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October 31, 2014

Research helps understanding of PNDs

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Prof Josep Dalmau

Aoife Connors speaks to Prof Josep Dalmau about recent research advances that have led to a better understanding of paraneoplastic neurologic disorders

The crucial difference between autoimmune disorders and paraneoplastic neurologic disorders (PNDs) is “the certainty that PNDs and their syndromes will only occur in the presence of a cancer tumour”, Prof Josep Dalmau, Professor of Neurology at the University of Pennsylvania School of Medicine told Irish Medical Times.

PNDs are autoimmune diseases that occur in response to the presence of cancer somewhere in the body. The cancer cells in paraneoplastic patients express proteins which are normally only made in the brain. These proteins cause the body’s immune system to produce anti-bodies in an attempt to suppress the cancer. Unfortunately, these same antibodies can trigger an autoimmune attack on the brain and the body’s neuro-logical systems.
In a recent study in The Lancet Neurology (2010 Aug;9(8):753-5), Prof Dalmau and colleagues reported on a new category of such disorders.

Autoimmune synaptic encephalopathies are neurologic disorders in which patients develop antibodies against proteins on neuronal synapses. Patients present with seizures and neuropsychiatric symptoms, including psychosis and changes in memory, cognition and behaviour. These symptoms are common in limbic encephalitis, which has been attributed to autoantibodies against voltage-gated potassium channels. Prof Dalmau pointed out that the results of their own antibody testing, using serum from patients with limbic encephalitis to cells expressing voltage-gated potassium channels, were negative.

“On the basis of the negative findings, we postulated that the antibodies of these patients might be directed against other neuronal cell-surface proteins. We aimed to identify the real autoantigen associated with limbic encephalitis,” he said.

Autoimmune diseases
Speaking to IMT ahead of his lecture on October 8 entitled ‘Paraneoplastic and non-paraneoplastic immune-mediated encephalitis’ at the 9th Neurology Update Meeting in Dublin, Prof Dalmau explained that patients with autoimmune disease respond to treatment, while many patients with PNDs do not respond well.

PNDs are caused by cancer-induced immunologic mechanisms affecting various parts of the central and peripheral nervous system. Patients can develop severe neurologic symptoms as a result of the immune response to these disorders (seizures, memory problems, sensory difficulties, hypothalamic dysfunction or paralysis).

Research by Prof Dalmau and his colleagues shows that an immune response can be triggered against the patient’s tumour by the growth of neuronal proteins from the cancer. The body’s response to tackle the tumour can wrongly attack the patient’s nervous system. He said this response is defined by high titer of serum antibodies that can be accompanied by cyto-toxic T-cell responses. These react with proteins in the neurons and the cancer cells (onconeuronal antigens). By identifying these antibodies, the neurologist can determine PND.

Treatment targets specific organs, attacking the tumour and relieving the patient from invasive tests. Recent research has lead to the clinical characterisation of certain PNDs. He listed a number of antibodies and antigens that are now used as diagnostic tests for PND and autoimmune diseases. PNDs are naturally key means of successful anti-tumour immunity; the ability of the tumour to trigger an immune response can lead to less aggressive cancers, he explained.

“We’re identifying new antibodies that may be associated with as-yet unknown diseases,” he said. “We identified five antibodies in the last three years; these target the proteins in the brain and critical receptors involved in human behaviour and memory,” he added. The five antibodies include: NMDAR, NMDA receptor, AMPA receptor, GABA receoptor, CASPR2 protein and LGI1. The neurol-ogist is studying these antibodies to characterise the proteins and symptoms of the disorder.

Research
Prof Dalmau said the discovery of antineuronal antibodies facilitated the diagnosis of PNDs, but treatment for these disorders is a challenge. Since certain antibodies are syndrome-specific unlike others, some syndromes suggest a paraneoplastic etiology more than others.

Some may occur in cancer patients without PNDs and their detection does not necessarily imply that a neurologic disorder is paraneoplastic. In his analyses of immune responses to CNS paraneoplastic and nonparaneoplastic disorders, he explained that a new cluster of encephalitides appear to be mediated by antibodies against the cell surface or synaptic proteins, which may occur with or without a tumour present, and these are responsive to treatment.

Prof Dalmau co-authored a paper published in Oncologist (2010;15(6):603-17). In the latest research on PNDs, he said that cancer patients are likely to experience neurologic symptoms during treatment that include metastasis, infections, coagulopathy, metabolic or nutritional disturbances and neurotoxicity. He said that folllowing tests on cancer therapies, one is generally found as the etiology.

However, where no etiology is identified, the diagnosis considered is often a PND. “This is becoming commonplace. As a result, I’d suggest that diagnosis and treatment for PNDs should begin early,” he said.

Prof Dalmau is excited about his future research and his trip to Ireland. This will be his second visit, but it is shortened as a result of his hectic schedule. “I have good friends in Ireland that I’m looking forward to seeing after the conference,” he quipped.