Paraneoplastic Cerebellar

Degeneration
Updated: Nov 04, 2014
Author: Abbas Mehdi, MD; Chief Editor: Stephen A Berman, MD, PhD,
MBA
Background
Paraneoplastic syndromes are a group of rare disorders that are triggered by an
abnormal immune system response to an underlying (usually undetected)
malignant tumor. Patients with paraneoplastic neurological syndrome (PNS) most
often present with neurologic symptoms before an underlying tumor is detected.
Paraneoplastic neurologic syndromes include many neurologic disorders
including paraneoplastic cerebellar degeneration (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. [1] 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.
Paraneoplastic cerebellar degeneration is a rare nonmetastatic complication of a
carcinoma, typically mediated by antibodies generated against tumor antigens
(proteins). Similar proteins are also expressed on Purinje cells and possibly other
cells within the cerebellum. The cancer-fighting antibodies mistakenly attack
these normal protein cells in the cerebellum. This immune activation in the
central nervous system (CNS) results in cerebellar injury and dysfunction defined
as paraneoplastic cerebellar degeneration.
An association between paraneoplastic cerebellar degeneration and occult
gynecologic cancers (breast or ovarian) was first identified in 1938, and the
syndrome was described fully by Brain in 1951. [2] Posner found that patients with
paraneoplastic cerebellar degeneration 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. [3]
Paraneoplastic cerebellar degeneration 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. [4, 5]
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.
The image below illustrates the workup of paraneoplastic cerebellar
degeneration.
 The workup of
paraneoplastic cerebellar degeneration.
View Media Gallery
Pathophysiology
Paraneoplastic cerebellar degeneration is 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. [6, 7] 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 precede diagnosis of the tumor more 60% of the time. Therefore,
detection of these antibodies greatly assists the diagnosis of this syndrome and
prompts investigations for the underlying tumor. Not all patients presenting with
paraneoplastic cerebellar degeneration and its clinical features have
recognizable antineuronal antibodies. However, this does not exclude the
likelihood of occult malignancy. [8, 9] In approximately 40% of patients, no
antibodies are identified.
The Yo antigen is a cytoplasmic protein (CDR2) that interacts with c-Myc. CDR2
is expressed mostly on the Purkinje cells of the cerebellum and can also be
present in neurons of the brain stem. Studies suggest that CDR2 sequesters c-
Myc in the neuronal cytoplasm and downregulates its activity. Disruption of this
interaction by anti-Yo antibodies may increase c-Myc activity, leading to
apoptosis of the Purkinje cells. [10, 11]
Antibodies could therefore play an initial pathogenic role in paraneoplastic
cerebellar degeneration, although the T-cell immune response is believed to be
the major effector of neuronal degeneration. In most of these syndromes, the
antigens have been identified and the genes have been cloned.
Epidemiology
Frequency
United States
In one study, paraneoplastic cerebellar degeneration was observed in
25% of paraneoplastic neurologic syndromes, occurring in 2 of every
1000 patients with cancer. [12]
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 paraneoplastic cerebellar degeneration led to the
diagnosis of cancer in 63% of patients, cancer progression was the
cause of death in 52%.[12]
Sex
Both sexes are affected, but paraneoplastic cerebellar degeneration is
far more common in women than in men.
Age
See the list below:
Paraneoplastic cerebellar degeneration associated with anti-Yo
antibody occurs in middle-aged women with occult ovarian or
breast cancer that is usually indolent.
Paraneoplastic cerebellar degeneration 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.
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.
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
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]
o
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.
o
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.
o
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-Yopositive 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
o
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.
o
The role of Hu proteins in small-cell lung cancer and the
other cancers in which they are expressed is also unclear. [19]
o
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]
o
Patients with the anti-Ri antibody are female, and many
have breast cancer.
o
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
Predominant Syndrome Associated Cancer
With PCD

