Drs. Lieberman and Schold have presented a comprehensive up-to-date review of paraneoplastic syndromes affecting the nervous system. The points are all well made, but a few deserve special comment:
(1) "Approximately 50% of pediatric cases [of opsoclonus
myoclonus] are paraneoplastic." Most pediatric neurologists now believe
that nonparaneoplastic opsoclonus is far more common than the paraneoplastic
variety associated with neuroblastoma. It is likely that only 5% of childrenrather
than the 50% referred to in the literaturewho present to physicians with
opsoclonus have neuroblastoma as the underlying cause.
(2) "Ma2 is…shared by the testis and normal brain." Curiously, Ma2, the paraneoplastic antigen associated with testicular cancer, is not found in normal testes, whereas Ma1, associated with a variety of nontesticular cancers, is.
(3) "Paraneoplastic peripheral neuropathy was an uncommon diagnosis." In most series, a final diagnosis of paraneoplastic peripheral neuropathy is made in about 5% of patients referred to a neurologic clinic for polyneuropathy. However, once obvious causes (ie, diabetes, hereditary or nutritional disorders) are eliminated, paraneoplastic peripheral neuropathy is a more common diagnosis.
(4) "Spinal muscular atrophy is an opportunistic viral syndrome." A recent study has described an amyotrophic lateral sclerosis-like syndrome in patients with acquired immunodeficiency syndrome. The neurologic disorder responds to antiviral therapy.
The major question for the clinician is how to approach a patient with or without a known cancer who develops a neurologic disorder, the cause of which is not apparent during the initial diagnostic evaluation. Such patients fall into two categories: The first, more common group includes patients without a known cancer. The second, less common group includes patients whose cancer was identified prior to the development of the neurologic symptoms. This group may either be under active treatment or in remission after initial treatment.
Patients in the first group are seen initially by a family practitioner or internist and are usually referred to a neurologist for diagnostic evaluation. As Lieberman and Schold point out, the best approach to managing a paraneoplastic syndrome is to identify and treat the underlying tumor. Therefore, an early diagnosis is important to prevent irreversible nervous system damage. As they also indicate, however, a clinical picture identical to each of the paraneoplastic syndromes can occur in patients without cancer. The increased incidence of such disorders in cancer patients establishes a syndrome as paraneoplastic. If, after careful neurologic evaluation, a paraneoplastic syndrome is a significant clinical consideration, the physician should measure the serum for paraneoplastic antibodies.
The nature of the antibodies searched for would depend on the clinical syndromes. For example, if the patient presents with a sensorimotor peripheral neuropathy, especially one that is demyelinating, immunoglobulin G or M antibodies against peripheral nerve tissue may suggest an underlying myeloma or lymphoma. If the disorder is a pure sensory neuropathy, and especially if there is evidence of central nervous system (CNS) dysfunction, serum should be assayed for anti-Hu antibodies. However, particularly with CNS paraneoplastic syndromes, the overlap among antibody-positive clinical syndromes warrants a much broader screen than simply looking for a single paraneoplastic antibody. Antibodies can be identified by immunohistochemistry, Western blotting, or, preferably, both.
If examination of the serum identifies a known paraneoplastic antibody, the physician can narrow the search for the underlying tumor. For example, a woman with a cerebellar syndrome and anti-Yo antibody in the serum has an almost 100% probability of having cancer, and a greater than 90% likelihood that the tumor will be either in the breast or the genital system (usually the ovary). A patient with a sensory neuropathy or encephalomyelitis and an anti-Hu antibody in the serum, likewise, has an almost 100% likelihood of having cancer, and a greater than 90% likelihood that it is small-cell lung cancer.
That said, the physician must recognize that all antibodies are not as specific as the two indicated above. For example, although cancer is the underlying cause of a Lambert-Eaton myasthenic syndrome in only two-thirds of such patients, virtually all patients harbor anti-P/Q voltage-gated calcium channels in their serum.
The physician must recognize that not all patients with paraneoplastic syndromes are antibody-positive, and that not all antibodies have been identified and characterized. Thus, if a strong suspicion remains even after serum testing fails to reveal a paraneoplastic antibody, the physician may still want to undertake a search for an underlying cancer. That search generally includes a careful physical examination, measurement of serum cancer markers, and computed tomography of the chest, abdomen, and pelvis. Recent evidence suggests that total-body positron-emission tomography using 18-fluorodeoxyglucose may be a rapid and sensitive approach to identifying an occult cancer.
Examination of the cerebrospinal fluid (CSF) is also helpful. Most CNS paraneoplastic syndromes, particularly early in their course, are accompanied by a modest pleocytosis (20 to 100 lymphocytes) and elevated immunoglobulins. Paraneoplastic antibodies found in the CSF are always present in the serum, albeit at a lower titer. Thus, CSF examination for antibodies is unnecessary.
For the patient with a known cancer, the problem is distinguishing paraneoplastic involvement of the nervous system from other more common complications of cancer such as nervous system metastases, or nonmetastatic syndromes, including opportunistic infections, lesions related to hyper- or hypocoagulability, nutritional and metabolic disorders, and the side effects of therapy. Imaging and, when appropriate, spinal fluid evaluation, generally exclude metastatic disease.
As in patients without a known cancer, the presence of paraneoplastic antibodies helps to establish a positive diagnosis, but the other abnormalities discussed above must always be considered. In the patient whose cancer has been remote and is considered in remission, development of the neurologic syndrome may presage relapse of the disease, and a search for recurrence is warranted.
As Lieberman and Schold indicate, treatment depends on the syndrome. Certain syndromes, such as Lambert-Eaton myasthenic syndrome, respond both to treatment of the underlying tumor and to immunosuppression. Others are poorly responsive to either. Nevertheless, vigorous treatment of the underlying cancer is certainly indicated.
Anticancer therapy may help stabilize or ameliorate neurologic symptoms. Although immunosuppression has not proven efficacious in most large series, individual case reports suggest the possibility that an occasional patient may respond to immunosuppression. Intravenous immunoglobulin is the most commonly used immunosuppressive therapy.