Paraneoplastic Cerebellar Degeneration (PCD)

Discussion

PCD is a paraneoplastic neurologic syndrome characterized by cerebellar dysfunction, typically presenting with ataxia, dysarthria, and intentional tremor. The onset may be abrupt, with symptoms developing over several days, or subacute, with symptoms evolving over many months. Depending on the involvement of other CNS structures, the symptoms and signs may also include nystagmus, oscillopsia, diplopia, and unexplained episodes of nausea, vomiting, and diarrhea. Hyperreflexia, extrapyramidal signs, or peripheral neuropathy may be seen in some cases.[1] Cognitive function is usually preserved. PCD can precede the detection of a cancer by months to years, herald a recurrence of cancer, or present in a patient with a known malignancy.[2] PCD is typically associated with breast cancer, ovarian or other gynecologic malignancies, Hodgkin's lymphoma, or small-cell lung cancer.[2,3] The pathogenesis of PCD is thought to be autoimmune-related. Thus far, 3 autoantibodies have been identified as associated with PCD. They are anti-Yo antibody, anti-Hu antibody, and anti-Ri antibody.[4] Anti-Yo antibodies have activity against Purkinje cells of the cerebellum, whereas anti-Hu and anti-Ri antibodies are directed against neuronal nuclear antigen I and II, respectively. Based on the specific autoantibodies involved and the associated predominant clinical features, PCD has been categorized into 3 clinical syndromes: (1) PCD with anti-Yo antibodies, (2) PCD with encephalomyelitis and anti-Hu antibodies, and (3) PCD with opsoclonus and anti-Ri antibodies.

The proposed pathogenesis of PCD with anti-Yo antibodies is as follows: Yo antigens present in the tumor initiate an immune reaction and cause the release of anti-Yo antibodies that identify and destroy the Purkinje cells, causing the clinical picture of PCD.[2] The underlying malignancy is breast or gynecologic in more than 85% of cases.[3,4] For instance, among 55 women with anti-Yo antibody-associated PCD, malignancy was identified in 53.[5] Thirty-three patients had an ovarian or other gynecologic malignancy, 13 had breast cancer, 1 had adenocarcinoma of the lung, and 6 had an adenocarcinoma of unknown primary origin. In the category of PCD with anti-Yo antibodies, the cancers are often of limited clinical stage at the time of presentation. For unclear reasons, the neurologic deficit tends to stabilize after a period of progression, and usually does not improve despite successful treatment of the underlying malignancy. The pathologic hallmark of PCD is diffuse loss of Purkinje cells throughout the cerebellar cortex.[6] Immunohistochemical staining may demonstrate expression of Yo antigen by the PCD-associated neoplasm.

The present case is remarkable not only because it is only the second case of PCD caused by esophageal cancer reported in the literature, but also because the patient is a man. For unknown reasons, anti-Yo antibodies occur mainly in women. Thus far, there are only 3 other reported cases of men with anti-Yo antibody-associated PCD -- 1 had an adenocarcinoma of the parotid gland,[7] the second had an adenocarcinoma of unknown primary origin,[8] and the third patient had esophageal cancer 9 months preceding his cerebellar dysfunction.[9] Therefore, it is important to appreciate that anti-Yo antibodies can occur in men. It is also important to realize that in patients older than 50 years, male or female, acute or subacute cerebellar degeneration is paraneoplastic in origin in about 50% of cases[2,10] and is often associated with a potentially curable occult malignancy.

Hence, when the paraneoplastic panel -- including anti-Yo antibodies in serum or CSF -- is positive, a wide search for a cancer should be undertaken. This case illustrates an unusual presentation of esophageal adenocarcinoma. Given a rapid rise in the incidence of esophageal adenocarcinoma in white men in the United States in recent years, and the fact that esophageal adenocarcinoma can originate from normal mucosa without preexisting Barrett's esophagus (as in this case), it is prudent for clinicians to consider such a diagnosis in an appropriate clinical setting.

Finally, although neither immunosuppressive therapy nor antitumor therapy (chemotherapy, radiation therapy, or surgery) is beneficial in many cases of PCD, with early treatment using these modalities and aggressive rehabilitation, complete or partial recovery of the neurologic symptoms has been reported.[1,2] Additional investigations in this setting are warranted to aid the development of effective therapeutics.