Paraneoplastic Neurological Syndromes: A Condition of Increasing Recognition.

main categories according to the location of the antibodies. The first group is known as the 'classical' paraneoplastic group (with onconeural antibodies). In this group, the antibodies are directed against intracellular neuronal proteins, such as anti-Hu, Yo, RI, CV2, amphiphysin, Ma1, and Ma2/ Ta. The autoantibodies are considered to be epiphenomena, not involved directly in the pathogenesis, while the inflammation is mainly mediated by cytotoxic T cells [2]. This group is related to cancers in 50–60% of positive tests. It is rare for these antibodies to appear in individuals under 18 years of age, and response to immunesuppressive treatment is weak. In the second group, known as autoimmune encephalitis (AE), auto-antibodies are directed against neural surface antigens or synaptic proteins including receptors, such as NMDA, AMPA, LGI1, CASPR2, and GABAR. These antibodies have a direct pathogenic effect on their target antigens [3]. Cancer relation varies according to antibody [4] and in some cases a genetic predisposition is present [5]. This group affects all ages, including children, and usually responds well to immunosuppressive therapy [6]. The PNS are a relatively newly recognized disorder, and awareness should be increased for clinicians, especially psychiatrists. It has been suggested that a certain percentage of psychiatric patients may actually experience an autoimmunemediated central nervous system disorder, such as neuropsychiatric lupus or AE [7]. Herken and colleagues [8] reviewed the clinical signs that should prompt evaluation of AE in psychiatric patients. The signs that their group detected included: cerebrospiI n this issue of the Israel Medical Association Journal (IMAJ), Boniel and coauthors [1] describe a 4 year old girl presenting with severe relapsing involuntary movements and personality changes due to encephalitis. Although the patient did not present with typical eye involvements, she was suspected of having opsoclonusmyoclonus-ataxia (OMA). She was treated with a synthetic adrenocorticotropic hormone (ACTH)-analogue, steroids, and intravenous immunoglobulins. Eventually she required maintenance therapy with azathioprine. Serological testing detected persistent anti-Ma2/Ta antibodies as well as antinuclear antibody, anti-dsDNS, and antiScl70 antibodies, while sera levels declined in further tests. Of interest, in the case presented by Boniel, each relapse appeared after a febrile disease or strenuous physical activity. Autoimmune-neuropsychiatric disorders, which may be associated with specific auto-antibodies and/or cancer, are termed collectively as paraneoplastic neurological syndromes (PNS). The PNS are a rare group of diseases (diagnosed in approximately 1% of cancer patients) that can affect any part of the central and peripheral nervous systems, as well as the neuromuscular system. They can be divided into two nal fluid lymphocytic pleocytosis without evidence of infection, epileptic seizures, faciobrachial dystonic seizures, suspicion of malignant neuroleptic syndrome, magnetic resonance imaging abnormalities (mesiotemporal hyperintensities, atrophy pattern), or electroencephalography abnormalities (slowing, epileptic activity, or extreme delta brush). Other clinical signs that should raise suspicion of an autoimmune etiology in a psychiatric patient include decreased levels of consciousness, abnormal postures or movements, autonomic instability, focal neurological deficits, aphasia or dysarthria, rapid progression of psychosis despite therapy, hyponatremia, catatonia, headache, and the presence of other autoimmune diseases. As mentioned earlier, the anti-Ma2/Ta antibody is a 'classical' paraneoplastic antibody. Its presence was brought to attention in a case series by Voltz and co-authors [9] who described 13 male patients with testicular cancer and brain stem and/or limbic encephalitis in which 10 had serum and cerebrospinal fluid antibodies to a 40 kD neuronal protein. This protein, which they called Ma2, was not found in the serum of 344 control subjects. Additional studies revealed that Ma2 was selectively expressed by normal brain tissue and by the testicular tumors of the patients. In some cases in which a rigorous cancer workup is unremarkable, orchiectomy is required to reveal microscopic testicular malignancy [10]. Anti-Ma2 PNS is also found in females in up to 30% of reported cases, in association with several cancer types [11]. In the case presented in this issue of IMAJ by Boniel and colleagues [1], anti-Ma2/Ta antibodies were not associated with malignancy up to date. The Ma2 has autoimmune encephalitis (AE), neuroblastoma, onconeural antibodies, paraneoplastic neurological syndromes (PNS) IMAJ 2018; 20: 649–650