Paraneoplastic Cerebellar Degeneration

Consequential
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Diagnosis and reasoning

This lady has presented with a constellation of signs and symptoms suggestive of worsening cerebella ataxia, a neurological syndrome which can be caused by a wide range of genetic and acquired diseases. Careful history taking is essential here, with important points being the age of onset, speed of onset and progression, and presence of a family history of similar conditions, as well as any features in the medical history that may help discern an underlying etiology. Thus, in this patient, the relatively older age of onset and absence of a positive family history make a genetic ataxia highly unlikely. Important causes of acquired cerebellar ataxias include Wernicke encephalopathy, Miller-Fisher syndrome (MFS), cerebellar strokes, parainfectious cerebellitis, Hashimoto's encephalopathy, paraneoplastic cerebellar degeneration (PCD), Creutzfeldt-Jakob disease (CJD), and antiglutamic acid decarboxylase (anti-GAD) associated cerebellar ataxia. However, the subacute onset of symptoms seen here makes Wernicke encephalopathy, MFS, cerebellar strokes, and parainfectious cerebellitis unlikely, as these conditions tend to present more acutely. Note also that the absence of signs and symptoms suggestive of Hashimoto's disease make Hashimoto's encephalopathy unlikely as well. Last but not least, note the strong family history of ovarian malignancy; gynecological cancers are well known to give rise to PCD, and are an important differential here. Neuroimaging via a contrast MRI is a good initial investigation; the unremarkable findings seen here make CJD unlikely, as these patients usually demonstrate characteristic changes; note also that while PCD results in cerebellar atrophy, this is often not seen in early disease. As PCD is the leading differential here, antineuronal antibody testing should follow; she turns out to be positive for anti-Yo antibodies, confirming the diagnosis; note that these antibodies are typically associated with malignancies of the breast and gynecological tract. Given the family history of ovarian cancer, CT imaging of the abdomen and pelvis is a suitable next step; not unsurprisingly, this reveals a mass in the right ovary which is suspicious of a malignancy. Note that audiometry is of little use here, given that there is no evidence of hearing loss, or of pathology involving in the VIIIth cranial nerve. Urgent oncology referral is a must. While surgical exploration of the abdomen will be necessary, this should be via a laparotomy; diagnostic laparoscopy should not be attempted, due to the possibility of dissemination of early stage disease. Plasmapheresis and immunosuppression (i.e. with cyclophosphamide) are generally of little benefit in PCD; they are mainly a last-resort treatment in patients in whom surgical resection of the tumor has failed to control symptoms.


Discussion

Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions; they are rare, being encountered in only 0.01% of malignancies. Note that PNS can involve the central nervous system, peripheral nervous system, or the neuromuscular junction and muscle; paraneoplastic cerebellar degeneration (PCD) is one of the forms affecting the central nervous system. PCD is an autoimmune disease; these patients experience antibody-mediated destruction of the purkinje cells of the cerebellum, possibly because these express proteins similar to the tumor antigens; the ultimate outcome is progressive inflammation, and cerebellar degeneration. While PCD can occur in association with almost any malignancy, the condition is most frequently associated with gynecological cancers, small-cell lung cancer, and lymphomas. Affected patients present with acute or subacute cerebellar dysfunction which is usually bilateral, affecting the trunk and peripheries; prominent features include gait unsteadiness which rapidly develops into ataxia, as well as diplopia, dysarthria, and dysphagia. Certain patients may experience a prodromal syndrome with a viral-like illness, nausea and vomiting. It is important to appreciate that the above symptoms may precede those of the underlying malignancy by months to years; thus, early diagnosis often affords these patients a better chance of survival. The possibility of PCD should be considered in patients who present with acute or subacute cerebellar ataxia - especially if there are no obvious risk factors for cerebellar disease (such as alcoholism, exposure to toxins or chemotherapeutic agents, or vitamin deficiencies). In patients who are suspected to have PCD, Magnetic resonance imaging (MRI) of the brain is a good first step; this may reveal atrophic changes in the cerebellum (although these may be absent in early disease), and helps exclude alternate structural, demyelinating, vascular and infectious causes of a similar presentation. An antineuronal antibody assay is also essential, as anti-Yo and anti-Hu antibodies may be encountered in these patients; note that anti-Ri antibodies are not encountered in PCD (but are seen in other forms of PNS). Anti-Yo antibodies are most closely associated with gynecological malignancies such as breast and ovarian cancer; anti-Hu antibodies are mainly encountered in small-cell carcinoma of the lung, and neuroblastomas. Cerebrospinal fluid (CSF) analysis in these patients may also demonstrate pleocytosis, elevated protein levels and elevated IgG levels. A thorough search for an underlying tumour is very important; this may include CT or MRI imaging of the chest, abdomen and pelvis, and screening for commonly encountered tumour markers. Note that as PCD may precede overt malignancy by months to years, initial imaging studies may be inconclusive; in such patients, a PET scan may be scheduled, given its ability to detect clinically occult tumours. PCD is best treated by eliminating the tumor antigen; this may require definitive management of the malignancy via surgery, chemotherapy, radiotherapy, or a combination of these modalities. If the patient shows rapid neurologic deterioration, immunotherapeutic methods such as plasma exchange, intravenous immunoglobulins, or immunosuppressive agents such as corticosteroids or cyclophosphamide may be used; however, these usually result in minimal improvement, if at all. Unfortunately, even following early identification and treatment of the underlying malignancy, complete remissions of cerebellar symptoms is rare; in the majority of patients, the best outcome achievable is prevention of further deterioration. This is believed to be because of persistence of tumour antigens.


Take home messages

  1. PCD should be suspected in patients who develop acute or subacute onset cerebellar ataxia, especially if there are no apparent risk factors for cerebellar disease.
  2. Neuroimaging may be negative in early disease.
  3. The suspicion of PCD warrants a thorough search for an underlying tumour.
  4. The mainstay of management is elimination of the tumour antigen; unfortunately, complete recovery is rare.

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