Paraneoplastic Cerebellar Degeneration Clinical Presentation

Updated: Nov 04, 2014
  • Author: Abbas Mehdi, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Presentation

History

The development of paraneoplastic cerebellar degeneration is quite rapid and patients are severely disabled in days to weeks.

Since most of the patients have occult malignancy, patients are less likely to develop symptoms of paraneoplastic cerebellar degeneration if they have a known history of malignancy.

Neoplasms associated with paraneoplastic cerebellar degeneration are adult onset and more prevalent in females. A common clinical presentation is middle age female with or without comorbid condition presents typically with mild dizziness and nausea followed by vertigo and nystagmus that may suggest a peripheral vestibular problem. These symptoms are followed by ataxia of the limbs and midline, oscillopsia, dysarthria, tremor, and sometimes dysphagia and blurry vision.

The ocular motor and bulbar abnormalities suggests some degree of brain stem involvement.

Mild memory and cognitive deficits as well as affective symptoms can occur in about 20% of patients with paraneoplastic cerebellar degeneration. This is known as cerebellar cognitive affective syndrome. [13]

Initially, patients can be misdiagnosed with cerebrovascular disease, demyelinating disease, infectious diseases, vitamin deficiency, toxic exposure, sarcoidosis, autoimmune diseases (eg, SLE, Sjogren syndrome), and alcohol-induced cerebellar degeneration.

Other diseases that can mimic this condition include late-onset spinocerebellar ataxia with or without a family history, olivopontocerebellar degeneration, and other degenerative diseases of the brain seen in elderly patients.

History, examination, and diagnostic testing help to differentiate paraneoplastic cerebellar degeneration from other conditions that are statistically more likely to occur than paraneoplastic cerebellar degeneration. Early diagnosis of paraneoplastic cerebellar degeneration can lead to early diagnosis and treatment of the occult malignancy.

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Physical

See the list below:

  • The hallmark of paraneoplastic cerebellar degeneration is cerebellar dysfunction.

  • Onset of paraneoplastic cerebellar degeneration symptoms can be very rapid or can be gradual.

  • A common initial symptom is loss of coordination, which usually starts on one side and rapidly progresses to involve both sides equally.

  • 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 are often 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.

  • After progressing for a few weeks, the symptoms stabilize, leaving the patient in a severely disabled state.

Findings that are inconsistent with a diagnosis of paraneoplastic cerebellar degeneration include the following:

  • Severely altered mental status with myoclonus and ataxia

  • Predominantly corticospinal tract dysfunction

  • Unilateral cerebellar dysfunction

  • Familial cerebellar degeneration

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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 [14, 15]

    • 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 paraneoplastic cerebellar degeneration 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 paraneoplastic cerebellar degeneration and appear to be cytotoxic for the tumor cells. [16] 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 paraneoplastic cerebellar degeneration. The anti-Yo antibody first was reported by Greenlee and Brashear in 1983 [17] and later by Jaeckle et al [18] in patients who mainly had either ovarian or breast cancer.

  • 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. [19]

    • 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. [20] 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. [21, 22]

  • Anti-Ri antibodies [23]

    • Patients with the anti-Ri antibody are female, and many have breast cancer.

    • Anti-Ri antibody is not associated with paraneoplastic cerebellar degeneration and presents as opsoclonus and ataxia.

  • Hodgkin disease: Paraneoplastic cerebellar degeneration 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. [8, 9]

Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al [24] ) (Open Table in a new window)

Antibodies Predominantly Associated With PCD

Predominant Syndrome

Associated Cancer

Anti-Yo (PCA-1) antibodies

PCD

Ovarian

Breast cancers

Anti-Tr antibodies

PCD

Hodgkin's lymphoma

Anti-mGluR1 antibodies**

PCD

Hodgkin's lymphoma

Anti-Zic4 antibodies†

PCD

Small-cell lung cancer

Sometimes Associated With PCD

 

 

Anti-VGCC antibodies

Eaton-Lambert syndrome, PCD

Small-cell lung cancer

Lymphoma

Anti-Hu (ANNA-1) antibodies

Encephalomyelitis, PCD, sensory neuronopathy

Small-cell lung cancer

Other cancers

Anti-Ri (ANNA-2) antibodies

PCD, brain-stem encephalitis, paraneoplastic opsoclonus-myoclonus

Breast cancer

Gynecologic cancer

Small-cell lung cancer

Anti-CV2/CRMPS antibodies

Encephalomyelitis, PCD, chorea, peripheral neuropathy, uveitis

Small-cell lung cancer

Thymoma

Other cancers

Anti-Ma protein antibodies‡

Limbic, hypothalamic, brain-stem encephalitis (infrequently PCD)

Testicular cancer

Lung cancer

Other cancers

Anti-amphiphysin antibodies

Stiff-person syndrome, encephalomyelitis, PCD

Breast cancer

Small-cell lung cancer

*There is no uniform nomenclature for some of these antibodies; variant names appear in parentheses. mGluR1: metabotropic glutamate receptor 1, Zic4: zing finger of the cerebellum 4, and VCGG: voltage-gated calcium channel.

**Anti-mGluR1 antibodies have been identified in only 2 patients.

† Anti-Zic4 antibodies are predominantly associated with PCD only when no other paraneoplastic antibodies are detectable.

‡Ma proteins include Ma1 and Ma2. Patients with brain-stem and cerebellar dysfunction usually have antibodies against both MA1 and Ma2.

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