eMedicine Specialties > Neurology > Neuro-oncology

Paraneoplastic Cerebellar Degeneration

Author: Abbas Mehdi, MD, Director, MDA Center of Central California; Consulting Staff, Department of Neurology, California Neurological Center, Inc
Coauthor(s): David Y Ko, MD, Associate Professor, Laboratory Director, Department of Neurology, University of Southern California Medical Center
Contributor Information and Disclosures

Updated: Mar 21, 2006

Introduction

Background

An association between paraneoplastic cerebellar degeneration (PCD) and occult gynecologic cancers (breast or ovarian) first was identified in 1938, and the syndrome was described fully by Brain in 1951. In the mid 1980s, Posner found that patients with PCD can be classified according to the presence or absence of an antibody that reacted with an antigen present in both the tumors and in cerebellar Purkinje neurons obtained from these patients.

Paraneoplastic neurologic syndromes include many neurologic disorders including PCD caused by an immune-mediated mechanism other than a metastatic complication in patients with an underlying malignancy. Any part of the nervous system can be involved depending on the type of primary malignancy. These syndromes affect 1-3% of all cancer patients. These syndromes are difficult to diagnose and respond poorly to treatment. However, the oncologic outcome of patients with antibody-associated paraneoplastic syndromes does not significantly differ from that of patients who do not have the antibodies or a paraneoplastic syndrome.

PCD is a syndrome that occurs predominantly in patients with cancer of the ovary, uterus, or adnexa; cancer of the breast; small-cell carcinoma of the lung; or Hodgkin lymphoma.

The onset of symptoms of cerebellar degeneration indicates the presence of an occult malignancy. Not all gynecologic cancers present as paraneoplastic neurologic syndrome; however, in a clinical presentation consistent with a paraneoplastic neurologic syndrome, the chances of underlying malignancy are very high.

Pathophysiology

Paraneoplastic neurologic syndrome (PCD) is a rare disorder caused by the secondary effects of cancer and is believed to be immune mediated. High titers in the patient's serum and cerebrospinal fluid (CSF) of autoantibodies directed against both neurons and tumor have been detected in some forms of this syndrome. These autoantibodies are considered the result of an immunologic response to tumor and may cross-react with cells of the nervous system, causing neuronal damage. Specific forms of this syndrome often are associated with specific antineuronal antibodies and tumors. The onset of neurologic symptoms and detection of these antibodies often precede diagnosis of the tumor; therefore, detection of these antibodies greatly assists the diagnosis of this syndrome and prompts investigations for the underlying tumor.

Strong evidence exists of cytotoxic T-cell mechanisms inducing a pathogenic role in several recent studies, yet no animal model is available to prove with concrete evidence.

Not all patients presenting with PCD and its clinical features have recognizable antineuronal antibodies. However, this does not exclude the likelihood of occult malignancy.

Frequency

United States

In one study, PCD was observed in 25% of paraneoplastic neurologic syndromes, occurring in 2 of every 1000 patients with cancer.

Mortality/Morbidity

In the study cited above, median survival duration was 100 months for patients with breast cancer and 22 months for those with gynecologic cancer. Although PCD led to the diagnosis of cancer in 63% of patients, cancer progression was the cause of death in 52%.

Sex

Both sexes are affected, but PCD is far more common in women than in men.

Age

• PCD associated with anti-Yo antibody occurs in middle-aged women with occult ovarian or breast cancer that is usually indolent.
• PCD associated with anti-Hu antibody occurs in middle-aged men and women or patients with risk factors for lung cancer.
• When the condition is associated with Hodgkin lymphoma, patients are usually young men, and the cerebellar disease often follows the diagnosis of lymphoma.

Clinical

History

• Onset of PCD symptoms can be very rapid or can be gradual.
• Symptoms begin with the acute onset of cerebellar dysfunction, which evolves over days to weeks.
• Common initial symptom is loss of coordination, which usually starts on one side and rapidly progresses to involve both sides equally.
• Patients present with limb and truncal ataxia, lack of coordination, dysarthria, and nystagmus.
• After progressing for a few weeks, the symptoms stabilize, leaving the patient in a severely disabled state.
• Some patients experience opsoclonus, myoclonus, memory disturbances, pyramidal signs, sensory disturbances, or hyporeflexia.

