The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 5, 2009 —  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.

Table 1. Differential Diagnosis of Some Classic PND (Click to enlarge table)

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. (Click for more details)

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.

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.

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.⁴ 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.^5,6 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.^7,8

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.

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.^5,6

• History taking in paraneoplastic cerebellitis

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.¹⁰

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.

Clinical examination

• 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

Etiology of paraneoplastic cerebellar degeneration

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 antibodies¹¹

• 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.¹² 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 1983¹³ and later by Jaeckle et al¹⁴ 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.¹⁵
• 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.¹⁶ 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.^17,18

Anti-Ri antibodies

• 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.

Table 2. Antibodies, Paraneoplastic Syndromes, and Associated Cancers (Click to enlarge table)

• Neuroimaging in paraneoplastic cerebellar degeneration

The brain MRI is often normal at the time the symptoms present. Several weeks or months after the neurological symptoms appear the MRI shows atrophy of the cerebellum (Figure 1). There are a number of antibodies and tumors that are associated with paraneoplastic cerebellar degeneration (see Figure 2).

• Management of Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration is one of the PND that is most difficult to treat. Although some patients may notice mild improvement after treatment of the tumor and immunotherapy (see below in section General Comments on Treatment), most patients do not improve. At best, treatment may result in stabilizing symptoms. In very rare instances, dramatic improvement occurs.

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.²⁰

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.

• 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.
• 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 and deserves further evaluation.

References

1. Lorusso L, Hart IK, Giometto B, et al. Immunological features of neurological paraneoplastic syndromes. Int J Immunopathol Pharmacol. May-Aug 2004;17(2):135-44.
2. Brain wr, Daniel pm, Greenfield JG. Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry. May 1951;14(2):59-75.
3. Posner JB. Paraneoplastic cerebellar degeneration. Can J Neurol Sci. May 1993;20 Suppl 3:S117-22.
4. Inuzuka T. Autoantibodies in paraneoplastic neurological syndrome. Am J Med Sci. Apr 2000;319(4):217-26.
5. Bolla L, Palmer RM. Paraneoplastic cerebellar degeneration. Case report and literature review. Arch Intern Med. Jun 9 1997;157(11):1258-62.
6. Nath U, Grant R. Neurological paraneoplastic syndromes. J Clin Pathol. Dec 1997;50(12):975-80.
7. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol. Jan 2000;47(1):9-17.
8. Okano HJ, Park WY, Corradi JP, Darnell RB. The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival. Genes Dev. Aug 15 1999;13(16):2087-97.
9. Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology. Sep 12 2000;55(5):713-5.
10. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. Apr 1998;121 ( Pt 4):561-79.
11. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. Oct 1992;42(10):1931-7.
12. Tanaka M, Tanaka K, Shinozawa K, et al. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci. Nov 26 1998;161(1):88-90.
13. Greenlee JE, Brashear HR. Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma. Ann Neurol. Dec 1983;14(6):609-13.
14. Jaeckle KA, Graus F, Houghton A. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol. Nov 1985;18(5):592-600.
15. Mason WP, Graus F, Lang B, Honnorat J, Delattre JY, Valldeoriola F. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain. Aug 1997;120 ( Pt 8):1279-300.
16. Wilkinson PC, Zeromski J. Immunofluorescent detection of antibodies against neurones in sensory carcinomatous neuropathy. Brain. Sep 1965;88(3):529-83.
17. Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. Apr 1985;35(4):538-43.
18. Graus F, Elkon KB, Cordon-Cardo C, Posner JB. Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor. Am J Med. Jan 1986;80(1):45-52.
19. Dalmau J, Gonzalez RG, Lerwill MF. Case records of the Massachusetts General Hospital. Case 4-2007. A 56-year-old woman with rapidly progressive vertigo and ataxia. N Engl J Med. Feb 8 2007;356(6):612-20.
20. Rosenfeld MR, Dalmau J. Current Therapies for Paraneoplastic Neurologic Syndromes. Curr Treat Options Neurol. Jan 2003;5(1):69-77.
21. Bataller L, Dalmau J. Paraneoplastic neurologic syndromes: approaches to diagnosis and treatment. Semin Neurol. Jun 2003;23(2):215-24.
22. Dalmau JO, Posner JB. Paraneoplastic syndromes. Arch Neurol. Apr 1999;56(4):405-8.
23. Darnell RB. The importance of defining the paraneoplastic neurologic disorders. N Engl J Med. Jun 10 1999;340(23):1831-3.
24. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. Oct 16 2003;349(16):1543-54.
25. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. Aug 2004;75(8):1135-40.
26. Greenlee JE. Cytotoxic T cells in paraneoplastic cerebellar degeneration. Ann Neurol. Jan 2000;47(1):4-5.
27. Greenlee JE, Brashear HR, Jaeckle KA, et al. Pursuing an occult carcinoma in a patient with subacute cerebellar degeneration and anticerebellar antibodies. Need for vigorous follow-up. West J Med. Feb 1992;156(2):199-202.
28. Jaeckle KA. Paraneoplastic nervous system syndromes. Curr Opin Oncol. May 1996;8(3):204-8.
29. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. Nov 2004;56(5):715-9.
30. Rousseau A, Benyahia B, Dalmau J, Connan F, Guillet JG, Delattre JY, et al. T cell response to Hu-D peptides in patients with anti-Hu syndrome. J Neurooncol. Feb 2005;71(3):231-6.
31. Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet. Apr 16-22 2005;365(9468):1406-11.
32. Voltz RD, Posner JB, Dalmau J, Graus F. Paraneoplastic encephalomyelitis: an update of the effects of the anti- Hu immune response on the nervous system and tumour. J Neurol Neurosurg Psychiatry. Aug 1997;63(2):133-6.
33. Paraneoplastic syndromes [Full text]