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doi:10.1111/jog.12331
J. Obstet. Gynaecol. Res. Vol. 40, No. 5: 1463–1465, May 2014
Paraneoplastic cerebellar degeneration as the first evidence of malignancy: A case report V. Aruna Kumari1, Prerna Gupta1, M. V. Padma Srivastava2, Lalit Kumar3, Alka Kriplani1 and Neerja Bhatla1 Departments of 1Obstetrics and Gynecology, 2Neurology and 3Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
Abstract Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated paraneoplastic disorder affecting the cerebellum. PCD associated with ovarian malignancy is a rare occurrence with fewer than 100 cases reported in published work. PCD patients express anti-Yo antibody, one of the anti-onconeuronal antibodies which is most likely associated with gynecologic or breast malignancies. In this report, we present the case of a 65-year-old postmenopausal woman presenting with acute symptoms of PCD as a first sign of ovarian malignancy. Key words: anti-Yo antibody, carcinoma ovary, paraneoplastic cerebellar degeneration.
Introduction Paraneoplastic neurological syndromes (PNS) are disorders associated with malignancy but not caused by direct tumor infiltration. They can affect neurons in multifocal encephalomyelitis-like pattern or they can present as involvement of a single system, like paraneoplastic cerebellar degeneration (PCD).1 The diagnosis of cancer can precede or follow the PNS, and in a few cases the primary is not found even at autopsy.2 In approximately two-thirds of female patients aged 50 years or more, subacute cerebellar degeneration is paraneoplastic in origin. PNS usually occurs in patients with cancer of the breast, ovary, endometrium or fallopian tube, small cell lung cancer and, rarely, Hodgkin’s disease. PCD patients express anti-Yo antibody, one of the anti-onconeuronal antibodies which is most likely associated with gynecologic or breast malignancies. We present a case of a 65-year-old postmenopausal lady presenting with
acute symptoms of PCD as the first sign of ovarian malignancy.
Case Report A 65-year-old nulliparous lady presented to our outpatient department with complaints of dizziness, nausea and weakness of 3 months’ duration. Two months later, she had sudden onset of slurring of speech, which gradually worsened, and over a period of 1 month, she also developed gait disturbances, involuntary head movements and inability to walk without support. She had lost 8 kg of weight over 3 months. On examination, she was alert and oriented. Her general physical examination including breast examination was normal. Neurological examination showed bilateral gaze-evoked nystagmus, severe dysarthria, truncal ataxia, titubation and dysdiadochokinesia. Coordination was significantly impaired, but there were no sensory deficits. Magnetic resonance imaging (MRI) of
Received: September 26 2013. Accepted: October 18 2013. Reprint request to: Dr Neerja Bhatla, Department of Obstetrics and Gynaecology, Room 3101, 3rd floor, Teaching Block, All India Institute of Medical Sciences, New Delhi 110029, India. Email: [email protected]; [email protected] Conflict of interest: There is no financial interest in the information contained in the manuscript by any of the authors.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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V. A. Kumari et al.
the brain and cerebrospinal fluid (CSF) examination did not reveal any abnormality. This raised a suspicion of paraneoplastic subacute degeneration and she was evaluated for a primary lesion. Meanwhile she received i.v. immunoglobulins (Ig; 2 g/kg bodyweight over 5 days), followed by oral steroids (prednisolone 60 mg/day). Her initial serum tumor markers were in the normal range (cancer antigen [CA]-125, 10.5 IU/L; CA-19.9, 43.3 IU/L). Although pelvic ultrasound was normal, whole-body positron emission tomography (PET) computed tomography (CT) revealed abnormal 18F-fluorodeoxyglucose (FDG) uptake in the right adnexal region leading to suspicion of ovarian cancer (Fig. 1). Pelvic MRI confirmed the presence of a small solid mass in the right ovary measuring 2 cm × 1.6 cm with significant post-contrast enhancement and diffusion restriction suggestive of possible malignancy. As PCD was suspected, antineuronal antibodies were estimated including anti-Yo, anti-Hu, anti-Ri, anti-amphiphysin and anti-PNM2 antibody. Anti-Yo antibody was positive in high titers (1:640), which is specific for gynecologic and breast malignancy. With mammography being normal, she was assumed to have PCD with gynecologic cancer and was taken up for exploratory laparotomy. Intraoperatively, there was no ascites. Peritoneal washings were taken for cytology. The uterus was atrophic; the left ovary was of normal size. The right ovary had a cyst of approximately 1 cm in diameter with papillary growths and the right fallopian tube had surface excrescence of approximately 1 cm diameter. There was a small 3-mm deposit on the uterus below the left round ligament. Total abdominal hysterectomy with bilateral salpingo-
Figure 1 (a) Axial computed tomography (CT) demonstrates 2 cm × 1.6 cm lesional mass involving the right ovary. (b) Corresponding positron emission tomography (PET) shows increased tracer uptake in the right ovarian lesion. No other hypermetabolic lesion was seen on PET-CT images.