Physical

The hallmark of PCD is cerebellar dysfunction.

• Patients have severe ataxia involving arms and legs equally.
• Also involved is midline cerebellar dysfunction presenting as severe truncal and neck ataxia with markedly affected ataxic gait; usually patients are unable to stand without assistance.
• Ocular findings often are abnormal, including horizontal or vertical nystagmus, dysconjugate gaze, ocular dysmetria, and opsoclonus.
• Speech can be affected severely, presenting initially as mild dysarthria and progressing to incomprehensible words in severe cases.
• Mild deterioration of mental status has been reported in the literature.
• Findings that are inconsistent with a diagnosis of PCD include the following:
  • Severe altered mental status with myoclonus and ataxia
  • Predominantly corticospinal tract dysfunction
  • Unilateral cerebellar dysfunction
  • Familial cerebellar degeneration

Causes

Two major patterns of antibody response have been described: anti-Hu (type IIa, antineuronal nuclear antibodies type 1) and anti-Yo (type 1, anti-Purkinje cell antibodies [APCA]). Both anti-Yo and anti-Hu antibodies label patient tumors and are believed to be elicited by tumor antigens that are cross-reactive with neuronal antigens.

• Anti-Yo antibodies
  • Anti-Yo antibody response, found virtually exclusively in women with cerebellar degeneration accompanying gynecologic and breast malignancies, recognizes 34-kD and 52-kD or 62-kD cytoplasmic proteins of Purkinje cells.
  • The role of the anti-Yo antibody in causing PCD is unclear, but high titers of an antibody reacting predominantly with Purkinje cells in a disease characterized by loss of all Purkinje cells with relative sparing of the remainder of the CNS certainly suggests a role. T cells that specifically recognize Yo antigens have been found in the blood of patients with PCD and appear to be cytotoxic for the tumor cells. Whether this cytotoxic mechanism causes Purkinje cell loss remains to be proven.
  • The term "Yo proteins" refers to a family of proteins highly expressed in the cytoplasm of cerebellar Purkinje cells and in the tumor cells (usually gynecologic or breast) of patients with anti-Yo–positive PCD. The anti-Yo antibody first was reported by Greenlee and Brashear in 1983 and later by Jaeckle et al in patients with ovarian cancer who had subacute cerebellar degeneration.
• Anti-Hu antibodies
  • Anti-Hu antibodies are expressed in a number of tumors, including all small-cell lung cancers and most neuroblastomas, as well as occasional other tumors (including several types of sarcoma and prostate carcinoma). Anti-Hu antibody, found predominantly in paraneoplastic neurologic syndromes associated with small-cell carcinoma of the lung, reacts with 35- to 42-kD proteins present in nuclei and cytoplasm of virtually all neurons.
  • The role of Hu proteins in small-cell lung cancer and the other cancers in which they are expressed is also unclear.
  • The term "Hu antigens" refers to a family of nuclear proteins normally expressed in all neurons of the central and peripheral nervous systems but not in other cell types (with the possible exception of testes). The antigen probably was identified first by Wilkinson and Zeromski in 1965, when they reported that 4 patients suffering from subacute sensory neuronopathy associated with lung cancer had in their serum a low-titer antibody that reacted with the cytoplasm of neurons in the guinea pig cerebral cortex. No additional information was forthcoming until 1985, when Graus and colleagues described first 2 and later 4 patients with subacute sensory neuropathy associated with small-cell lung cancer; these patients had in their serum high titers of a complement-fixing antibody that reacted predominantly with the nuclei of neurons of the central and peripheral nervous systems.
• Anti-Ri antibodies
  • Patients with the anti-Ri antibody are female, and many have breast cancer.
  • Anti-Ri antibody is not associated with PCD and presents as opsoclonus and ataxia.
• Hodgkin disease: PCD in association with Hodgkin disease is found predominantly in men, and neurologic symptoms often develop after tumor detection.
• Absence of paraneoplastic antibodies does not rule out a paraneoplastic syndrome particularly in patients with known cancer and neurologic symptoms; however, the presumptive diagnosis requires the absence of the metastatic and nonmetastatic complications of the tumor.

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