History
Neoplasms associated with paraneoplastic cerebellar degeneration (PCD) are adult onset and more prevalent in females. A common clinical presentation is a middle-aged female with or without a comorbid condition who presents with mild dizziness and nausea followed by vertigo and nystagmus that may suggest a peripheral vestibular problem. These symptoms are followed shortly by ataxia of the limbs and midline, oscillopsia, dysarthria, tremor, and sometimes dysphagia and blurry vision. [14] The development of paraneoplastic cerebellar degeneration is quite rapid and patients are severely disabled in days to weeks.
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]
Most patients have occult malignancy (60–70%), so patients are less likely to develop symptoms of paraneoplastic cerebellar degeneration if they have a known history of malignancy. However, there is an exception with Hodgkin's lymphoma, which is a diagnosis that must be considered if the clinical presentation fits. [12, 14]
PCD can also present with other neurologic symptoms as part of a larger paraneoplastic syndrome (see Causes section below).
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.
Physical
The hallmark of paraneoplastic cerebellar degeneration (PCD) is cerebellar dysfunction.
Onset of PCD symptoms can be subacute or very rapid. 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:
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Severely altered mental status with myoclonus and ataxia
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Predominantly corticospinal tract dysfunction
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Unilateral cerebellar dysfunction
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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
These are the most common antibodies associated with isolated PCD. [14, 15]
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. These target antigens are also known as cerebellar degeneration related proteins (CDR). 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-Yo antibody response, found almost 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
Anti-Hu (ANNA-1) 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 was likely 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]
Patients with PCD related to anti-Hu antibodies typically have additional neurologic symptoms, such as encephalomyelitis. [45]
Anti-Ri antibodies
Patients with the anti-Ri antibody are female, and many have breast cancer. [23]
Anti-Ri antibody is not associated with isolated paraneoplastic cerebellar degeneration and presents as opsoclonus and ataxia.
In addition to those noted above, several other paraneoplastic antibodies have been associated with PCD, typically as part of a larger syndrome with other neurologic deficits (see table below). Two other antibodies, anti-Tr and anti-mGluR1, are associated with Hodgkin's lymphoma and often present as isolated PCD. [5, 46] Paraneoplastic cerebellar degeneration in association with Hodgkin disease is found predominantly in men, and neurologic symptoms often develop after tumor detection. [47]
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 |
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|
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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The workup of paraneoplastic cerebellar degeneration.
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MRI of a 29-year-old female with ARCA1. Sagittal T1 shows marked diffuse cerebellar atrophy with no atrophy of the cerebral cortex, midbrain, pons, or medulla. Image from National Institutes of Health.
Tables
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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