1291
Paraneoplastic Encephalomyelitis Dramatic Response to Chemotherapy Alone Oliver A. Batson, MD, David M . Fantle, MD, and James A. Stewart, M D
Neurologic paraneoplastic syndromes are usually a debilitating and untreatable manifestationof malignancy.The case is presented of a woman with severe paraneoplastic encephalomyelitis that was characterized predominantly by cerebellar degeneration associated with small cell lung cancer, both of which respondedrapidly to cytotoxic chemotherapy alone. She is alive with some neurologic residua but no signs of recurrent cancer more than 2 years after diagnosis. Recommendations for aggressive management of this rare but disabling syndrome are outlined. Cancer 1992: 691291-1293. Neurologic paraneoplastic syndromes can be challenging diagnostically and therapeutically. Unfortunately, therapy for these syndromes usually is unsuccessful even in the presence of a tumor response.',' We report a case of severe encephalomyelitis and cerebellar degeneration in a patient with limited-stage small cell lung cancer, both of which responded dramatically to cytotoxic chemotherapy.
Case Report A 66-year-old white female smoker, who was an occasional alcohol drinker, had a sensation of pressure over the forehead 2 months before admission to the Medical Center Hospital of Vermont. After 1 month, the headache became left frontal and was associated with nausea, vomiting, and occasionaldiplopia. She also had progressive ataxia and was referred to a neurologist. Computed tomography (CT) of the head was interpreted as normal. The clinical impression was that of a brainstem infarction, and she was treated with aspirin, diazepam, and nifedipine. Her symptoms progressively worsened, and she presented to an emergency room the next week. Chest radiography showed a right hilar mass. A contrast-enhanced head CT was done and read as normal.
From the Vermont Regional Cancer Center, University of Vermont, Burlington, Vermont. Address for reprints: James A. Stewart, MD, Vermont Regional Cancer Center, 1 South Prospect Street, Burlington, VT 05401. Accepted for publication May 31, 1991.
At the time of transfer to the Medical Center Hospital of Vermont, her headaches were improving, but she had severe motion-induced nausea and vomiting, with vertigo. No pulmonary or other constitutional symptoms were reported. Physical examination revealed no adenopathy, skin lesions, or abnormalities of the respiratory, cardiac, gastrointestinal, or genitourinary systems. On initial neurologic examination, she had slurred, dysarthric speech. Eye movements were conjugate, and visual fields were full. Optic fundi were normal. There was a coarse, horizontal, gaze-evoked nystagmus to the left greater than the right. There was mild spasticity of both legs. Power was graded 5/5 diffusely. There was no spontaneous tremor, but there was dysmetria with intention tremor on finger-to-nose testing; this was more pronounced on the left, as was ataxia on the heel-to-shin maneuver. Rapid fine movements also were slowed, more on the left. There was mild hypesthesia to pinprick on the left arm and leg. Reflexes were pathologically brisk throughout, with clonus at both ankles. Bilateral palmomental reflexes were present, along with snout and a brisk jaw jerk. Plantar response was flexor on the left and equivocal on the right. Blood chemistries were normal including serum sodium, creatinine, calcium, and liver enzymes. Repeat CT scan of the head was normal as was a magnetic resonance imaging (MRI) scan of the brain. Examination of the cerebrospinal fluid (CSF) showed 48 leukocytes per high-power field, all of which were lymphocytes; 2 erythrocytes per high-power field; protein, 71 mg/dl; glucose, 59 mg/dl; and immunoglobulin G, 14%. Testing for anti-Purkinje cell or anti-Hu antibodies was not done. Abnormalities of the right middle lobe mucosa were found with bronchoscopy, but aspirates, washings, and biopsies were negative for tumor. A CT-guidedpercutaneous fine-needle aspiration of the hilar mass was negative. Repeat bronchoscopy with transbronchial needle aspirates showed small cell lung carcinoma. Staging included a negative bone marrow biopsy and negative upper abdominal CT scan. During this evaluation, she had progressive neurologic deterioration despite empiric high-dose dexamethasone therapy initiated 7 days before chemotherapy. By the day of initial antineoplastic therapy, she was bed-ridden, profoundly disoriented, and somnolent. She was treated with cyclophosphamide 1000 mg/m2 and doxorubicin 40 mg/m2. Within 3 days, she had significant improvement in her mental status with decreasing dysarthria. After 5 days, her diplopia had
