Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal immune system response to an underlying malignant tumor. Patients with paraneoplastic neurological syndrome (PNS) most often present with neurologic symptoms before an underlying tumor is detected or coincide with the cancer diagnosis.
Paraneoplastic neurologic syndromes include a variety of neurologic disorders, such as paraneoplastic cerebellar degeneration (PCD), that are caused by an immune-mediated mechanism rather than a metastatic complication or medication effect. Any malignancy can cause a paraneoplastic syndrome and 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 typically 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.
PCD is a rare nonmetastatic complication of a carcinoma, typically mediated by antibodies generated against tumor antigens (proteins). Similar proteins are also expressed on Purkinje 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.[2, 3]
An association between PCD and occult gynecologic cancers (breast or ovarian) was first identified in 1938, and the syndrome was described fully by Brain in 1951.[4] Posner found that patients with PCD 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.[5]
PCD 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.[6, 7]
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 PCD.
View Image
The workup of paraneoplastic cerebellar degeneration.
Diagnostic criteria
The 2021 updated diagnostic criteria for paraneoplastic neurologic syndromes (PNS), which include PCD as one of the more common presentations, provide a refined approach to diagnosing PNS by incorporating new insights into the phenotypes and associated antibodies.[8, 2] The key aspects of the updated criteria include:
Classification of phenotypes
The criteria substitute the older term "classical syndromes" with "high-risk phenotypes" for cancer and introduce "intermediate-risk phenotypes" to capture a broader spectrum of clinical presentations.
Risk categorization of antibodies
Antibodies are now categorized into "high-risk" (more than 70% associated with cancer) and "intermediate-risk" (30%–70% associated with cancer). This categorization helps in determining the likelihood of a paraneoplastic origin.
Levels of evidence
The criteria define three levels of evidence for diagnosing PNS: definite, probable, and possible. The level is determined by a scoring system known as the PNS-Care Score, which considers the clinical phenotype, type of antibody detected, presence or absence of cancer, and follow-up duration.
Diagnostic pathway
A diagnosis of definite PNS generally requires the presence of high- or intermediate-risk antibodies, except in the case of opsoclonus-myoclonus syndrome, which has separate considerations.
Paraneoplastic cerebellar degeneration (PCD) is caused by the secondary effects of cancer and is believed to be immune mediated[2, 3] 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.[9, 10] 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.[2] Not all patients presenting with PCD and its clinical features have recognizable antineuronal antibodies. However, this does not exclude the likelihood of occult malignancy.[11, 12] In approximately 40% of patients, no antibodies are identified. Although any paraneoplastic antibody may cause PCD, only anti-Yo, anti-Tr, and antimetabotropic glutamate receptor 1 (mGluR1) have been shown to have specific association with isolated cerebellar dysfunction.
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.[13, 14] The finding of gliosis and near total loss of Purkinje cells on autopsies of patients with anti-Yo antibodies supports this theory.[15]
In cases with associated Lambert-Eaton myasthenic syndrome, anti-voltage-gated calcium channel (anti-VGCC) antibodies mediate auto-immunity against P/Q type VGCC, which are membrane proteins on Purkinje cells that drive the activity and survival of neurons. Thus, some patients with anti-VGCC antibody have been found to have diffuse loss of Purkinje cells, causing cerebellar degeneration.[16]
Antibodies could therefore play an initial pathogenic role in PCD, but the T-cell immune response is believed to be the major effector of neuronal degeneration.41[3] As a result, patients with PCD have been shown to have infiltration of CD8+ T cells in the cerebellum, with cytotoxic T cells appearing proximal to damaged neurons.[15]
In one study, paraneoplastic cerebellar degeneration (PCD) was observed in 25% of paraneoplastic neurologic syndromes, occurring in 2 of every 1000 patients with cancer.[17]
In a large-scale UK study of 1500 patients with progressive cerebellar ataxia, 3% were found to have PCD.[18]
Mortality and 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%.[17]
Demogrpahics
Both sexes are affected, but PCD is far more common in women than in men.
PCD associated with anti-Yo antibody occurs in middle-aged women with occult ovarian or breast cancer that is usually indolent.
