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Distant Effects of Cancer on the Nervous System

Distant Effects of Cancer on the Nervous System

The first descriptions of neurologic disorders in patients with cancer identified those who had peripheral neuropathy. Most neurologists thought these patients actually had a peripheral neuropathy secondary to the inanition associated with their cancer. Still other patients clearly had peripheral neurologic damage from chemotherapy (eg, vincristine).

Paraneoplastic Disorders

A different kind of illness was recognized in patients who had neurologic disorders, but whose cancer presented after the neurologic symptoms and had not invaded the nervous system. These disorders were dubbed "remote effects of cancer on the nervous system." Several specific syndromes were recognized—eg, an acutely progressive cerebellar syndrome in a woman who was later found to have ovarian, uterine, or breast cancer.

It was eventually discovered that, in their serum and cerebrospinal fluid (CSF), some of these patients harbored antibodies that reacted to neurons in the cerebellum. The antibodies were directed against specific antigens in these neurons, which were also present in the tumor cells themselves. Other syndromes were soon recognized, consisting of neurologic disorders associated with the development of lung cancer or testicular cancer. These were a class of neurologic diseases that became known as paraneoplastic disorders.

Lieberman and Schold catalog these disorders, listing the associated immunologic changes, and touching on the advances in molecular biology that have led to a better understanding of their pathogenesis. However, their paper omits descriptions of the syndromes themselves, making it difficult for the nonneurologist to recognize them. In this regard, it can be instructive to present vignettes of the more typical syndromes, with the caveat that there is frequently overlap among the syndromes.

Paraneoplastic Cerebellar Degeneration

A middle-aged woman presents to her doctor because she has become unsteady in gait and clumsy with her hands. In a matter of weeks to a couple of months, her speech becomes dysarthric. She is found to be ataxic, falling when she walks. She has normal mentation, but her eye movements demonstrate nystagmus, and she may have autonomic signs and extensor plantar responses. She becomes unable to use her hands because they are so dysmetric; her speech becomes unintelligible; she cannot eat and becomes wheelchair-bound. All of this may occur rapidly over a few days or weeks, or gradually over several months.

The magnetic resonance imaging (MRI) scan of her brain is normal or, at most, shows a small cerebellum. The CSF is normal or near normal, but both the CSF and the serum demonstrate an antineuronal antibody identified as anti-Yo. A search reveals ovarian, uterine, or breast cancer, although the tumor may be so small as not to be discovered for several months.

Despite treatment of the cancer, the patient does not recover from her neurologic disorder. At postmortem examination, the cerebellum is found to be devoid of Purkinje cells. Variants of this syndrome include a more widespread neurologic disorder in which the cerebellar syndrome is part of paraneoplastic encephalomyelitis (see below) and the cancer is small-cell lung cancer (SCLC).

Paraneoplastic Encephalomyelitis

A middle-aged man develops partial complex seizures—"psychomotor" in type—characterized by behavioral disturbances associated with minor motor or sensory features. His examination demonstrates an amnestic syndrome, with poor recent memory but a preserved ability to perform arithmetic and other complex mental operations. The man’s behavior is erratic; he may be agitated, disoriented, and confused. All of this evolves as a progressive disorder.

Focal examination may be normal, or he may be unsteady and have diplopia, nystagmus, autonomic problems, and extensor plantars. Both upper and lower motor neuron signs and symptoms may be present. An MRI of the brain discloses medial temporal lobe (hippocampal) signal abnormalities bilaterally. The bilateral changes and the subacute course differentiate the disorder from herpes encephalitis, but a CSF polymerase chain reaction assay for herpes should be performed if any question remains. The patient’s serum and CSF contain an antinuclear antineuronal antibody called anti-Hu. A search discloses SCLC.

Treatment of the cancer may alleviate some of the neurologic symptoms, especially the seizures and agitated behavior, but the memory disorder persists. A biopsy or autopsy of the brain reveals infiltrates of lymphocytes in multiple brain sites, but predominantly in the limbic structures. Death occurs from direct complications of the lung cancer and its metastases. Two variants are limbic encephalopathy, in which there is an isolated syndrome of memory loss, and subacute sensory neuronopathy, which accompanies the paraneoplastic encephalomyelitis.

Subacute Sensory Neuronopathy

A middle-aged woman presents with progressive difficulty walking and a complaint of leg weakness of several months’ duration. Instead of true muscle weakness, her physician finds she has a profound sensory disturbance, with loss of position sense and, to a lesser extent, decreased pin and temperature perception. Deep tendon reflexes are decreased or absent. Her hands and arms become affected to the point that she cannot use her hands, even to feed herself. Lung cancer is found, and if it is SCLC, the blood and CSF contain anti-Hu antibodies. Treatment of the cancer does not improve her neurologic deficit, which tends to progress relentlessly.

A postmortem examination reveals marked inflammation of the dorsal root ganglia. As noted above, this patient might also have symptoms of the paraneoplastic encephalomyelitis syndrome.

Lambert-Eaton Myasthenic Syndrome

A middle-aged man presents with progressive proximal leg weakness, with a major component being fatigability. Although myasthenia gravis is considered, the patient does not have eye movement abnormalities typical of myasthenia gravis, and instead complains of paresthesias, autonomic difficulties, dry mouth, erectile dysfunction, and dysphagia. Electrical studies of his muscles also produce findings that differ from myasthenia gravis in that repetitive stimulation actually improves muscle power.

This is Lambert-Eaton myasthenic syndrome, and the patient is highly likely to have SCLC. Immunologic studies demonstrate high-titer antibodies against P/Q-type voltage-gated calcium channels. Effective anticancer therapy may improve the patient’s symptoms. Lambert-Eaton myasthenic syndrome is often responsive to pyridostigmine (Mestinon, Regonol), guanidine, and the aminopyridines. Death is due to the cancer and its direct complications.


These vignettes present typical examples, but there is frequent overlap, and the syndromes may be accompanied by other signs. In addition, there are other, even rarer afflictions of the nervous system associated with cancer.

As Lieberman and Schold point out, our understanding of these disorders has increased markedly over the past 10 years, with numerous molecular biologic observations. However, two conundrums persist. First, although the immunologic data suggest a causative relationship, this has not been proven. In the case of Lambert-Eaton myasthenic syndrome, anti-voltage-gated calcium channel antibodies are directly causative. For the other paraneoplastic disorders, we do not actually know if the immunologic abnormalities are etiologically relevant or merely epiphenomena of another, unknown mechanism. Second, the cancers in patients with paraneoplastic neurologic disorders are often small and difficult to find; they may even be fairly indolent in their progression. Understanding the reason for this oncologic behavior might offer clues to the development of future cancer therapies.

One last point for the medical oncologist: A patient with known cancer who develops neurologic symptoms is almost never suffering from a paraneoplastic syndrome. He either has a direct invasive complication of his cancer, a vascular or infectious complication, or a toxic side effect of the cancer therapy.

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