What is a paraneoplastic neurological syndrome?

Paraneoplastic syndromes or remote effects of cancer on the nervous system, are neurological disorders of unknown cause that occur at a higher frequency in patients with cancer than in the general population. Some of these disorders, including limbic encephalitis or Lambert-Eaton myasthenic syndrome (LEMS), are usually associated with cancer, whereas others, such as sensorimotor neuropathy, may have multiple causes which may or may not be cancer-related.

In patients with cancer, the development of neurological symptoms is frequently due to metastatic or direct involvement of the nervous system by the tumor. Other common neurological complications include neurotoxicity from chemotherapy and radiation therapy, vascular and metabolic disorders, infections, and much less frequently, paraneoplastic syndromes.

The frequency of neurological paraneoplastic syndromes is low. In series of patients with cancer, mild or subclinical muscular weakness or peripheral neuropathies not explained by other causes are found in 10% to 20% of patients. Clinically significant paraneoplastic syndromes occur in less than 1% of all patients with cancer. Even in series of patients with small cell lung cancer, which is the tumor most commonly associated with paraneoplastic syndromes, the incidence of these disorders is less than 1%.

Neurological paraneoplastic syndromes may involve the central or peripheral nervous system, including the neuromuscular junction and muscle (Table 1). Although these disorders are rare, their study is important for several reasons: 1) they are frequently the cause of severe disability greater than that caused by cancer, 2) diagnosis is difficult and sometimes the patient is misdiagnosed, 3) paraneoplastic neurological syndromes usually develop before diagnosis of the tumor, that may be diagnosed in a limited stage when it can be cured by currently available therapies, and 4) the study of the pathophysiology of these syndrome may provide clues to better understanding of tumor immunology and how the nervous system is damaged in other autoimmune neurological disorders. 

Although the cause of paraneoplastic neurological syndromes remains unknown, in the last two decades, the discovery that many PNS are associated with the presence in the serum and CSF of antibodies against antigens expressed in the tumor and the nervous system (onconeural antibodies), suggests that the cause of some paraneoplastic neurological syndromes is an initial immune response against tumors, that express neural antigens, that are misdirected to the nervous system (Table 2). Demonstrating onconeural antibodies as biological markers of paraneoplastic neurological syndromes has proved very useful in the diagnosis of a given neurological syndrome as paraneoplastic. However, onconeural antibodies may be found in a minority of patients with cancer without neurological symptoms.

The onconeural antibodies are directed against intracellular antigens so the common belief is that they are not pathogenic. However, these antibodies are probably the tumor counterpart of a more complex, significant, immune response that leads to damage of the nervous system. Animals harbouring tumors which are vaccinated with these antigens do not develop the paraneoplastic neurological syndrome but the immune response is able to delay the tumor growth. The onconeural antibodies are directed against intracellular antigens so the common believe is that they are not patoghenic. However, these antibodies probably are ttthe humor counterpart of a more complex, significant, immune response that leads to the damage of the nervous system. Animal bearing tumors and vaccinated with these antigens do not develop the paraneoplastic neurological syndrome but the immune response is able to delay tumor growth.

Selected references

• Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-1554.

• Henson RA, Urich H. In: Henson RA and Urich H, eds. Cancer and the Nervous system. Oxford. Blackwell Scientific Publications 1982; 311-431.
• Posner JB. Neurologic complications of cancer. FA Davis Company, 1995; 353-385.

TABLE 1

PARANEOPLASTIC SYNDROMES OF THE NERVOUS SYSTEM

Paraneoplastic syndromes of the central nervous system

• Paraneoplastic cerebellar degeneration
• Paraneoplastic encephalomyelitis(*)
  (limbic encephalitis, brainstem encephalitis, myelitis)
• Paraneoplastic opsoclonus-myoclonus
• Cancer associated retinopathy
• Paraneoplastic Stiff-man syndrome
• Paraneoplastic necrotizing myelopathy
• Motor neuron syndromes
• (ALS; subacute motor neuronopathy)

Paraneoplastic syndromes of the peripheral nervous system

• Subacute sensory neuronopathy
• Autonomic neuropathy
• Acute sensorimotor neuropathy
• Polyradiculoneuropathy (Guillain-Barré)
• Brachial neuritis
• Chronic sensorimotor neuropathy
• Sensorimotor neuropathies associated with plasma cell dyscrasias
• Vasculitic neuropathy
• Neuromyotonia

Paraneoplastic syndromes of the neuromuscular junction and muscle

• Lambert-Eaton myasthenic syndrome
• Polymyositis/Dermatomyositis
• Acute necrotizing myopathy
• Cachectic myopathy
• Carcinomatous neuromyopathy
• Carcinoid myopathy

(*) Can include cerebellar symptoms, autonomic dysfunction, and sensory neuronopathy