Ovarian

Anti-Yo (PCA-1) antibodies PCD Breast cancers

Anti-Tr antibodies PCD Hodgkin's lymphoma

Anti-mGluR1 antibodies** PCD Hodgkin's lymphoma

Small-cell lung
Anti-Zic4 antibodies PCD
cancer

Sometimes Associated With PCD

Small-cell lung
cancer

Anti-VGCC antibodies Eaton-Lambert syndrome, PCD

Lymphoma

Small-cell lung
cancer

Anti-Hu (ANNA-1) antibodies Encephalomyelitis, PCD, sensory neuronopathy

Other cancers

Breast cancer

Gynecologic cancer

PCD, brain-stem encephalitis, paraneoplastic

Anti-Ri (ANNA-2) antibodies
opsoclonus-myoclonus
Small-cell lung
cancer

Small-cell lung
cancer

Thymoma
Encephalomyelitis, PCD, chorea, peripheral
Anti-CV2/CRMPS antibodies
neuropathy, uveitis

Other cancers

Anti-Ma protein antibodies Limbic, hypothalamic, brain-stem encephalitis Testicular cancer

(infrequently PCD)
 Lung cancer

Other cancers

Breast cancer

Anti-amphiphysin antibodies Stiff-person syndrome, encephalomyelitis, PCD 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.

Differential Diagnoses
Acute Disseminated Encephalomyelitis
Ataxia with Identified Genetic and Biochemical Defects
Brainstem Gliomas
Cardioembolic Stroke
Cavernous Sinus Syndromes
Cerebellar Hemorrhage
Cerebral Aneurysms
Cerebral Venous Thrombosis
Dissection Syndromes
Glioblastoma Multiforme
Intracranial Hemorrhage
Lacunar Syndrome
Leptomeningeal Carcinomatosis Imaging
Meningioma
Multiple Sclerosis
Neurosarcoidosis
Olivopontocerebellar Atrophy
 Posterior Cerebral Artery Stroke
Primary CNS Lymphoma
Prion-Related Diseases
Secondary CNS Melanomas
Laboratory Studies
See the list below:
Consider a diagnosis of paraneoplastic cerebellar degeneration in patients
who present with acute or subacute cerebellar degeneration and no risk
factors for cerebellar disorders (eg, stroke, alcoholism, primary or metastatic
neoplasms in the cerebellum, treatment with chemotherapeutic agents).
Once a diagnosis of paraneoplastic cerebellar degeneration is made, a
thorough search for an underlying malignancy is warranted. Analysis of
samples of serum and CSF for autoantibodies helps to determine the
underlying primary malignancy.
Diagnosis and treatment of paraneoplastic cerebellar degeneration is
important because the disability caused by the paraneoplastic cerebellar
degeneration is severe; correct diagnosis can lead to early discovery of an
occult tumor with chances of being cured.
Imaging Studies
See the list below:

Magnetic resonance imaging (MRI) findings are normal early in the course
of paraneoplastic cerebellar degeneration but can show cerebellar atrophy
in advanced cases. [25]

MRI of the brain with contrast is recommended to exclude any structural,
demyelinating, vascular, or infectious causes. See the image below.

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.
View Media Gallery

In paraneoplastic cerebellar degeneration with anti-Yo antibodies, perform
radiography of the chest, mammography, and CT of the abdomen or chest
to identify the primary malignancy.

