Paraneoplastic Neurologic Syndromes antibodies detected in the PNS database.8 The distribution of
the onconeural antibodies corresponds to findings in the literature. The ion channel antibodies were routinely examined for voltage gated calcium channels (VGCC) and VGCK, but these were not recorded by all centers. PNS listed without detectable antibodies may represent cases where antibodies are yet to be identified.
Surface Antibodies
Recent developments have led to the discovery of surface antigens, which act either on channels or receptors. Examples of surface antibodies include a diversity of potassium channel, NMDA receptor (NMDAR), AMPA, and GABA antibodies, which react with surface antigens of either channels or receptors and have been described in conjunction with some well-known disease entities, such as LE, and with new psychiatric and neurological diseases. These antibodies are antineuropil antibodies and are directed against the NMDA,13 (GluR1/2),14
AMPA and GABA receptors.15 The spectrum of these diseases is
wide and, in addition to psychiatric manifestations, hyperkinesia, hypoventilation, and severe autonomic symptoms have been observed.13 Most cases have been described with NMDAR encephalitis. The full clinical spectrum and treatment responses are not yet clear and a recent study reported a high proportion of patients without a detectable tumor.16
Table 3: Frequency of Onconeural Antibodies Type of Antibody
%
Hu Yo Ri
CV2 Tr
Amphiphysin Ma or Ta VGCC VGCK
Atypical
PNS without detectable antibody Surface antibodies
38 13 5 6
1.7 3.4 4.5 4 1 3
18 Not recorded
PNS = paraneoplastic neurological syndromes; VGCC = presynaptic calcium channels; VGCK = voltage-gated potassium channels. Source: Giometto et al., 2010.8
Figure 1: Neurologic and Psychiatric Presentations of Limbic Encephalitis
Neurological signs
Seizures Hu
Accordingly, recently it has been suggested that these syndromes be referred to as ‘autoimmune synaptic encephalopathies’17 since the epitope localization is not always at channel level and most of them are not paraneoplastic. Indeed, the potassium channel antibodies have been demonstrated to target two secreted neuronal proteins that function as ligands for other proteins. The antigens identified are leucin-rich, glioma inactivated 1 protein (LGI1) and contactin-associated protein-2 (CASPR2). Such synaptic encephalopathies are characterized by extracellular location of epitopes and altered function of receptors after antibody binding. The syndromes are severe but treatable (in contrast to many PNS), and the clinical syndrome has symptoms similar to those seen in animal models of pharmacological or genetic dysfunction of the related receptors. Indeed, linkage analysis has shown that mutations in LGI1 genes cause autosomal dominant lateral temporal lobe epilepsy.18
Others
Despite the many classifications and descriptions available, several phenomena—which can be clearly described as ‘paraneoplastic’—are yet to be fully explained. Three examples include paraneoplastic neuropathy, terminal neuropathy, and cancer cachexia.
Paraneoplastic Neuropathy
and that asymmetry, onset in the upper extremities, and characteristic sensory ataxia can be confirmed in most cases that are identified. A considerable number of patients with SSN (117/238) also showed motor involvement, thus prompting the introduction of the term ‘sensorimotor neuronopathy’. It remains unclear what causes this weakness: motor neurone loss or axonal degeneration.
The PNS Euronetwork database has revealed that SSN is one of the most frequent PNS8
Terminal Neuropathy
Patients with advanced cancer often develop signs of neuropathy. This has been well described as a terminal neuropathy, and consists of mild
US NEUROLOGY Diencephalic symptoms, sleep Ma 2
Chorea CV2
Seizures, REM, hyponatrenia, hypothermia: VGCK
Seizure, hypoventilation REM, EPS, NMDA
AMPA
Seizures GABA
LE core symptoms
Short-term memory loss,
amnesia, confusion Seizures
Psychiatric signs
Depression Hu
Obsessive–compulsive panic disorder Ma2
Subacute dementia CV2
Confusion, desorientation
apathy, lethargy: VGCK
Autonomic signs
NMDA: HypoNa, sweating,
dysautonomia
Confusion, hallucination memory, GABA
The core symptoms of memory loss, amnesia, and confusion are in the center. Almost every antibody syndrome has additional specific neurologic and psychiatric features. Autonomic signs seem to be more frequent in the N-methyl-D-aspartic acid (NMDA) and voltage-gated potassium channels (VGCK) types of limbic encephalitis (LE). AMPA = alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid; EPS = extrapyramidal signs; GABA = gamma aminobutyric acid; LE = limbic encephalitis; REM = rapid eye movement.
wasting of muscle, areflexia, and few sensory changes. This phenomenon resembles neuropathies that occur in patients with severe disease, particularly infections, and may be caused by weight loss or unidentified metabolic factors.
Cancer Cachexia
Weight loss and sarcopoenia are also increasingly observed in other generalised diseases, and these may share a common pathway. For cancer patients it has been postulated that reducing or stopping weight loss may yield a better prognosis.20
Cancer cachexia is well known, but still lacks a satisfactory explanation. Many patients experience weight loss, in particular loss of muscle mass.19
Psychosis, anxiety, bizarre, NMDA
Memory loss,confusion, agitation, AMPA
Ion channel Ion channel
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