Paraneoplastic cerebellar disorders

Paraneoplastic cerebellar disorders ROBERTW. BALOH, MD, Los

Angeles, California

Paraneoplastic cerebellar degeneration typically begins with rapidly progressive ataxia of the trunk and extremities. Antineuronal antibodies are found in about half the patients. The most specific autoantibody is an anti-Purkinje cell antibody found in women with gynecologic tumors. Even after the tumor is removed, the cerebellar deficit persists in most patients. (OTOLARYNGOLHEADNECK SURG1995;112:125- 7.]

The remote effects of cancer on the brain were first described at the end of the last century, but case reports were largely anecdotal, and because similar syndromes occur without cancer, many questioned a cause-and-effect relationship. 1 The mechanism by which a tumor can damage the nervous system without directly invading it is still not entirely clear; both viral and autoimmune causes have been suspected. Cancer can have remote effects on the nervous system from the cortex to the peripheral nerves. Just about all tumors have been associated with such effects, but small cell carcinoma of the lung is most common. The characteristic pathologic findings are perivascular cuffing by lymphocytes, activation of microglia with the formation of microglial nodules, and selective loss of neurons. 1'2 The process is predominantly, although not exclusively, confined to gray matter. CLINICAL SYMPTOMS

The clinical symptoms of patients with paraneoplastic cerebellar degeneration are no different from those of other patients with diffuse cerebellar lesions. The trunk and extremities are ataxic, and the speech is usually slurred. The course is subacute, with most patients severely disabled within 6 months From the Department of Neurology,University of California, Los Angeles School of Medicine. Dr. Baloh is supported by grants from the National Institute on Aging (AG09683) and the National Institute on Deafness and Other Communication Disorders (DC01404). Presented at Clinical Applications of Vestibular Science, University of California, Los _Angeles School of Medicine, Los Angeles, CaliL, Feb. 12-13, 1994. Received for publication July 14, 1994; accepted July 15, 1994. Reprint requests: Robert W. Baloh, MD, UCLA Department of Neurology, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA 90024-1769. Copyright © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$3.00 -b 0 23/1/59199

of onset. Often intractable nausea and vomiting occur early. All types of spontaneous nystagmus are seen, but downbeat nystagmus is most common (Table 1). Gaze-evoked and rebound nystagmus are also common. Eye movement recordings document impaired smooth pursuit, optokinetic nystagmus, and fixation-suppression of vestibular nystagmus (Table 1). Saccades may be dysmetric, but peak velocity remains normal. Vestibular responses are normal or hyperactive. A dramatic neuro-ophthalmologic paraneoplastic snydrome is the opsoclonusmyoclonus syndrome.3 This disorder is characterized by chaotic conjugate eye movements in all directions along with myoclonus of the trunk and limbs. It is usually seen in children with neuroblastoma, although it also occurs in adults with paraneoplastic cerebellar degeneration. The opsoclonus is readily identified even by the uninitiated. Conjugate saccades occur continuously in all directions, often with torsional components. Eye movement recordings document that the saccades have normal peak velocities for their amplitude. LABORATORY EVALUATION

Any patient with subacute cerebellar degeneration should be examined carefully for an occult malignancy (Fig. 1). Antineuronal antibodies are identified in approximately 50% of patients with paraneoplastic cerebellar degeneration. 4 The most specific antibody is the anti-Purkinje cell antibody found in women with gynecologic tumors (the socalled anti-Yo antibody in the classification of Furneaux et al.5). With immunohistochemical staining, this antibody binds to the Purkinje cell cytoplasm, producing a characteristic "ring of pearls" on microscopic examination of the cerebellum. It is so specific for gynecologic tumors that surgical exploration of the pelvis is indicated in any woman with the antibody and without an obvious malignancg regardless of the outcome of other diagnostic stud125

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SubacuteCerebellar Degeneration

Q

Physical Examination

)

~i Cancerof breast, rl. ' pelvis,thyroid

I Normal .~fAnti-Ri

I

Antineuronal Antibodies

I-~

1

I

~Mammography ~

Breastr

Anti-Yo '~.~Surgical exploration j " Lof pelvis )

Anti-Hu ~ I None ) , ./ gl ~._~ Smallceil CT Chest ) - i cancerof lung

Cancerof uterus, ovaries,fallopian tube

Normal I

Search forother

typesof cancer

~

Hodgkin'sdisease,

cancerof throat andstomach

~ Normal

I

Regular follow-up

examinations

1

Fig. I. Diagnosisof paraneoplasticcerebellar degeneration.CT,Computed tomography.

