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
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,
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
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
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
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.
1. Verghese J, Bieri PL, Gellido C, et al: Peripheral neuropathy
in young-old and old-old patients. Muscle Nerve 24:1476-1481, 2001.
2. MacGowan DJ, Scelsa SN, Waldron M: An ALS-like syndrome with
new HIV infection and complete response to antiretroviral therapy. Neurology
3. Dalmau J, Posner JB: Neurologic paraneoplastic antibodies
(anti-Yo; anti-Hu; anti-Ri): The case for a nomenclature based on antibody and
antigen specificity. Neurology 44:2241-2246, 1994.
4. Rees JH, Hain SF, Johnson MR, et al: The role of
[18F]fluoro-2-deoxyglucose-PET scanning in the diagnosis of paraneoplastic
neurological disorders. Brain 124:2223-2231, 2001.