of the Paraneoplastic Neurological Syndromes Euronetwork, and eight patients from the literature who presented with isolated brainstem encephalitis and had anti-Hu antibodies. Results: The median age of the 22 patients was 64 years (range 42–83), and 50% were men. All patients developed a subacute neurological syndrome, in days or weeks. Brain MRI was always normal. Mild cerebrospinal fluid pleocytosis was reported in only two patients. The following syndromes were identified on admission: A medullary syndrome was seen in 11 (50%) patients. Seven of them presented with dysphagia, dysarthria and central hypoventilation. The other four in addition of bulbar symptoms, without central hypoventilation, presented pontine manifestations. Six (27%) patients developed a pontine syndrome with paresis of the VI or VII cranial nerves, nystagmus, usually vertical, and gait ataxia. There was a rapid downward progression to the medulla in all patients. Five (23%) patients presented a ponto-mesencephalic syndrome with uni- or bilateral palsy of the III and VI cranial nerves and gait ataxia, but rapidly progressed to complete gaze paresis and medullary dysfunction. Conclusions: The study confirms the predominant medullary involvement but also shows that half of the patients present with clinical features that indicate an upper, mainly pontine, dysfunction before downward progression.

A consensus review on the development of palliative care for patients with chronic and progressive neurological disease

The European Association of Palliative Care Taskforce, in collaboration with the Scientific Panel on Palliative Care in Neurology of the European Federation of Neurological Societies (now the European Academy of Neurology), aimed to undertake a review of the literature to establish an evidence‐based consensus for palliative and end of life care for patients with progressive neurological disease, and their families.

Treatment for paraneoplastic neuropathies

BACKGROUNDnIt is not unusual to observe peripheral nervous system involvement in people with tumours outside the nervous system. Any part of the peripheral nervous system can be involved, from sensory and motor neurons to nerve roots and plexuses, from distal trunks to neuromuscular junctions. Pathogenesis also varies from direct infiltration by cancer cells, to treatment toxicity, to metabolic derangement, cachexia, infections and paraneoplastic syndromes.Paraneoplastic neurological syndromes are symptoms or signs resulting from damage to organs or tissues that are remote from the site of the malignancy or its metastases. The pathogenesis is thought to be immune-mediated as a result of a cross-reaction against antigens shared by the tumour and nervous system cells.Paraneoplastic neuropathies are the most frequently reported paraneoplastic syndromes. They are, however, heterogeneous and require several therapeutic approaches. This review was undertaken to systematically assess any data available from randomised controlled trials (RCTs) on the treatment of paraneoplastic syndromes of the peripheral nervous system and not the whole range of paraneoplastic neurological syndromes.nnnOBJECTIVESnTo assess the benefits and harms of treatments for paraneoplastic neuropathies.nnnSEARCH METHODSnWe searched thexa0Cochrane Neuromuscular Disease Group Specialized Registerxa0(14 February 2012), CENTRAL (2012, Issue 1), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012) and LILACS (January 1982 to February 2012) for RCTs, quasi-RCTs, historically controlled studies and trials with concurrent controls.We adapted this strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control studies and case series.nnnSELECTION CRITERIAnWe planned to include all RCTs and quasi-RCTs (in which allocation is not random but is intended to be unbiased, for example alternate allocation) of any treatment for paraneoplastic neuropathies. Since we expected there to be few or no included studies, we also planned to assess and summarise observational studies, prospective and retrospective comparative cohort studies, case-control studies and case series that met minimum criteria in the discussion.nnnDATA COLLECTION AND ANALYSISnThree review authors selected the trials for inclusion. When there was any disagreementxa0we reached an agreement by discussion. Two review authors extracted data independently onto a specially designed data extraction form. We would have collected adverse event data from included studies.nnnMAIN RESULTSnDespite many reports on paraneoplastic neuropathy, we identified no RCT or quasi-RCTs for inclusion in this review. We found only six studies, involving 54 participants, from among the non-randomised evidence that were judged by predefined criteria to be of suitable quality for inclusion in the discussion. These studies were not readily comparable. The treatments focused on tumour treatment and immunomodulation, mainly intravenous immunoglobulin.nnnAUTHORS CONCLUSIONSnAt present there are no RCTs or quasi-RCTs of treatment for paraneoplastic neuropathies on which to base practice. There is only evidence from case series, case reports or expert opinion (class IV evidence) for the effect of immunomodulation (intravenous immunoglobulin, plasma exchange, steroid treatment or chemotherapy) on paraneoplastic neuropathy. xa0