ies. 5'6 An antineuronal nuclear antibody (anti-Hu) has been found in a few patients with small cell carcinoma of the lung and cerebellar degeneration, but this antibody is more commonly associated with paraneoplastic peripheral neuropathy. 5 Its role in the pathophysiology of cerebellar degeneration is uncertain, although a recent study showed that the antibody damaged cerebellar granular cells in tissue culture. 7 A subgroup of adults with opsoclonus and cerebellar ataxia (primarily truncal) have an antineuronal nuclear antibody called anti-Ri. 8 Nearly all of these patients have cancer of the breast? Neuroimaging studies in patients with paraneoplastic cerebellar degeneration are usually normal, although occasionally there can be mild cerebellar atrophy. Cerebrospinal fluid examination may show a mild pleocytosis and elevated v-globulin or may be completely normal.

TREATMENT

The first goal is to identify and remove the underlying cancer. Although infrequent, there are a few reports of clinical improvement after resection of the tumor. 1 Most patients reach a "burned out stage" where they remain with a moderate-to-severe cerebellar deficit. We have followed a woman with paraneoplastic c,erebellar degeneration for more than 4 years after a fallopian tube cancer was removed. Exploratory surgery was initiated after antiPurkinje antibodies (anti-Yo) were identified in her serum. Despite complete removal of the tumor and tumor markers returning to normal, her clinical examination has been relatively unchanged. She continues to have severe ataxia of the trunk and extremities, although her severe nausea and vomiting have markedly diminished. Plasmapheresis or immunosuppression are generally not effective,z,4 although there are a few isolated reports of improve-

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Table I. Eye movement abnormalities in five patients with paraneoplastic cerebellar degeneration seen in our clinic Patient no.

Age Antineuronal (yr]/sex antibody

Tumor

Nystagmus

Torsional on lateral and down gaze Downbeat on lateral gaze Downbeat on lateral and down gaze Downbeat on lateral and down gaze Horizontal and vertical gaze-evoked

1

72/F

Yo

Fallopian tube

2 3

65/F 50/F

Yo None

None so far Small cell lung

4*

62/F

Hu

Small cell lung

5

50/M

None

Adenocarcinoma lung

Saccades

Smooth pursuit and OKN slow phases

Vestibulo-ocular reflex

Normal

Mildly impaired

Increased gain

Hypermetric Hypometric

Severely impaired Severely impaired

Increased gain Normal

Hypermetric

Severely impaired

-

Hypermetric

Severely impaired

Normal

OKN, Optokinetic nystagmus. *Bedside examination only.

ment in the cerebellar deficit after plasmapheresis. Unlike cerebellar symptoms and signs, spontaneous remissions are more common with paraneoplastic opsoclonus. In some, the opsoclonus remits after the malignancy is removed. Some have exacerbations after months of remission. Steroids, thiamine, and clonazepam have been reported to improve opsoclonus in some adults with cerebellar degeneration, but many do not respond to any of these medications. 9,1° REFERENCES

1. Henson RA, Urich H. Cancer and the nervous system. In: Henson RA, Urich H, eds. The neurological manifestations of systemic malignant disease. Oxford: Blackwell Scientific, 1982:311-621. 2. Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: clinical-immunological correlations. Ann Neurol 1988;24:55%67. 3. Dropcho E, Payne R. Paraneoplastic opsoclonus-myoclonus. Association with medullary thyroid carcinoma and review of the literature. Arch Neurol 1986;43:410-5.

4. Hammack JE, Kimmel DW, O'Neill BP, Lennon VA. Paraneoplastic cerebellar degeneration: a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc 1990;65:1423-31. 5. Furneaux HM, Rosenblum MK, Dalman J, et al. Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med 1990;322:1844-51. 6. Hetzel D J, Stanhope CR, O'Neill BP, Lennon VA. Gynecologic cancer in patients with subacute eerebellar degeneration predicted by anti-Purkinje cell antibodies and limited in metastatic volume. Mayo Clin Proc 1990;65:1558-63. 7. Greenlee JE, Parks TN, Jaeckle KA. Type IIa ("anti-Hu") antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro. Neurology 1993;43:2049-54. 8. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-51. 9. Nausieda PA, Tanner CM, Weiner WJ. Opsoclonic cerebellopathy: a paraneoplastic syndrome responsive to thiamine. Arch Neurol 1981;38:780-1. 10. Leigh RJ, Zee DS. The neurology of eye movements. Philadelphia: FA Davis Co., 1983.