In paraneoplastic cerebellar degeneration with anti-Hu antibodies, perform
radiography and CT of the chest to identify a likely small-cell lung cancer.
Also investigate other organs where small-cell cancers present, such as the
cervix, esophagus, and prostate.
Other Tests
See the list below:
In addition to the imaging studies listed above, a thorough gynecologic
examination should be performed in patients with paraneoplastic cerebellar
degeneration with anti-Yo antibodies to identify the primary malignancy.
CSF samples demonstrate mononuclear pleocytosis, elevated protein
levels (immunoglobulin G), and oligoclonal bands. These findings may
normalize late in the course of the illness. Evaluate CSF for antineuronal
autoantibodies. Anti-Yo and Anti-Tr antibodies have the highest specificity
for cerebellar dysfunction.
Whole body fluorodeoxyglucose positron emission tomography (FDG-
PET) is useful in demonstrating occult neoplasms or small metastatic
lesions.
See the image below for an illustration of the workup of paraneoplastic cerebellar
degeneration.
 The workup of
paraneoplastic cerebellar degeneration.
View Media Gallery
Procedures
See the list below:
If the initial workup of a patient who has paraneoplastic cerebellar
degeneration with anti-Yo antibodies is nonrevealing, the usual next step is
a total abdominal hysterectomy and a bilateral salpingo-oophorectomy in
postmenopausal women.[26] If histologic examination reveals no malignancy
and/or the patients are men or premenopausal women, periodic surveillance
is necessary. At times, the primary malignancy is discovered up to 2 years
after the initial onset of paraneoplastic cerebellar degeneration.
Perform tumor resection.
Histologic Findings
The hallmark of paraneoplastic cerebellar degeneration is severe loss of
Purkinje cells diffusely throughout the cerebellar cortex. These cells are
completely absent on specimens. Other cell loss is observed but is rare.
Occasionally, Purkinje cell loss is patchy. Inflammatory changes are also
observed with lymphocytic infiltration. Atrophy of the granular and
molecular layers is demonstrated, with microglial proliferation and
astrocytosis but relative sparing of basket cells. The deep cerebellar
nuclei and the cerebellar connections to the brain stem are normal.
Patients with APCA-1/anti-Yo antibody tend to demonstrate more
inflammatory changes and characteristic immunofluorescence patterns
with coarse granular staining of Purkinje cell cytoplasm as well as
proximal axons and dendrites; nuclei and systemic tissues are not
stained. In paraneoplastic cerebellar degeneration associated with anti-
Hu, the cortical and cerebellar neuronal nuclei are stained.
Medical Care
Two approaches can be used to treat paraneoplastic neurologic
syndrome. The first treatment is directed toward the underlying tumor,
while the second approach is toward the autoimmune disease causing
the cerebellar dysfunction.
Since neurologic paraneoplastic syndromes are immune-mediated, 2
distinct approaches to therapy have been reported: removal of the
antigen source by treatment of the underlying tumors and suppression
of the immune response. Immunosuppression can be beneficial for
some conditions. [27]
Paraneoplastic syndromes are a therapeutic challenge for the
neurologist, and treatment of paraneoplastic syndromes is
generally unsatisfactory.
Early tumor detection and treatment should be the primary
objective in these patients.
The response of the paraneoplastic neurologic syndromes to
immunosuppressive agents or antitumor treatment is influenced
greatly by the underlying neuropathology.
o The effect of the combination of intravenous
immunoglobulins (IVIG), cyclophosphamide, and
methylprednisolone on the clinical course of patients with
paraneoplastic neurologic syndrome or paraneoplastic
cerebellar degeneration and antineuronal antibodies is
unsatisfactory.
o Some reports indicate partial or complete remission of
cerebellar symptoms after treating the primary neoplasm. This
has been observed only in small-cell carcinomas and is not
reported in gynecologic malignancies.
o In a minority of patients who are not disabled severely at the
onset of treatment, a transient stabilization is possible and
deserves further evaluation.
Surgical Care
Surgical care is required for patients who undergo tumor resection.
Consultations
A team approach is required in treating patients with paraneoplastic
cerebellar degeneration.
Neurologic consultation is needed for basic workup and to
exclude other possible causes of cerebellar dysfunction.
 Oncology consultation is needed for tumor workup and treatment
protocols.
Surgical consultation is needed in patients for whom tumor
resection is recommended.
Diet
The patient may require nutritional support in severe cases of nausea
and vomiting.
Activity
Bed rest is usual because patients with severe cerebellar dysfunction
are at high risk of falls.
Further Outpatient Care
See the list below:

Patients usually require long-term rehabilitation and/or hospice
care in severe situations. Treatment is unsatisfactory, and chance
of long-term survival is poor in reported cases. [28]

In patients in whom no tumor can be detected after a
comprehensive workup, routinely perform outpatient measurement
of antibody levels with tumor markers and other tests related to
diagnosis of possible malignancies.
Prognosis
Prognosis greatly depends on early detection of the underlying
neoplasm and its stage at the time of detection.