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oophorectomy and infracolic omentectomy was performed. Histopathology showed serous cystadenocarcinoma of the right ovary with breach in capsule, fallopian tube and unremarkable endometrium, and stage IIC ovarian malignancy was diagnosed. Her postoperative recovery has been unremarkable. The patient has received three cycles of chemotherapy with paclitaxel and carboplatin. Ultrasound performed 3 months post-surgery showed no residual disease. However, there has been no improvement in her neurological symptoms.
Discussion Paraneoplastic cerebellar degeneration is an immunemediated paraneoplastic disorder affecting the cerebellum. It is identified when the patient develops severe cerebellar signs and symptoms over less than 12 weeks, while MRI shows no evidence of cerebellar atrophy. PCD associated with ovarian malignancy is a rare occurrence with less than 100 cases reported in the published work. It is due to the remote effect of malignancy on the nervous system leading to various neurological features like dysarthria, ataxia, gait disturbances, diplopia, nystagmus and titubation. The ovarian malignancy was suspected based on acute presentation of the patient and the presence of anti-Yo antibodies. Anti-Yo antibodies are specific antineuronal antibodies which are identified in the sera of up to 70% of the patients with malignancy causing PCD, usually ovarian and breast carcinoma.3 Onconeuronal antibodies like anti-Hu, anti-Ri and anti-CV2 antibodies are found in small cell carcinoma of the lung whereas anti-Yo antibody is usually associated with ovarian or breast malignancies. Anti-Yo antibody is a polyclonal IgG antibody that crosses the blood–brain barrier and reacts with a cytoplasmic component of cerebellar Purkinje cells.4 In almost 80% of cases, the underlying malignancy can be identified.5 Hence, in a patient with anti-Yo antibody and cerebellar symptoms, ovarian malignancy should be specifically looked for and excluded. Thorough investigation including CSF examination and serum tumor markers should be performed in a patient with PCD. Also, whole-body imaging including CT scan and MRI can be done to detect the primary tumor. If no positive findings are seen, recent studies have shown that whole-body FDG-PET has improved the diagnostic rate, as in our case, in which clinical examination as well as ultrasound missed the diagnosis, neither did she have any gynecologic complaints.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Paraneoplastic cerebellar degeneration
PET scan can identify a lesion as small as 1 cm. In patients with paraneoplastic syndromes, the sensitivity of PET scanning to detect malignancies has been estimated to be 83.3% and the specificity 25%. Positive and negative predictive values were 83.3% and 25%, respectively.6 Treatment options are limited: there is no definitive treatment for cerebellar symptoms. Removal of the tumor with specific chemotherapy is recommended, but it only prevents disease progression and does not usually reverse the neurological damage already done. Immunotherapy and steroids have been tried, but the effects seem to be limited. More recent studies report initial encouraging results with rituximab in patients with anti-Yo- or anti-Hu-positive PCD.7 The 5-year survival in PCD patients is devastating. Shams’ili et al. reported that the 5-year survival rate of 19 PCD patients with anti-Yo antibody was less than 25%, with the median survival time from diagnosis being 13 months.5 Rojas et al. reported that approximately half of PCD patients die from their cancer, while the rest die because of neurological progression.8 As the prognosis of PCD patients is very poor, the decision of whether to undergo radical surgery or not has to be made by the treating physician and family, because neurological recovery is not confirmatory even after such radical procedures. Perlmutter et al. reported a PCD patient who showed functional improvement after 3 weeks of comprehensive inpatient rehabilitation.9 Counseling and rehabilitation are very important in these patients. In conclusion, patients with paraneoplastic syndromes should have an aggressive search performed
for underlying malignancy. The anti-Yo antibody is a very important marker in the absence of specific gynecologic complaints. The prognosis is grim but with emerging treatment modalities and good rehabilitation there may be improvement in the future.