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CANCER March 1,1992, Volume 69,No. 5
resolved, frontal release signs had disappeared, and the degree of hyperreflexia had improved, with clearly flexor plantar reflexes found bilaterally. By 7 days, she was able to eat and stand with assistance and was discharged home shortly thereafter. She received a total of six cycles of chemotherapy with continued neurologic recovery and complete resolution of the right hilar mass. Addition of low-dose (1mg) vincristine during two of the cycles caused transient but significantdeterioration of her neurologic status with worsening gait and weakness. Follow-up brain imaging after five cycles showed greater prominence of the cerebellar folia, indicating atrophy. After chemotherapy, she received radiation therapy to the chest only. There is no sign of recurrent tumor 24 months after initiation of chemotherapy, and serum and CSF antineuronal antibodies were not detectable at 22 months (Nichols, San Juan Capistrano, CA). She is neurologically stable, with power graded as 5/5 diffusely, but with a persistent wide-based gait.
Comment
Encephalomyelitis associated with malignancy that has not metastasized to the brain has been well de~cribed.~ The - ~ specific clinical syndromes are varied, depending on the predominant site of pathologic involvement. Our patient had signs of diffuse cerebral dysfunction, but her presentation was dominated by the cerebellar signs of vertigo, ataxia, diplopia, and nystagmus. Paraneoplastic encephalomyelitisand cerebellar degeneration have been associated with numerous malignancies, but carcinomas of the lung, ovary, and breast account for most cases.6Until recently, the antemortem diagnosis of neurologic paraneoplastic syndrome was one of exclusion, requiring a careful search for central nervous system vasculopathies, metastases, infections, toxins, trauma, and primary neurologic disorders, such as multiple sclerosis. Before the availability of CT and MRI technology, only a pathologist could make the diagnosis with certainty. The pathologic findings in paraneoplastic encephalomyelitis of nerve cell loss and occasional perivascular mononuclear inflammation led to a search for immune mediators of these disorders.Anti-Purkinje cell antibodies were described fist by Trotter ef aL7 in 1976, and subsequent authors found similar antibodies in both the circulation and CSF of approximately 50% of patients with cerebellar degeneration.'T6-" Several types of antibodies have been described, including the typical anti-Purkinjecell cytoplasmic antibody in patients with ovarian and breast cancer and classic cerebellar degenerat"n.'r6-'' By contrast, the antineuronal nucleoprotein antibody, anti-Hu, is found in patients with small cell lung cancer who have more varied clinical syndromes such as subacute sensory neuronopathy, limbic
encephalitis, and cerebellar degenerati~n.~.~ These antibodies are found rarely in appropriate control populations, such as normal individuals, neurologically normal cancer patients, and neurologic patients without ~ancer,~,~," but whether the antibodies cause the syndrome or are an epiphenomenon currently is unknown. The target antigens for these antibodies are being characterized and, in some instances, share homology with tumor antigens, suggesting a possible pathogenetic role for the antibodie~.'