MONTREALParaneoplastic syndromes are increasingly being
recognized as the earliest warning signs of some cancers, according
to presentations at the Presidential Symposium of the 123rd Annual
Meeting of the American Neurological Association (ANA).
These syndromes are particularly associated with small-cell lung
cancers (SCLC), thymomas, lymphomas, and melanomas. They are caused
either by antibodies that are produced against tumor antigens and
that also attack neural structures, or by antibodies produced by the
tumor itself. Some paraneoplastic syndromes improve only with
successful treatment of the tumor, but others respond to modalities
such as plasma exchange and corticosteroids.
Paraneoplastic syndromes are remote effects of cancer that are
not a direct result of the tumor mass or its metastases, said
Alan Pestronk, MD, of Washington University School of Medicine.
The syndromes may occur before or after the onset of clinical
manifestations of the tumor, sometimes years before or after.
Paraneoplastic syndromes are particularly common in patients who have
lost 15% or more of body weight, Dr. Pestronk said. Nearly all such
patients have disorders of muscle or nerve, such as type II muscle
fiber atrophy or distal sensory neuropathy. If such a syndrome is
present, there is a high probability of finding a neoplasm.
If you find what appears to be a paraneoplastic syndrome, you
need to look for a neoplasmrepeatedly, over time, he
said. He also has found that paraneoplastic syndromes can be more
disabling than the associated neoplasm.
When these syndromes are caused by antibodies generated in response
to the tumor, the antibodies are either to membrane-associated tumor
antigens or to intracellular tumor antigens. These antibodies react
both to the tumor antigen and to an epitope present in normal nerve
tissue. When the causative antibody is a tumor-produced antibody, it
attacks nerve tissue directly.
The tumor antigens most likely to induce harmful antibody responses
are membrane proteins such as neurotransmitter receptors or
voltage-gated ion channels. Dr. Pestronk said that, in such cases,
the resulting paraneo-plastic syndrome tends to be a membrane
dysfunction, often including focal evidence of damage to the nerve or
These syndromes are often treatable with plasma exchange and
corticosteroids. Examples include Lambert-Eaton myasthenic syndrome,
autonomic neuropathy, Isaacs neuromyotonia, and myasthenia
gravis. Associated cancer types include SCLC, thymoma, and lymphoma.
Paraneoplastic syndromes due to tumor-secreted antibodies are
determined by antigen binding patterns. Tumor antibodies against
myelin-associated glycoprotein typically cause demyelination
neuropathies, which affect sensory more often than motor function.
Antibodies against GM-1 ganglioside more often affect motor function
and may include a conduction block along motor axons.
Dr. Pestronk said that treatment of these syndromes is more difficult
and often requires drugs that reduce titers of associated antibodies,
such as cytotoxic agents, or that interfere with antibody action,
such as IV immunoglobulin G (IVIG). The one treatment that
seems to be effective is a combination of plasma exchange with
intravenous cyclophosphamide over several months, he said.
The main autoimmune disorders that affect the neuromuscular junction
can all occur as paraneoplastic syndromes, said John Newsom-Davis,
MD, of the Institute of Molecular Medicine, University of Oxford, UK.
Thymoma is present in 10% of myasthenia gravis patients and in
15% of autoimmune neuromyotonia patients. SCLC is present in about
50% of patients with Lambert-Eaton myasthenic syndrome, Dr.
Symptoms and the associated antibody appearance can precede tumor
clinical presentation by up to 5 years. The damaging antibodies in
these disorders bind to the muscle acetylcholine receptor, neuronal
voltage-gated potassium channels, or presynaptic P/Q-type
voltage-gated calcium channels at the neuromuscular junction and at
postganglionic autonomic synapses. These ion channels have
large extracellular domains and lack the protection of the
blood-brain or blood-nerve barrier, Dr. Newsom-Davis pointed out.
Symptoms of these syndromes may include muscle twitches, cramps,
stiffness, weakness, increased sweating, pares-thesias, mood change,
or insomnia. The muscle twitches are easy to miss if you
dont strip the patient and look carefully, he added.
Plasma exchange is often useful in relieving these symptoms, which
will also usually improve with successful tumor treatment.
The tumor is driving the immune response, but is the immune response
helping the patient? Apparently so. Dr. Newsom-Davis reported that
the survival curve is significantly improved in SCLC patients who
also develop Lambert-Eaton myasthenic syndrome.
Cancer-associated retinopathy is a paraneoplastic disorder associated
with SCLC, in which antibodies against retinal rods and cones cause
visual problems. John L. Keltner, MD, said that these can cause a
remarkable devastation of retinal structure. Dr. Keltner
is chair of the Department of Ophthalmology, University of California
Davis Medical Center.
Symptoms include unexplained visual loss, photopsias (flashes of
light), poor night vision, abnormal visual acuity, color vision
abnormalities, and ring scotomas, but few signs of inflammation. Dr.
Keltner described the syndrome as like an accelerated retinitis
pigmentosa and said that visual loss occurs usually over months
and frequently precedes the discovery of the cancer. Symptoms often
stabilize with steroid treatment.
Melanoma-associated retinopathy usually develops after cutaneous
melanoma. It includes characteristic shimmering, flickering, or
pulsating flashes of light, often associated with progressive loss
over several months. Both of these syndromes are difficult to treat,
he said. Steroids, plasma exchange, and IVIG have been tried, with
variable results, he said.
Most paraneoplastic syndromes that affect the peripheral nervous
system are associated with antigens located on the cell surface.
Removal of the antibodies with plasma exchange often improves the
neurological problem. CNS paraneoplastic syndromes, on the other
hand, are usually associated with antibodies against cytoplasmic
antigens and are much more difficult to treat. In general,
these syndromes respond poorly to treatment, and the corresponding
antibodies, rather than perceived as pathogenic, should be considered
markers of syndromes associated with specific neoplasms, said
Josep Dalmau, MD, PhD, of Memorial Sloan-Kettering Cancer Center.
CNS syndromes, including opsoclonus, ataxia, limbic and brainstem
encephalitis, and cerebellar degeneration, have all been associated
with tumors. The target antigens include CDR34, CDR62, amphiphysin,
and the nuclear antigens Hu and Yo. Associated neoplasms include
SCLC, ovarian cancer, and breast cancer. Dr. Dalmau said that these
syndromes are less responsive to treatment than peripheral nerve
syndromes, possibly because the neurological damage occurs earlier
and is irreversible.