Diagnostic Considerations

When suspecting an immune-mediated etiology for the patient's cerebellar dysfunction, consideration of the targeted structures and the presence or absence of other associated conditions may help to narrow down the differential diagnoses.^[48]

Diagnostic criteria

Graus et al put forth the following diagnostic criteria for paraneoplastic neurological syndromes (PNS).^[33]

Definite PNS

1. A classical syndrome and cancer that develops within five years of the diagnosis of the neurological disorder.

2. A non-classical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission.

3. A non-classical syndrome with onconeural antibodies (well characterized or not) and cancer that develops within five years of the diagnosis of the neurological disorder.

4. A neurological syndrome (classical or not) with well characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin), and no cancer.

Possible PNS

1. A classical syndrome, no onconeural antibodies, no cancer but at high risk to have an underlying tumor.

2. A neurological syndrome (classical or not) with partially characterized onconeural antibodies and no cancer.

3. A non-classical syndrome, no onconeural antibodies.

Differential Diagnoses

Acute Disseminated Encephalomyelitis
Anti-GAD Cerebellar Ataxia
Ataxia with Identified Genetic and Biochemical Defects
Beriberi (Thiamine Deficiency)
Brainstem Gliomas
Cardioembolic Stroke
Cavernous Sinus Syndromes
Cerebellar Hemorrhage
Cerebellar or Brainstem Metastases
Cerebral Aneurysms
Cerebral Venous Thrombosis
Dissection Syndromes
Glioblastoma
Gluten ataxia
Intracranial Hemorrhage
Lacunar Syndrome
Leptomeningeal Carcinomatosis (Metastasis) Imaging
Meningioma
Miller-Fisher syndrome
Multiple Sclerosis
Neurosarcoidosis
Olivopontocerebellar Atrophy
Post-infectious Cerebellitis
Posterior Cerebral Artery Stroke
Primary CNS Lymphoma
Prion-Related Diseases
Secondary CNS Melanomas
Vitamin E Deficiency