~,'~ Such antibody detection is the only potentially diagnostic test for neurologic paraneoplastic syndromes; their demonstration in the absence of other possible causes mandates scrutiny for occult malignancy. Neurologic paraneoplastic syndromes are often the most debilitating aspect of a patient's disease process and are typically resistant to therapy despite their association with relatively responsive turn or^.',^*^,^," In the past 10 years, only a few cases of paraneoplastic cerebellar degeneration that responded even moderately to antineoplastic therapy have been rep~rted.~,*,",'~-'~ Most such cases did not improve, even after a good tumor response. Surgery alone or various combinations of surgery, radiation therapy, chemotherapy, and plasmapheresis were used for treatment; only one partial neurologic response was seen after chemotherapy alone.l1 Spontaneous remissions of these syndromes have been reported," but the prompt response of our patient's signs and symptoms is compelling evidence for a chemotherapeuticeffect. Our patient thereforerepresents, not only one of the fist, but also one of the most dramatic responses to chemotherapy alone of paraneoplastic encephalomyelitis dominated by cerebellar degeneration. We recommend that patients with cerebellar degeneration related to small cell lung cancer be considered for aggressive chemotherapy and that vincristine or other potentially neurotoxic drugs not be included in the regimen used. References 1. JaeckleKA, Graus F, Houghton A, Cardon-Cardo C, Nielsen SL, Posner JB. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol 1985; 18:592-600. 2. Markman M. Response of paraneoplastic syndromes to antineoplastic therapy. West Med 1986; 144:580-585. 3. Corsellis JAN, Goldberg GJ, Norton AR. "Limbic encephalitis" and its association with carcinoma of the brain. Bruin 1968; 91:481-496. 4. Dorfman LJ, Fomo LS. Paraneoplastic encephalomyelitis. Acfu Neurol Scand 1972; 48:556-574. 5. Henson FL4, Hoffman HL, Urich H. Encephalomyelitiswith carcinoma. Bruin 1965; 88:449-464. 6. Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: Clinical-immunological correlations. Ann Neurol 1988; 24:559-567.
Paraneoplastic Encephalomyelitis/Batson et al. 7. Trotter JL, Hendin BA, Osterland K. Cerebellar degeneration with Hodglun’s disease: An immunological study. Arch Neurol 1976; 33~660-661. 8. Tsukamato T, Yoshie 0, Tada K, Iwasaki U. Anti-Purkinje cell antibody producing B-cell lines from a patient with paraneoplastic cerebellar degeneration. Arch Neurol 1987; 111:833-837. 9. Anderson NE, Rosenblum MK, Graus F, Wiley RG, Posner JB. Autoantibodies in paraneoplastic syndromes associated with small cell lung cancer. Neurology 1988; 38:1391-1398. 10. Greenlee JE, Lipton HL. Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration. Ann Neurol 1986; 19:82-85. 11. Hammock JE, Kimmel DW, ONeill BP, Lennon VA. Paraneoplastic cerebellar degeneration: A clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc 1990; 65:1423-1431. 12. Dropcho EJ, Chen Y-T, Posner JB, Old LJ. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc Nutl Acad Sci U S A 1987; 84~4552-4556.
1293 13. Furneaux HM, Rosenblum M, Wong E, Woodruff P, Posner J. Selective expression of Purkinje neuron antigens in ovarian and breast tumors of patients with paraneoplastic cerebellar degeneration (Abstr). Neurology 1989; (Suppl 1) 39:260. 14. Paone JF, Jeyasingham K. Remission of cerebellar dysfunction after pneumonectomy for bronchogenic carcinoma. N Engl j Med 1980; 302156. 15. Kearsley JH, Johnson P, Halmagyi GM. Paraneoplastic cerebellar disease: Remission with excision of the primary tumor. Arch Neurol 1985; 42:1208-1210. 16. Greenlee JE, Brashear HR, Rodnitzky RL, Corbett JJ, Digre KB. Fall in antineuronal antibody titers and improvement of neurologic deficit following tumor removal in paraneoplastic cerebellar degeneration (Abstr). Neurology 1986; (Suppl) 36:334. 17. Royal W, Galasko DR, McKhann GM, Cunningham JM, Dropcho EJ. Clinical course, immunologic, and biochemical features of a patient with paraneoplastic cerebellar dysfunction (Abstr). Neurology 1987; (Suppl) 37305-306. 18. Auch TL, Chodoff P. Transient cerebellar syndrome from extracerebral carcinoma. Neurology 1957; 7370-372.