References 1. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet 2008; 7: 327–340. 2. Lachance DH, Lennon VA. Paraneoplastic neurological autoimmunity. In: Kalman B, Brannagan TH 3rd (eds). NeuroImmunology in Clinical Practice. Oxford: Blackwell Publishing, 2008; 210–217. 3. Posner JB. Paraneoplastic syndromes. In: DeAngelis LM, Posner JB (ed.). Neurologic Complications of Cancer. Philadelphia, PA: Oxford University Press Inc, 1995; 353–385. 4. Levite R, Fishman A. Paraneoplastic cerebellar degeneration heralding fallopian tube adenocarcinoma. Int J Gynecol Cancer 2001; 11: 169–171. 5. Shams’ili S, Grefkens J, de Leeuw B et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: Analysis of 50 patients. Brain 2003; 126: 1409–1418. 6. Younes-Mhenni S, Janier MF, Cinotti L et al. FDG-PET improves tumor detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127: 2331–2338. 7. Shams’ili S, de Beukelaar J, Gratama JW et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253: 16–20. 8. Rojas I, Graus F, Keime-Guibert F et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55: 713– 715. 9. Perlmutter E, Gregory PC. Rehabilitation treatment options for a patient with paraneoplastic cerebellar degeneration. Am J Phys Med Rehabil 2003; 82: 158–162.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1465
doi:10.1111/jog.12331
J. Obstet. Gynaecol. Res. Vol. 40, No. 5: 1463–1465, May 2014
Paraneoplastic cerebellar degeneration as the first evidence of malignancy: A case report V. Aruna Kumari1, Prerna Gupta1, M. V. Padma Srivastava2, Lalit Kumar3, Alka Kriplani1 and Neerja Bhatla1 Departments of 1Obstetrics and Gynecology, 2Neurology and 3Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
Abstract Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated paraneoplastic disorder affecting the cerebellum. PCD associated with ovarian malignancy is a rare occurrence with fewer than 100 cases reported in published work. PCD patients express anti-Yo antibody, one of the anti-onconeuronal antibodies which is most likely associated with gynecologic or breast malignancies. In this report, we present the case of a 65-year-old postmenopausal woman presenting with acute symptoms of PCD as a first sign of ovarian malignancy. Key words: anti-Yo antibody, carcinoma ovary, paraneoplastic cerebellar degeneration.
Introduction Paraneoplastic neurological syndromes (PNS) are disorders associated with malignancy but not caused by direct tumor infiltration. They can affect neurons in multifocal encephalomyelitis-like pattern or they can present as involvement of a single system, like paraneoplastic cerebellar degeneration (PCD).1 The diagnosis of cancer can precede or follow the PNS, and in a few cases the primary is not found even at autopsy.2 In approximately two-thirds of female patients aged 50 years or more, subacute cerebellar degeneration is paraneoplastic in origin. PNS usually occurs in patients with cancer of the breast, ovary, endometrium or fallopian tube, small cell lung cancer and, rarely, Hodgkin’s disease. PCD patients express anti-Yo antibody, one of the anti-onconeuronal antibodies which is most likely associated with gynecologic or breast malignancies. We present a case of a 65-year-old postmenopausal lady presenting with
acute symptoms of PCD as the first sign of ovarian malignancy.