Workup

Lorusso L, Hart IK, Giometto B, et al. Immunological features of neurological paraneoplastic syndromes. Int J Immunopathol Pharmacol. 2004 May-Aug. 17(2):135-44. [QxMD MEDLINE Link].
BRAIN WR, DANIEL PM, GREENFIELD JG. Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry. 1951 May. 14(2):59-75. [QxMD MEDLINE Link].
Posner JB. Paraneoplastic cerebellar degeneration. Can J Neurol Sci. 1993 May. 20 Suppl 3:S117-22. [QxMD MEDLINE Link].
Zaborowski MP, Spaczynski M, Nowak-Markwitz E, Michalak S. Paraneoplastic neurological syndromes associated with ovarian tumors. J Cancer Res Clin Oncol. 2014 Jun 26. [QxMD MEDLINE Link].
Graus F, Ariño H, Dalmau J. Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas. Blood. 2014 May 22. 123(21):3230-8. [QxMD MEDLINE Link]. [Full Text].
Inuzuka T. Autoantibodies in paraneoplastic neurological syndrome. Am J Med Sci. 2000 Apr. 319(4):217-26. [QxMD MEDLINE Link].
Vernino S. Paraneoplastic cerebellar degeneration. Handb Clin Neurol. 2012. 103:215-23. [QxMD MEDLINE Link].
Bolla L, Palmer RM. Paraneoplastic cerebellar degeneration. Case report and literature review. Arch Intern Med. 1997 Jun 9. 157(11):1258-62. [QxMD MEDLINE Link].
Nath U, Grant R. Neurological paraneoplastic syndromes. J Clin Pathol. 1997 Dec. 50(12):975-80. [QxMD MEDLINE Link].
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. 2000 Jan. 47(1):9-17. [QxMD MEDLINE Link].
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. 1999 Aug 15. 13(16):2087-97. [QxMD MEDLINE Link].
Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology. 2000 Sep 12. 55(5):713-5. [QxMD MEDLINE Link].
Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998 Apr. 121 ( Pt 4):561-79. [QxMD MEDLINE Link].
Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992 Oct. 42(10):1931-7. [QxMD MEDLINE Link].
Finsterer J, Voigtländer T, Grisold W. Deterioration of anti-Yo-associated paraneoplastic cerebellar degeneration. J Neurol Sci. 2011 Sep 15. 308(1-2):139-41. [QxMD MEDLINE Link].
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. 1998 Nov 26. 161(1):88-90. [QxMD MEDLINE Link].
Greenlee JE, Brashear HR. Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma. Ann Neurol. 1983 Dec. 14(6):609-13. [QxMD MEDLINE Link].
Jaeckle KA, Graus F, Houghton A. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol. 1985 Nov. 18(5):592-600. [QxMD MEDLINE Link].
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. 1997 Aug. 120 ( Pt 8):1279-300. [QxMD MEDLINE Link].
Wilkinson PC, Zeromski J. Immunofluorescent detection of antibodies against neurones in sensory carcinomatous neuropathy. Brain. 1965 Sep. 88(3):529-83. [QxMD MEDLINE Link].
Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985 Apr. 35(4):538-43. [QxMD MEDLINE Link].
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. 1986 Jan. 80(1):45-52. [QxMD MEDLINE Link].
Mancuso M, Orsucci D, Bacci A, Caldarazzo Ienco E, Siciliano G. Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature. Arch Ital Biol. 2011 Sep. 149(3):318-22. [QxMD MEDLINE Link].
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. 2007 Feb 8. 356(6):612-20. [QxMD MEDLINE Link].
Masangkay N, Basu S, Moghbel M, Kwee T, Alavi A. Brain 18F-FDG-PET characteristics in patients with paraneoplastic neurological syndrome and its correlation with clinical and MRI findings. Nucl Med Commun. 2014 Oct. 35(10):1038-46. [QxMD MEDLINE Link].
Bhargava A, Bhushan B, Kasundra GM, Shubhakaran K, Pujar GS, Banakar B. Response to abdominal hysterectomy with bilateral salpingo-oophorectomy in postmenopausal woman with anti-yo antibody mediated paraneoplastic cerebellar degeneration. Ann Indian Acad Neurol. 2014 Jul. 17(3):355-7. [QxMD MEDLINE Link]. [Full Text].
Rosenfeld MR, Dalmau J. Current Therapies for Paraneoplastic Neurologic Syndromes. Curr Treat Options Neurol. 2003 Jan. 5(1):69-77. [QxMD MEDLINE Link].
Fu JB, Raj VS, Asher A, Lee J, Guo Y, Konzen BS, et al. Inpatient Rehabilitation Performance of Patients With Paraneoplastic Cerebellar Degeneration. Arch Phys Med Rehabil. 2014 Jul 19. [QxMD MEDLINE Link].
Bataller L, Dalmau J. Paraneoplastic neurologic syndromes: approaches to diagnosis and treatment. Semin Neurol. 2003 Jun. 23(2):215-24. [QxMD MEDLINE Link].
Dalmau JO, Posner JB. Paraneoplastic syndromes. Arch Neurol. 1999 Apr. 56(4):405-8. [QxMD MEDLINE Link].
Darnell RB. The importance of defining the paraneoplastic neurologic disorders. N Engl J Med. 1999 Jun 10. 340(23):1831-3. [QxMD MEDLINE Link].
Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003 Oct 16. 349(16):1543-54. [QxMD MEDLINE Link].
Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004 Aug. 75(8):1135-40. [QxMD MEDLINE Link].
Greenlee JE. Cytotoxic T cells in paraneoplastic cerebellar degeneration. Ann Neurol. 2000 Jan. 47(1):4-5. [QxMD MEDLINE Link].
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. 1992 Feb. 156(2):199-202. [QxMD MEDLINE Link].
Jaeckle KA. Paraneoplastic nervous system syndromes. Curr Opin Oncol. 1996 May. 8(3):204-8. [QxMD MEDLINE Link].
Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004 Nov. 56(5):715-9. [QxMD MEDLINE Link].
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. 2005 Feb. 71(3):231-6. [QxMD MEDLINE Link].
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. 2005 Apr 16-22. 365(9468):1406-11. [QxMD MEDLINE Link].
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. 1997 Aug. 63(2):133-6. [QxMD MEDLINE Link].
Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nature Medicine. 1998 Nov. 4 (11):1321-4. [QxMD MEDLINE Link]. [Full Text].
Venkatraman A., Opal P. Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review. Ann. Clin. Transl. Neurol. 2016. 3(8):655-663. [QxMD MEDLINE Link]. [Full Text].
Fukuda T, Motomura M, Nakao Y, Shiraishi H, Yoshimura T, Iwanaga K, et al. Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome. Annals of Neurology. 25 Nov 2002. 53(1):21-8. [QxMD MEDLINE Link]. [Full Text].
Hadjivassiliou M., Martindale J., Shanmugarajah P., Grünewald R.A., Sarrigiannis P.G., Beauchamp N., et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J. Neurol. Neurosurg. Psychiatry. 2017 Apr. 88 (4):301-309. [QxMD MEDLINE Link]. [Full Text].
Shams'ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003 Jun. 126:1409-18. [QxMD MEDLINE Link]. [Full Text].
Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000 Jan 6. 342:21-7. [QxMD MEDLINE Link]. [Full Text].
Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology. 1992 Oct. 42 (10):1938-43. [QxMD MEDLINE Link]. [Full Text].
Mitoma H, Manto M, Hampe CS. Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges. Curr Neuropharmacol. 2019. 17 (1):33-58. [QxMD MEDLINE Link]. [Full Text].
Dalmau J., Rosenfeld M.R. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008. 7(4):327–340. [QxMD MEDLINE Link]. [Full Text].
Ducray F., Demarquay G., Graus F., Decullier E., Antoine J.C., Giometto B., et al. Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience. Eur. J. Neurol. 2014. 21(5):731-735. [QxMD MEDLINE Link]. [Full Text].
Höftberger R, Rosenfeld MR, Dalmau J. Update on neurological paraneoplastic syndromes. Curr Opin Oncol. 2015 Nov. 27(6):489–495. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

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.

of 2

Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al^[24] )

Table. Antibodies Associated With Paraneoplastic Cerebellar Degeneration* (Adapted from Dalmau et al ^[24])

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.

Back to List

Author

Erika Lan, DO, MA Fellow in Headache Medicine, Department of Neurology, USC Keck Medical Center

Erika Lan, DO, MA is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Abbas Mehdi, MD Director, MDA Center of Central California; Consulting Staff, Department of Neurology, California Neurological Center, Inc

Abbas Mehdi, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Medical Association

Disclosure: Nothing to disclose.

David Y Ko, MD Associate Professor of Clinical Neurology, Loma Linda University School of Medicine

David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society

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 Editor Board

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

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Stephen A Berman, MD, PhD, MBA Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, Phi Beta Kappa

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

Frederick M Vincent, Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners Institute, American College of Legal Medicine, American College of Physicians

Disclosure: Nothing to disclose.

Sections Paraneoplastic Cerebellar Degeneration
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Media Gallery
Tables
References

Paraneoplastic Cerebellar Degeneration Differential Diagnoses

Diagnostic Considerations

Diagnostic criteria

Differential Diagnoses

References

Tables

Contributor Information and Disclosures

What would you like to print?