Paraneoplastic Encephalomyelitis Dramatic Response to Chemotherapy Alone Oliver A. Batson, MD, David M . Fantle, MD, and James A. Stewart, M D
Neurologic paraneoplastic syndromes are usually a debilitating and untreatable manifestationof malignancy.The case is presented of a woman with severe paraneoplastic encephalomyelitis that was characterized predominantly by cerebellar degeneration associated with small cell lung cancer, both of which respondedrapidly to cytotoxic chemotherapy alone. She is alive with some neurologic residua but no signs of recurrent cancer more than 2 years after diagnosis. Recommendations for aggressive management of this rare but disabling syndrome are outlined. Cancer 1992: 691291-1293. Neurologic paraneoplastic syndromes can be challenging diagnostically and therapeutically. Unfortunately, therapy for these syndromes usually is unsuccessful even in the presence of a tumor response.',' We report a case of severe encephalomyelitis and cerebellar degeneration in a patient with limited-stage small cell lung cancer, both of which responded dramatically to cytotoxic chemotherapy.
Case Report A 66-year-old white female smoker, who was an occasional alcohol drinker, had a sensation of pressure over the forehead 2 months before admission to the Medical Center Hospital of Vermont. After 1 month, the headache became left frontal and was associated with nausea, vomiting, and occasionaldiplopia. She also had progressive ataxia and was referred to a neurologist. Computed tomography (CT) of the head was interpreted as normal. The clinical impression was that of a brainstem infarction, and she was treated with aspirin, diazepam, and nifedipine. Her symptoms progressively worsened, and she presented to an emergency room the next week. Chest radiography showed a right hilar mass. A contrast-enhanced head CT was done and read as normal.
From the Vermont Regional Cancer Center, University of Vermont, Burlington, Vermont. Address for reprints: James A. Stewart, MD, Vermont Regional Cancer Center, 1 South Prospect Street, Burlington, VT 05401. Accepted for publication May 31, 1991.
At the time of transfer to the Medical Center Hospital of Vermont, her headaches were improving, but she had severe motion-induced nausea and vomiting, with vertigo. No pulmonary or other constitutional symptoms were reported. Physical examination revealed no adenopathy, skin lesions, or abnormalities of the respiratory, cardiac, gastrointestinal, or genitourinary systems. On initial neurologic examination, she had slurred, dysarthric speech. Eye movements were conjugate, and visual fields were full. Optic fundi were normal. There was a coarse, horizontal, gaze-evoked nystagmus to the left greater than the right. There was mild spasticity of both legs. Power was graded 5/5 diffusely. There was no spontaneous tremor, but there was dysmetria with intention tremor on finger-to-nose testing; this was more pronounced on the left, as was ataxia on the heel-to-shin maneuver. Rapid fine movements also were slowed, more on the left. There was mild hypesthesia to pinprick on the left arm and leg. Reflexes were pathologically brisk throughout, with clonus at both ankles. Bilateral palmomental reflexes were present, along with snout and a brisk jaw jerk. Plantar response was flexor on the left and equivocal on the right. Blood chemistries were normal including serum sodium, creatinine, calcium, and liver enzymes. Repeat CT scan of the head was normal as was a magnetic resonance imaging (MRI) scan of the brain. Examination of the cerebrospinal fluid (CSF) showed 48 leukocytes per high-power field, all of which were lymphocytes; 2 erythrocytes per high-power field; protein, 71 mg/dl; glucose, 59 mg/dl; and immunoglobulin G, 14%. Testing for anti-Purkinje cell or anti-Hu antibodies was not done. Abnormalities of the right middle lobe mucosa were found with bronchoscopy, but aspirates, washings, and biopsies were negative for tumor. A CT-guidedpercutaneous fine-needle aspiration of the hilar mass was negative. Repeat bronchoscopy with transbronchial needle aspirates showed small cell lung carcinoma. Staging included a negative bone marrow biopsy and negative upper abdominal CT scan. During this evaluation, she had progressive neurologic deterioration despite empiric high-dose dexamethasone therapy initiated 7 days before chemotherapy. By the day of initial antineoplastic therapy, she was bed-ridden, profoundly disoriented, and somnolent. She was treated with cyclophosphamide 1000 mg/m2 and doxorubicin 40 mg/m2. Within 3 days, she had significant improvement in her mental status with decreasing dysarthria. After 5 days, her diplopia had
