Ask the Expert: An Interview with Myrna Rosenfeld, MD, PhD

Myrna Rosenfeld, MD, PhD is a leading researcher on central nervous system (CNS) paraneoplastic disorders. An Associate Professor of Neurology at the University of Arkansas for Medical Sciences, Little Rock, Arkansas, she is also Co-Director of the Molecular Neuro-oncology Laboratory at the Arkansas Cancer Research Center. Dr. Rosenfeld is author and co-author of numerous articles published in leading scientific journals. Her research interests include the molecular biology of primary brain tumors and the pathogenesis of the autoimmune response in patients with paraneoplastic neurologic disorders (PND). In this interview, Dr. Rosenfeld shares her perspective on the importance of diagnosing PND.

Athena:		What symptoms or clinical presentation should prompt a neurologist to suspect that a patient has a paraneoplastic syndrome?
Dr. Rosenfeld:		Paraneoplastic syndromes can affect any part of the nervous system, from the cerebral cortex to peripheral nerve and muscle; therefore, any neurological symptom could be the presentation of a paraneoplastic syndrome.   Some features that may suggest the possibility of a paraneoplastic syndrome are: Symptom presentation: In general (although not always) paraneoplastic syndromes develop in an acute or subacute fashion, in days or weeks, and have a fast progression towards symptom stabilization; Age: Most paraneoplastic syndromes typically affect middle-aged or older patients; Type of neurological syndrome: Some disorders, such as the Lambert-Eaton myasthenic syndrome (LEMS), are paraneoplastic in about 60% of patients, while others, such as opsoclonus or cerebellar degeneration, are less frequently of paraneoplastic origin; History of cancer: Suggests that the development of neurological symptoms of unknown cause (i.e., without evidence of metastasis or other neurological complications of cancer) can have a paraneoplastic origin; Syndrome presents before the cancer: In most patients, paraneoplastic neurological syndromes develop before the presence of a cancer is known. In these cases, additional information (history of smoking, loss of weight without a cause, abnormal chest x-ray, etc.) should raise the possibility that the patient may have an occult cancer and that the neurological symptoms could be paraneoplastic.
Athena:		What is the next step for a neurologist after receiving a positive paraneoplastic test result?
Dr. Rosenfeld:		A positive paraneoplastic test in a patient with a neurological syndrome indicates that the cause of the neurologic disease is paraneoplastic. If the presence of a tumor is not known, the type of paraneoplastic antibody detected may help to focus the search for the tumor to certain organs. Detection and treatment of the tumor should be the main goal of patient management. In a patient with a tumor in remission, the development of a paraneoplastic syndrome may represent tumor recurrence. Of note, because cancer may affect the nervous system in many different ways, and because metastases are common, the detection of a paraneoplastic antibody does not exclude the possibility that the patient may have additional metastatic disease in the nervous system. Neuroimaging studies of the symptomatic areas should be considered in all patients with neurological symptoms of the central nervous system, including spinal cord and nerve roots (if appropriate).
Athena:		In general, what is the prognosis for patients with paraneoplastic symptoms?
Dr. Rosenfeld:		This depends on the type of syndrome. Those syndromes that affect the peripheral nervous system and are associated with antibodies (myasthenia gravis, Lambert-Eaton myasthenic syndrome, neuromyotonia) may improve with treatment of the tumor or immunosuppression. By contrast, the paraneoplastic syndromes of the central nervous system rarely improve with treatment, although exceptions have been reported for all types of syndromes. Syndromes that may improve include stiff-man syndrome, opsoclonus-myoclonus, and some paraneoplastic syndromes associated with anti-Ta and anti-Ma2 antibodies.
Athena:		What should a physician do when he/she strongly suspects that a patient has a paraneoplastic disorder, but the test results are negative?
Dr. Rosenfeld:		The physician should search for other causes of the neurologic disorder and still search for a tumor. Studies with PET scan may uncover tumors that are not detectable with CT or MRI studies.
Athena:		Why is the laboratory method used to perform paraneoplastic testing important? What is the benefit of Western blot using recombinant human antigens over immunohistochemistry?
Dr. Rosenfeld:		Different antibodies (including some that are not associated with paraneoplastic syndromes) may have a similar immunohistochemical staining pattern. This does not occur with Western blot studies of recombinant paraneoplastic antigens and this type of testing is more specific than immunohistochemistry with the same sensitivity. In addition, Western blot studies are very useful for patients with several antibodies (i.e., paraneoplastic antibody and ANA or anti-Ro, or other non-paraneoplastic antibodies), which can make interpretation by immunohistochemistry difficult.
Athena:		What would you tell a neurologist who says that paraneoplastic disorders are too rare to test for?
Dr. Rosenfeld:		Although rare, the identification of paraneoplastic neurologic syndromes is important for two main reasons. First, in more than two-thirds of patients, symptoms develop before the presence of the cancer is known; therefore, suspicion of the paraneoplastic nature of the disorder may lead to the early diagnosis of the tumor. Second, the correct identification of the paraneoplastic nature of the neurologic disorder avoids unnecessary, and at times, invasive and expensive diagnostic testing.
Athena:		What would you tell a neurologist who says that he/she gets too many negative results, therefore the tests are not useful?
Dr. Rosenfeld:		Testing for paraneoplastic antibodies should be performed when there is a high index of suspicion that the patient's symptoms are paraneoplastic in origin. As noted in the answer to question 1, there are clinical clues that should prompt a neurologist to suspect the presence of paraneoplasia. Careful selection of patients will increase the likelihood of positive testing. [See table below for summary]   Table: Diagnostic Check List for Paraneoplastic Disorders   Clinical Feature Comments Symptom progression Acute or subacute course Age of the patient Typically middle-aged or elderly Type of syndrome Certain syndromes are more likely to be of paraneoplastic origin (i.e., LEMS) History of cancer and/or history of smoking Suggests that symptoms may be of paraneoplastic origin
Athena:		What is the future of research in paraneoplastic disorders?
Dr. Rosenfeld:		Research is directed toward facilitating the prompt diagnosis of these syndromes by developing specific and sensitive assays that detect different types of antibodies. Studies are also directed at identifying the mechanisms of neurological damage and the development of animal models, which may help to develop specific treatment strategies.
Athena:		Thank you, Dr. Rosenfeld.

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