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Paraneoplastic Neurologic Syndromes – An Update on Current Understanding and Future Perspectives
European Neurological Review, 2010;5(2):73-76
AbstractParaneoplastic neurological syndromes (PNS) are remote effects of tumours on the nervous system. They can strike at single or at multiple sites of the central nervous system (CNS) and the peripheral nervous system, and often appear before the detection of cancer. PNS can be disabling and debilitating and may be either an additional burden to cancer or the cause of death. The PNS Euronetwork group has collected a series of approximately 1,000 patients in several European centres. This study is the largest systematic series of patients with PNS and, for the first time, can answer questions about the most frequent PNS, their detailed symptoms, associated antibodies and the types of underlying tumours. The clinical course and laboratory findings for many PNS suggest an autoimmune pathogenesis; however research into this heterogeneous immunological relationship has been evolving over recent decades. The classical syndromes are antigen-target-oriented syndromes such as myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and ion channelmediated diseases. Onconeuronal antibodies constitute a large group of PNS, characterised by the appearance of specific antibodies, defined clinical signs and often an association with specific tumours. In recent years, a new group of antibodies directed at surface antigens as receptors has been identified. Finally there is a long list of ‘other’ PNS, which are evident to clinicians but which have no pathogenetic explanation. Examples include the mild terminal neuropathies and sarcopoenia in cancer patients. In addition to the emerging classification based on pathophysiology, other new syndromes and symptoms have appeared, including apnoea in brainstem encephalitis, a neuropsychiatric spectrum of limbic encephalitis and increased knowledge about LEMS. Two important aspects warrant attention: some PNS respond to therapy and not all paraneoplastic-like syndromes are tumour related. This view is based on the current understanding of immune pathogenesis and on the enlarged spectrum of PNS.
Acknowledgement: Joanne Fleming assisted with the text preparation. Grants QLG1-CT-2002-01756 and LSSM-CT-2005-518174 from the Paraneoplastic Neurological Syndromes European Commission (PNS-EURONETWORK).
Keywords: Paraneoplastic neurological syndromes, onconeuronal antibodies, ion channel antibodies, surface antibodies, psychiatric manifestations, limbic encephalitis, therapy
Disclosure: The authors have no conflicts of interest to declare.
Received: September 28, 2010 Accepted November 09, 2010 Citation European Neurological Review, 2010;5(2):73-76
Correspondence: Wolfgang Grisold, Neurology Department and Ludwig Boltzmann Institute for Neuro-oncology, KFJ Hospital, 1100 Vienna, Austria. E: firstname.lastname@example.org
Paraneoplastic neurological syndromes (PNS) were first described in the 20th century. A summary of observations dating back to 1982 was published in the seminal book by Henson and Urich.1 The detection of autoantibodies for myasthenia gravis (MG) and later for Lambert-Eaton myasthenic syndrome (LEMS), marked a new era of antibody-mediated disease. Several onconeural antibodies were described by the group at Memorial Sloan Kettering2 and were subsequently named according to the initials of the patients (Hu, Yo, Ri, etc.) in whom they were discovered. These remain a mainstay of PNS. The group at the Mayo Clinic provided different terminology.3
In recent years, two more pathogenetically different types of immune-mediated neurological paraneoplastic syndrome have been described. The first is a group of diseases with antibodies against ion channels (voltage-gated potassium channels; VGCK). This group of diseases behaves like the target-specific antibodies – the effect of autoantibodies on potassium channels was described by Hart et al.4 The new class of antibodies is directed against the neuropil – in particular against synaptic surface antigens such as N-methyl-D-aspartic acid (NMDA), gamma-aminobutyric acid (GABA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA).5,6 Clinically, they are often associated with psychiatric disease and present with neurologic core symptoms such as seizures.7 However, this new class does have three particular aspects: they are not always paraneoplastic, but do present as autoimmune syndromes; they can be treated and are potentially reversible; and they constitute a new spectrum of diseases, which may be related to several other diseases, in particular psychiatric diseases. The important question for clinicians seeing patients with malignant disease is to decide whether the cause of a patient’s condition is metastatic, metabolic, neurotoxic or infectious. Due to the rarity of PNS, this answer cannot accurately be given. Between 2002 and 2008 the PNS Euronetwork project8 collected about 1,000 patients with definite PNS according to the Graus criteria.9 This study showed lung cancer to be the most common malignancy (see Table 1), subacute sensory neuronopathy (SSN) and paraneoplastic cerebellar degeneration (PCD) as the most frequent syndromes and Hu and Yo as the most frequent onconeuronal antibodies.
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