1292
CANCER March 1,1992, Volume 69,No. 5
resolved, frontal release signs had disappeared, and the degree of hyperreflexia had improved, with clearly flexor plantar reflexes found bilaterally. By 7 days, she was able to eat and stand with assistance and was discharged home shortly thereafter. She received a total of six cycles of chemotherapy with continued neurologic recovery and complete resolution of the right hilar mass. Addition of low-dose (1mg) vincristine during two of the cycles caused transient but significantdeterioration of her neurologic status with worsening gait and weakness. Follow-up brain imaging after five cycles showed greater prominence of the cerebellar folia, indicating atrophy. After chemotherapy, she received radiation therapy to the chest only. There is no sign of recurrent tumor 24 months after initiation of chemotherapy, and serum and CSF antineuronal antibodies were not detectable at 22 months (Nichols, San Juan Capistrano, CA). She is neurologically stable, with power graded as 5/5 diffusely, but with a persistent wide-based gait.
Comment
Encephalomyelitis associated with malignancy that has not metastasized to the brain has been well de~cribed.~ The - ~ specific clinical syndromes are varied, depending on the predominant site of pathologic involvement. Our patient had signs of diffuse cerebral dysfunction, but her presentation was dominated by the cerebellar signs of vertigo, ataxia, diplopia, and nystagmus. Paraneoplastic encephalomyelitisand cerebellar degeneration have been associated with numerous malignancies, but carcinomas of the lung, ovary, and breast account for most cases.6Until recently, the antemortem diagnosis of neurologic paraneoplastic syndrome was one of exclusion, requiring a careful search for central nervous system vasculopathies, metastases, infections, toxins, trauma, and primary neurologic disorders, such as multiple sclerosis. Before the availability of CT and MRI technology, only a pathologist could make the diagnosis with certainty. The pathologic findings in paraneoplastic encephalomyelitis of nerve cell loss and occasional perivascular mononuclear inflammation led to a search for immune mediators of these disorders.Anti-Purkinje cell antibodies were described fist by Trotter ef aL7 in 1976, and subsequent authors found similar antibodies in both the circulation and CSF of approximately 50% of patients with cerebellar degeneration.'T6-" Several types of antibodies have been described, including the typical anti-Purkinjecell cytoplasmic antibody in patients with ovarian and breast cancer and classic cerebellar degenerat"n.'r6-'' By contrast, the antineuronal nucleoprotein antibody, anti-Hu, is found in patients with small cell lung cancer who have more varied clinical syndromes such as subacute sensory neuronopathy, limbic
encephalitis, and cerebellar degenerati~n.~.~ These antibodies are found rarely in appropriate control populations, such as normal individuals, neurologically normal cancer patients, and neurologic patients without ~ancer,~,~," but whether the antibodies cause the syndrome or are an epiphenomenon currently is unknown. The target antigens for these antibodies are being characterized and, in some instances, share homology with tumor antigens, suggesting a possible pathogenetic role for the antibodie~.'