Brain Trauma Oncology
Table 1: Paraneoplastic Neurological Syndromes Frequency of Tumors
Type of Tumor
Small cell lung cancer Ovary
%
38 10
Breast 10 Non-small-cell lung cancer Non-Hodgkin’s lymphoma Hodgkin’s lymphoma Thymoma Prostate
8 3 3 3
Unknown primary Source: Giometto et al., 2010.8
Table 2: Most Frequent Paraneoplastic Neurological Syndromes (PNS) in the PNS Euronetwork Database
Type of PNS Paraneoplastic cerebellar
degeneration (PCD) Limbic encephalitis (LE)
Paraneoplastic encephalomyelitis Brainstem encephalitis Opsoclonus/myoclonus
Motor neuron disease (MND) Sensory neuronopathy (SSN)
Acute inflammatory polyradiculopathy Chronic inflammatory polyradiculopathy Dysautonomia
Patients (n=979) % 238
98 55 55 23 20
238 16 13 51
Lambert Eaton myasthenic syndrome (LEMS) 43 Dermato-/polymyositis
14 PNS = paraneoplastic neurological syndrome. Source: Giometto et al., 2010.8
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, an answer cannot accurately be given.
Between 2002 and 2008 the PNS Euronetwork project8 1,000 patients with definite PNS according to the Graus criteria.9
assessed around 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. This distribution, which potentially could be biased by the participating centers and types of disease, is a systematic overview (see Table 2).8
The study also detected
43 cases of LEMS and 10 cases of neuromyotonia, which are classic immune-mediated diseases. The surface antibodies were not available at the time of the PNS Euronetwork study. It is important that neurologists seeing patients with cancer are aware not only of the spectrum of PNS, but also of differential diagnoses, particularly in patients with signs of encephalitis such as infectious and inflammatory diseases, neoplasms of the brain, vascular (in particular hypoxic) damage, seizures, autoimmune disorders, and toxic metabolic diseases such as Wernicke’s encephalopathy. The presentation of the surface-antibody-associated diseases (e.g. NMDA encephalitis) also could suggest a primarily psychiatric disease, including those presenting as catatonia.
54 24.3 10
5.6 5.6 2.3 2
24.3 1.6 1.3 5.2 4.2 1.4
2.6 2
Classical Target-oriented Immune-mediated Diseases In neurology the classic target antibody-mediated diseases are MG, LEMS, and neuromyotonia. Antibody-mediated diseases are fairly well understood, although some details are still missing. MG, which can only be considered a PNS of thyoma, has been the pattern for immune models of PNS. In MG, MuSK antibodies have been described in addition to the acetylcholinesterase antibodies, and other antibodies still may be detected in seronegative MG. LEMS is an interesting neuromuscular transmission disorder, affecting the presynaptic calcium channels. It can appear as a paraneoplastic syndrome, or as an autoimmune syndrome. As early as 1988, O’Neill10
reported that the ratio of incidences of
neoplastic to non-neoplastic LEMS was approximately 50:50. These data seem to be confirmed by the time course and more criteria appear, which make it possible to distinguish between the two types of LEMS.11 Neuromyotonia was described by Hart et al.4
in the PNS study. It is a
nerve hyperexcitability syndrome of the presynaptic endplate. It is also known as Morvan’s syndrome, neuromyotonia, and continuous muscle fiber activity (CMFA) syndrome. Antibodies against potassium channels have been described4
and animal experiements have shown that the
disease can by transmitted by antibody transfer. Based on these observations, additional aspects, such as dysautonomia, hyponatremia, sleep disorders, and psychiatric disorders—in particular limbic encephalitis (LE)—have been found. The antibodies are directed against potassium channels and in several cases go beyond causing neuromuscular disease to encompass CNS symptoms (LE) or autonomic syndromes such as hyponatremia and hyperhydrosis.12
LE seems to be
related to antibodies against the Kv1.1 subunit of the potassium channel, whereas symptoms of neuromyotonia and Morvan’s syndrome are more closely related to antibodies to the Kv1.2 channel.5
Onconeuronal Antibodies
The description of onconeuronal antibodies has been very useful for studies of PNS. A pragmatic definition and classification of PNS9
was
made by the PNS Euronetwork group. Based on this consensus, the PNS Euronetwork database was used to analyse in detail diseases associated with onconeural antibodies. The database contains not only the number of syndromes, antibody types and tumor types, but also detailed descriptions of clinical symptoms and several paraclinical aspects.8 Despite these well-described features, the relationship between cause and effect still remains unclear. Transfer between animal and human studies in particular has remained unsuccessful, but pathological studies often demonstrate cytotoxic T-cell infiltrates in the CNS parenchyma and dorsal root ganglia (in neuronopathies). Onconeuronal antibodies anti-Hu, Yo, Ri are most frequently detected, and detection can also be performed by commercial kits. There are three particularly interesting groups: one is a group of less common antibodies—Ma2, Ta, CV2, and CRMP5—which have been investigated by several centers and have high specificity. The second is a heterogeneous group of ‘atypical antibodies that are only detected in individual cases and are often observed in interesting clinical settings. The third are glutamic acid decarboxylase (GAD) antibodies, which can also appear in paraneoplastic diseases that do not fit into this spectrum. Table 3 shows the distribution of the
US NEUROLOGY
Paraneoplastic Neurological Disease Subgroups For the purposes of this article, PNS will be classified into four subgroups based on pathogenetic criteria.
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