PCD 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.
Prognosis in paraneoplastic cerebellar degeneration (PCD) greatly depends on early detection of the underlying neoplasm and its stage at the time of detection.
In most cases, prognosis is poor. There tends to be little response to further antineoplastic or immunotherapy after tumor resecton. particulary in patients with anti-Yo and anti-Hu antibodies.[19] Those with other antibodies, such as anti-Tr, may have a better chance of responding to treatment.
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.[20] The development of PCD 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 PCD. This is known as cerebellar cognitive affective syndrome.[21]
Most patients have occult malignancy (60–70%), so patients are less likely to develop symptoms of PCD 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.[17, 20]
PCD can also present with other neurologic symptoms as part of a larger paraneoplastic syndrome (see Causes).
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 PCD from other conditions that are statistically more likely to occur than PCD. Early diagnosis of PCD can lead to early diagnosis and treatment of the occult malignancy.
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 PCD include the following:
Severely altered mental status with myoclonus and ataxia
Two major patterns of antibody response in paraneoplastic cerebellar degeneration (PCD) 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.[20, 22]
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[23] and later by Jaeckle et al[24] 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 PCD 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 PCD and appear to be cytotoxic for the tumor cells.[25] 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.[26]
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 four 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.[27] No additional information was forthcoming until 1985, when Graus and colleagues described first two and later four 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.[28, 29]
Patients with PCD related to anti-Hu antibodies typically have additional neurologic symptoms, such as encephalomyelitis.[19]
Anti-Ri antibodies
Patients with the anti-Ri antibody are female, and many have breast cancer.[30]
Anti-Ri antibody is not associated with isolated PCD 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.[7, 31] PCD in association with Hodgkin disease is found predominantly in men, and neurologic symptoms often develop after tumor detection.[32]
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.[11, 12]
Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al[33] )
Consider a diagnosis of paraneoplastic cerebellar degeneration (PCD) 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 PCD 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 PCD is severe; correct diagnosis can lead to early discovery of an occult tumor, which can improve the chance of recovery.
Serum testing should include a basic metabolic and infectious workup to exclude other causes, including but not limited to:
CBC, CMP, vitamin levels (especially thiamine and Vitamin E), alcohol level, and HIV
CSF analysis typically shows a mild pelocytosis, mild protein elevation, high IgG index, and oligoclonal bands.[20, 35]
In addition to the above studies, serum and CSF should also be tested for known onconeural antibodies.
It is important to note that up to 40% of patients with paraneoplastic cerebellar degeneration (PCD) are seronegative.[36] Thus, negative antibody testing does not exclude the diagnosis.
Since many of the paraneoplastic biomarkers are associated with specific types of cancer, the identification of one of these onconeural antibodies in serum or CSF can be very helpful in guiding the workup for an occult malignancy.
Magnetic resonance imaging (MRI) findings are normal early in the course of paraneoplastic cerebellar degeneration (PCD) but can show cerebellar atrophy in advanced cases.[37]
MRI of the brain with contrast is recommended to exclude any structural, demyelinating, vascular, or infectious causes.
View Image
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....
PET (FDG-PET) may be useful to identify the underlying malignancy.
In PCD with anti-Yo antibodies, perform radiography of the chest, mammography, and CT of the abdomen or chest to identify the primary malignancy.
In PCD 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.
In addition to the imaging studies listed above, a thorough gynecologic examination should be performed in patients with paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies to identify the primary malignancy.
Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) is useful in demonstrating occult neoplasms or small metastatic lesions.
If no primary mailignancy is identified, patients should have serial monitoring.
If the initial workup of a patient who has paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is nonrevealing, consider a total abdominal hysterectomy and a bilateral salpingo-oophorectomy in postmenopausal women.[38] 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 5 years after the initial onset of paraneoplastic cerebellar degeneration.
Tumor resection is necessary once the malignancy is identified.
The hallmark of paraneoplastic cerebellar degeneration (PCD) 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 PCD associated with anti-Hu, the cortical and cerebellar neuronal nuclei are stained.