~,'~ Such antibody detection is the only potentially diagnostic test for neurologic paraneoplastic syndromes; their demonstration in the absence of other possible causes mandates scrutiny for occult malignancy. Neurologic paraneoplastic syndromes are often the most debilitating aspect of a patient's disease process and are typically resistant to therapy despite their association with relatively responsive turn or^.',^*^,^," In the past 10 years, only a few cases of paraneoplastic cerebellar degeneration that responded even moderately to antineoplastic therapy have been rep~rted.~,*,",'~-'~ Most such cases did not improve, even after a good tumor response. Surgery alone or various combinations of surgery, radiation therapy, chemotherapy, and plasmapheresis were used for treatment; only one partial neurologic response was seen after chemotherapy alone.l1 Spontaneous remissions of these syndromes have been reported," but the prompt response of our patient's signs and symptoms is compelling evidence for a chemotherapeuticeffect. Our patient thereforerepresents, not only one of the fist, but also one of the most dramatic responses to chemotherapy alone of paraneoplastic encephalomyelitis dominated by cerebellar degeneration. We recommend that patients with cerebellar degeneration related to small cell lung cancer be considered for aggressive chemotherapy and that vincristine or other potentially neurotoxic drugs not be included in the regimen used. References 1. JaeckleKA, Graus F, Houghton A, Cardon-Cardo C, Nielsen SL, Posner JB. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol 1985; 18:592-600. 2. Markman M. Response of paraneoplastic syndromes to antineoplastic therapy. West Med 1986; 144:580-585. 3. Corsellis JAN, Goldberg GJ, Norton AR. "Limbic encephalitis" and its association with carcinoma of the brain. Bruin 1968; 91:481-496. 4. Dorfman LJ, Fomo LS. Paraneoplastic encephalomyelitis. Acfu Neurol Scand 1972; 48:556-574. 5. Henson FL4, Hoffman HL, Urich H. Encephalomyelitiswith carcinoma. Bruin 1965; 88:449-464. 6. Anderson NE, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: Clinical-immunological correlations. Ann Neurol 1988; 24:559-567.
Paraneoplastic Encephalomyelitis/Batson et al. 7. Trotter JL, Hendin BA, Osterland K. Cerebellar degeneration with Hodglun’s disease: An immunological study. Arch Neurol 1976; 33~660-661. 8. Tsukamato T, Yoshie 0, Tada K, Iwasaki U. Anti-Purkinje cell antibody producing B-cell lines from a patient with paraneoplastic cerebellar degeneration. Arch Neurol 1987; 111:833-837. 9. Anderson NE, Rosenblum MK, Graus F, Wiley RG, Posner JB. Autoantibodies in paraneoplastic syndromes associated with small cell lung cancer. Neurology 1988; 38:1391-1398. 10. Greenlee JE, Lipton HL. Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration. Ann Neurol 1986; 19:82-85. 11. Hammock JE, Kimmel DW, ONeill BP, Lennon VA. Paraneoplastic cerebellar degeneration: A clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc 1990; 65:1423-1431. 12. Dropcho EJ, Chen Y-T, Posner JB, Old LJ. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc Nutl Acad Sci U S A 1987; 84~4552-4556.
1293 13. Furneaux HM, Rosenblum M, Wong E, Woodruff P, Posner J. Selective expression of Purkinje neuron antigens in ovarian and breast tumors of patients with paraneoplastic cerebellar degeneration (Abstr). Neurology 1989; (Suppl 1) 39:260. 14. Paone JF, Jeyasingham K. Remission of cerebellar dysfunction after pneumonectomy for bronchogenic carcinoma. N Engl j Med 1980; 302156. 15. Kearsley JH, Johnson P, Halmagyi GM. Paraneoplastic cerebellar disease: Remission with excision of the primary tumor. Arch Neurol 1985; 42:1208-1210. 16. Greenlee JE, Brashear HR, Rodnitzky RL, Corbett JJ, Digre KB. Fall in antineuronal antibody titers and improvement of neurologic deficit following tumor removal in paraneoplastic cerebellar degeneration (Abstr). Neurology 1986; (Suppl) 36:334. 17. Royal W, Galasko DR, McKhann GM, Cunningham JM, Dropcho EJ. Clinical course, immunologic, and biochemical features of a patient with paraneoplastic cerebellar dysfunction (Abstr). Neurology 1987; (Suppl) 37305-306. 18. Auch TL, Chodoff P. Transient cerebellar syndrome from extracerebral carcinoma. Neurology 1957; 7370-372.
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