Case Report A 65-year-old nulliparous lady presented to our outpatient department with complaints of dizziness, nausea and weakness of 3 months’ duration. Two months later, she had sudden onset of slurring of speech, which gradually worsened, and over a period of 1 month, she also developed gait disturbances, involuntary head movements and inability to walk without support. She had lost 8 kg of weight over 3 months. On examination, she was alert and oriented. Her general physical examination including breast examination was normal. Neurological examination showed bilateral gaze-evoked nystagmus, severe dysarthria, truncal ataxia, titubation and dysdiadochokinesia. Coordination was significantly impaired, but there were no sensory deficits. Magnetic resonance imaging (MRI) of
Received: September 26 2013. Accepted: October 18 2013. Reprint request to: Dr Neerja Bhatla, Department of Obstetrics and Gynaecology, Room 3101, 3rd floor, Teaching Block, All India Institute of Medical Sciences, New Delhi 110029, India. Email: [email protected]; [email protected] Conflict of interest: There is no financial interest in the information contained in the manuscript by any of the authors.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1463
V. A. Kumari et al.
the brain and cerebrospinal fluid (CSF) examination did not reveal any abnormality. This raised a suspicion of paraneoplastic subacute degeneration and she was evaluated for a primary lesion. Meanwhile she received i.v. immunoglobulins (Ig; 2 g/kg bodyweight over 5 days), followed by oral steroids (prednisolone 60 mg/day). Her initial serum tumor markers were in the normal range (cancer antigen [CA]-125, 10.5 IU/L; CA-19.9, 43.3 IU/L). Although pelvic ultrasound was normal, whole-body positron emission tomography (PET) computed tomography (CT) revealed abnormal 18F-fluorodeoxyglucose (FDG) uptake in the right adnexal region leading to suspicion of ovarian cancer (Fig. 1). Pelvic MRI confirmed the presence of a small solid mass in the right ovary measuring 2 cm × 1.6 cm with significant post-contrast enhancement and diffusion restriction suggestive of possible malignancy. As PCD was suspected, antineuronal antibodies were estimated including anti-Yo, anti-Hu, anti-Ri, anti-amphiphysin and anti-PNM2 antibody. Anti-Yo antibody was positive in high titers (1:640), which is specific for gynecologic and breast malignancy. With mammography being normal, she was assumed to have PCD with gynecologic cancer and was taken up for exploratory laparotomy. Intraoperatively, there was no ascites. Peritoneal washings were taken for cytology. The uterus was atrophic; the left ovary was of normal size. The right ovary had a cyst of approximately 1 cm in diameter with papillary growths and the right fallopian tube had surface excrescence of approximately 1 cm diameter. There was a small 3-mm deposit on the uterus below the left round ligament. Total abdominal hysterectomy with bilateral salpingo-
Figure 1 (a) Axial computed tomography (CT) demonstrates 2 cm × 1.6 cm lesional mass involving the right ovary. (b) Corresponding positron emission tomography (PET) shows increased tracer uptake in the right ovarian lesion. No other hypermetabolic lesion was seen on PET-CT images.
1464
oophorectomy and infracolic omentectomy was performed. Histopathology showed serous cystadenocarcinoma of the right ovary with breach in capsule, fallopian tube and unremarkable endometrium, and stage IIC ovarian malignancy was diagnosed. Her postoperative recovery has been unremarkable. The patient has received three cycles of chemotherapy with paclitaxel and carboplatin. Ultrasound performed 3 months post-surgery showed no residual disease. However, there has been no improvement in her neurological symptoms.
