An Overview of Paraneoplastic Neurologic Syndromes

Paraneoplastic neurological syndromes (or paraneoplastic neurological disorders), are a class of conditions which arise due to an autoimmune attack on neural tissue (amongst others) in response to cancer progression.

These disorders are degenerative and rare in occurrence (though some forms are more common).

Symptoms & prognoses depend on the type of cancer and the type of paraneoplastic neurologic syndrome that arises.

Different Types of Paraneoplastic Neurologic Syndromes

Some of the common paraneoplastic syndromes that develop include:

• Limbic encephalitis – amnesia, disorientation, psychosis (including hallucinations and paranoia), confusion, depression & anxiety. Patients may also develop seizures. The most common cancers to trigger limbic encephalitis are small-cell lung cancer (SCLC),  germ cell tumours of the testis, breast cancer, Hodgkins lymphoma, and teratoma.

• Subacute sensory neuropathy – upper limb pain or paraesthesia (tingling), sensory loss, sensory ataxia and absence of reflexes. At a later stage, the neuropathy may also spread to the face, chest and abdomen. Most cases of subacute sensory neuropathy occur due to SCLC, but also breast & ovarian cancers, sarcoma or Hodgkins lymphoma.

• Cerebellar degeneration – severe truncal and limb ataxia, dysarthria (problem articulation of speech), nystagmus (involuntary eye movement), vertigo and diplopia (double vision). Onset can be as rapid as a few hours to a few days and leads to the patient becoming bed-bound. Cerebellar degeneration occurs in association with  ovarian cancer, breast cancer, Hodgkins lymphoma, and SCLC.

• Lambert-Eaton myasthenic syndrome – similar to myasthenia gravis but less severe; muscle weakness within the legs, before spreading upwards towards the top of the body, ptosis (falling of upper eyelid), ophthalmoplegia (eye muscle paralysis), dry mouth, dry eyes, impotence, constipation and excessive sweating. Most commonly associated with SCLC.

• Peripheral nerve hyperexcitability syndrome – most common paraneoplastic neurologic syndrome associated with thymoma, SCLC, Hodgkins lymphoma, and other cancers. It is characterised by twitching and cramping of muscles, muscle stiffness, muscle weakness, in addition to excessive sweating (sensory nerve related). Other CNS features can include psychosis and autonomic disturbances (e.g. Morvan’s syndrome.

There are numerous other syndromes that can develop with many overlapping symptoms, depending on what tissue(s) is/are affected.

The majority involve some form of muscle weakness, as well as being progressive in nature.

What Causes Paraneoplastic Neurologic Syndromes?

Paraneoplastic neurologic syndromes are thought to be caused by an autoimmune attack by the body on cancer cells, rather than the cancer itself.

The attack can target healthy neural tissue, leading to the multitude of syndromes described above.

Within the blood (and CSF), there may be elevations in specific antibodies which can aid in the diagnosis of a paraneoplastic neurologic syndrome:

• Limbic encephalitis – Hu, CV2, AMPAR, VGKC, Ma2
• Subacute sensory neuropathy – Hu, VC2
• Cerebellar degeneration – Hu, Yo, Tr
• Peripheral nerve hyperexcitability – VGKC

The multitude of different antibodies being generated can cause differing syndromes, with many overlaps.

Specific antibodies are related to specific forms of these conditions, in particular groups of people, with a particular cancer.

How are Paraneoplastic Neurologic Syndromes Treated?

Treating the cancer/tumour is of paramount importance, as the autoimmune attack is directly caused by onconeural antigens that arise due to the cancer.

Elimination of the cancer will prevent further antibodies against neural tissue being generated. Cancer treatment is often achieved by surgery, chemotherapy, radiotherapy or the combination of the three.

If a paraneoplastic syndrome has arisen, it is important to target the antibodies already generated, as they continue to pose an autoimmune threat.

Immunotherapy is often used to target endogenous antibodies. Immunotherapy includes the administration of steroids, intravenous immunoglobulin (IVIg) containing healthy donated antibodies and plasma exchange (plasmapheresis), in which plasma containing antibodies is separated from your blood cells and blood cells returned cells with new replacement plasma.

Drugs such as cyclophosphamide, azathioprine and rituximab may also be given.

Some of the therapies may work on specific syndromes, however, not all treatments will work for everybody. It is therefore important to trial a treatment to test its efficacy before proceeding.

In addition to immunotherapy, supportive therapy to target symptoms e.g. psychiatric medication, or physiotherapy would also be encouraged.

Further Reading

• All Paraneoplastic Neurologic Syndromes Content

Written by

Osman Shabir

Osman is a Neuroscience PhD Research Student at the University of Sheffield studying the impact of cardiovascular disease and Alzheimer's disease on neurovascular coupling using pre-clinical models and neuroimaging techniques.