Two approaches can be used to treat paraneoplastic neurologic syndrome (PNS). The first treatment is directed toward the underlying tumor, while the second approach is directed toward the autoimmune disease causing the cerebellar dysfunction.
Since neurologic paraneoplastic syndromes are immune-mediated, two 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.[39]
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.[40]
In patients in whom no tumor can be detected after a comprehensive workup, long-term periodic surveillance for occult malignancy is recommended.
Paraneoplastic syndromes are a therapeutic challenge for the neurologist, and treatment of paraneoplastic syndromes is generally unsatisfactory.
Early tumor detection and treatment with resection, sometimes the addition of chemotherapy, 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.
The effect of the combination of intravenous immunoglobulins (IVIG), cyclophosphamide, and methylprednisolone on the clinical course of patients with paraneoplastic neurologic syndrome (PNS) or paraneoplastic cerebellar degeneration (PCD) and antineuronal antibodies is poor. This may be partly due to T-cell involvement in the cerebellar damage. However, due to the severe disability of the condition and the presence of some positive responders found in the literature, it is reasonable to trial a course of immunotherapy in an attempt to reduce morbidity.
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.
In a minority of patients who are not disabled severely at the onset of treatment, a transient stabilization is possible if the tumor is appropriately treated.
After review of the current literature regarding immune-mediated cerebellar ataxias, Hiroshi et al proposed the following treatment strategy for PCD.[34]
Immediate attention to the treatment of neoplasm should be the first objective of treatment.
Immediate induction of immunotherapy using corticosteroids (intravenous methylprednisolone or oral prednisolone), IVIg, plasmapheresis, immunosuppressants, or rituximab, either alone or in different combinations. There are no significant differences in the response to these types of immunotherapies.
The anti-neoplasm therapies and immunotherapies have no benefits in most cases, with a relatively short median survival time (10.2 to 43 months), although retrospective studies on a few responders have identified some prognostic factors (eg, anti-Tr or anti-Ro antibody).
There is no specific medication approved for treatment of paraneoplastic cerebellar degeneration (PCD). Treatment is mainly directed at the underlying malignancy. However, immunotherapy may also be tried, such as the medications listed below. These may also be used in combination with plasmapheresis.
Clinical Context:
Intravenous immune globulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It downregulates proinflammatory cytokines (eg, interferon gamma), blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells. IVIg also blocks the complement cascade and promotes remyelination. In addition, it may increase IgG in cerebrospinal fluid.
IVIg is a purified preparation of gamma globulin. It is derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.
Clinical Context:
Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.
Clinical Context:
Methylprednisolone decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability. This agent is slightly more potent than prednisone; 4 mg of methylprednisolone is equivalent to 5 mg of prednisone.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli and inhibit the synthesis of tumor necrosis factor (TNF)-alpha, interleukin-2 (IL-2), IL-6, and interferon (IFN)-gamma. In addition, glucocorticoids modulate serum and leukocyte-bound levels of cell adhesion molecules.
Clinical Context:
Exerts its cytotoxic effect by alkylation of DNA, which leads to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.
Cancer chemotherapy is based on an understanding of tumor cell growth and on how drugs affect this growth. After cells divide, they enter a period of growth (G1 phase), followed by DNA synthesis (S phase). The next phase is a premitotic phase (G2 phase), then finally a phase mitotic cell division (M phase).
Rates of cell division vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant ones. This is partly the rationale for current cyclic dosage schedules.
Erika Lan, DO, MA, Fellow in Headache Medicine, Department of Neurology, USC Keck Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Abbas Mehdi, MD, Director, MDA Center of Central California; Consulting Staff, Department of Neurology, California Neurological Center, Inc
Disclosure: Nothing to disclose.
David Y Ko, MD, Associate Professor of Clinical Neurology, Loma Linda University School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SK<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Lundbeck, Sunovion, Supernus, UCB.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Jorge C Kattah, MD, Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Disclosure: Nothing to disclose.
Chief Editor
Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Frederick M Vincent, Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine
The workup of paraneoplastic cerebellar degeneration.
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.
The workup of paraneoplastic cerebellar degeneration.
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.
*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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