Discussion Paraneoplastic cerebellar degeneration is an immunemediated paraneoplastic disorder affecting the cerebellum. It is identified when the patient develops severe cerebellar signs and symptoms over less than 12 weeks, while MRI shows no evidence of cerebellar atrophy. PCD associated with ovarian malignancy is a rare occurrence with less than 100 cases reported in the published work. It is due to the remote effect of malignancy on the nervous system leading to various neurological features like dysarthria, ataxia, gait disturbances, diplopia, nystagmus and titubation. The ovarian malignancy was suspected based on acute presentation of the patient and the presence of anti-Yo antibodies. Anti-Yo antibodies are specific antineuronal antibodies which are identified in the sera of up to 70% of the patients with malignancy causing PCD, usually ovarian and breast carcinoma.3 Onconeuronal antibodies like anti-Hu, anti-Ri and anti-CV2 antibodies are found in small cell carcinoma of the lung whereas anti-Yo antibody is usually associated with ovarian or breast malignancies. Anti-Yo antibody is a polyclonal IgG antibody that crosses the blood–brain barrier and reacts with a cytoplasmic component of cerebellar Purkinje cells.4 In almost 80% of cases, the underlying malignancy can be identified.5 Hence, in a patient with anti-Yo antibody and cerebellar symptoms, ovarian malignancy should be specifically looked for and excluded. Thorough investigation including CSF examination and serum tumor markers should be performed in a patient with PCD. Also, whole-body imaging including CT scan and MRI can be done to detect the primary tumor. If no positive findings are seen, recent studies have shown that whole-body FDG-PET has improved the diagnostic rate, as in our case, in which clinical examination as well as ultrasound missed the diagnosis, neither did she have any gynecologic complaints.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Paraneoplastic cerebellar degeneration
PET scan can identify a lesion as small as 1 cm. In patients with paraneoplastic syndromes, the sensitivity of PET scanning to detect malignancies has been estimated to be 83.3% and the specificity 25%. Positive and negative predictive values were 83.3% and 25%, respectively.6 Treatment options are limited: there is no definitive treatment for cerebellar symptoms. Removal of the tumor with specific chemotherapy is recommended, but it only prevents disease progression and does not usually reverse the neurological damage already done. Immunotherapy and steroids have been tried, but the effects seem to be limited. More recent studies report initial encouraging results with rituximab in patients with anti-Yo- or anti-Hu-positive PCD.7 The 5-year survival in PCD patients is devastating. Shams’ili et al. reported that the 5-year survival rate of 19 PCD patients with anti-Yo antibody was less than 25%, with the median survival time from diagnosis being 13 months.5 Rojas et al. reported that approximately half of PCD patients die from their cancer, while the rest die because of neurological progression.8 As the prognosis of PCD patients is very poor, the decision of whether to undergo radical surgery or not has to be made by the treating physician and family, because neurological recovery is not confirmatory even after such radical procedures. Perlmutter et al. reported a PCD patient who showed functional improvement after 3 weeks of comprehensive inpatient rehabilitation.9 Counseling and rehabilitation are very important in these patients. In conclusion, patients with paraneoplastic syndromes should have an aggressive search performed
for underlying malignancy. The anti-Yo antibody is a very important marker in the absence of specific gynecologic complaints. The prognosis is grim but with emerging treatment modalities and good rehabilitation there may be improvement in the future.
References 1. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet 2008; 7: 327–340. 2. Lachance DH, Lennon VA. Paraneoplastic neurological autoimmunity. In: Kalman B, Brannagan TH 3rd (eds). NeuroImmunology in Clinical Practice. Oxford: Blackwell Publishing, 2008; 210–217. 3. Posner JB. Paraneoplastic syndromes. In: DeAngelis LM, Posner JB (ed.). Neurologic Complications of Cancer. Philadelphia, PA: Oxford University Press Inc, 1995; 353–385. 4. Levite R, Fishman A. Paraneoplastic cerebellar degeneration heralding fallopian tube adenocarcinoma. Int J Gynecol Cancer 2001; 11: 169–171. 5. Shams’ili S, Grefkens J, de Leeuw B et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: Analysis of 50 patients. Brain 2003; 126: 1409–1418. 6. Younes-Mhenni S, Janier MF, Cinotti L et al. FDG-PET improves tumor detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127: 2331–2338. 7. Shams’ili S, de Beukelaar J, Gratama JW et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol 2006; 253: 16–20. 8. Rojas I, Graus F, Keime-Guibert F et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55: 713– 715. 9. Perlmutter E, Gregory PC. Rehabilitation treatment options for a patient with paraneoplastic cerebellar degeneration. Am J Phys Med Rehabil 2003; 82: 158–162.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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