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127
Neurologic Complications of Ovarian Carcinoma
Lauren E. Abrey, M.D.
Josep O. Dalmau, M.D.,
BACKGROUND. Neurologic complications of ovarian carcinoma are uncommon and
Ph.D.
to the authors’ knowledge the full spectrum has not been delineated previously.
METHODS. The authors reviewed the findings of 121 neurologic consultations on 83
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.
ovarian carcinoma patients between 1993 and 1996; this represents 4% of all
ovarian carcinoma patients seen at the study institution in this time period.
RESULTS. The most common reasons for consultation were altered mental status,
pain, weakness, numbness, headache, and seizure. Twenty-seven consultations
diagnosed metastatic disease, 14 diagnosed cerebrovascular disease, and 4 diagnosed paraneoplastic syndromes; however, iatrogenic complications (n ⫽ 38)
comprised the majority of diagnoses. Greater than 50% of patients improved
neurologically after diagnosis and treatment.
CONCLUSIONS. Neurologic disease accompanying ovarian carcinoma may be more
common and more diverse than recognized previously. Definitive neurologic diagnosis and treatment benefits the majority of patients. Cancer 1999;85:127–33.
© 1998 American Cancer Society.
KEYWORDS: ovarian neoplasms, metastasis, brain, cerebrovascular disorders, syndrome, paraneoplastic, iatrogenic disease.
N
eurologic problems in patients with ovarian carcinoma may be
the result of treatment, metastatic disease, paraneoplastic syndromes, or coincidental neurologic disease. Although brain metastases are uncommon and neurologic paraneoplastic syndromes are
rare, the full spectrum of neurologic complications in ovarian carcinoma patients is not known. To describe the range and impact of
neurologic disease in these patients more fully, we analyzed 121
consecutive neurology consultations performed on ovarian carcinoma patients at our institution over a 3-year period.
METHODS
Presented in part at the American Neurological
Association Meeting, San Diego, California, September 28-October 1, 1997.
Address for reprints: Lauren E. Abrey, M.D., Department of Neurology, Memorial Sloan-Kettering
Cancer Center, 1275 York Avenue, New York, NY
10021.
Received February 20, 1998; revision received
April 22, 1998; accepted May 26, 1998.
© 1998 American Cancer Society
The charts of all ovarian carcinoma patients seen by the neurology
service between January 1993 and December 1996 were identified
from a departmental database and reviewed. A hospital database was
used to identify the total number of patients with ovarian carcinoma
seen at our institution in the same time period. Both inpatient and
outpatient encounters were included. The following information was
recorded: total number of patients, number of consultations, neurologic diagnoses, patient age, type and stage of ovarian carcinoma,
date of diagnosis, presence or history of other malignancy, prior
cancer treatment, date of last follow-up, and outcome of the neurologic problem. Analysis of discrete variables was performed using the
chi-squared method; Yates correction was applied where expected
values were ⬍ 5.
128
CANCER January 1, 1999 / Volume 85 / Number 1
FIGURE 1. Reasons for obtaining neurologic consultation.
FIGURE 2. Neurologic diagnoses. Asterisk indicates that chemotherapyinduced peripheral neuropathy and medication-induced encephalopathy were
excluded from this category. TIA: transient ischemic attack.
RESULTS
Between January 1993 and December 1996, 121 neurologic consultations were performed on 83 patients
with ovarian carcinoma. During that same period 2050
patients with ovarian carcinoma were seen, indicating
that the neurology service saw 4% of all ovarian carcinoma patients. The most common reasons for consultation and diagnosis are summarized in Figures 1
and 2.
The median age of the patients was 51 years
(range, 13– 86 years). Seventy-six patients had epithelial ovarian carcinoma and 7 patients had other
pathology (4 germ cell tumors [2 teratomas, 1
endodermal sinus tumor, and 1 germinoma], 1 hemangioendothelioma, 1 ovarian lymphoma, and 1
müllerian cell carcinoma). Staging information was
available in 66 of the 76 patients with epithelial
ovarian carcinoma; 10 patients were Stage I (tumor
limited to the ovaries), 3 patients were Stage II (tu-
mor involving 1 or both ovaries with pelvic extension), 40 patients were Stage III (tumor involving 1
or both ovaries with microscopically confirmed
peritoneal metastasis outside the pelvis and/or regional lymph node metastasis), and 13 patients were
Stage IV (distant metastasis, excluding peritoneal
metastasis).1 Seventy-five patients (78%) had active
ovarian tumor at the time of neurology consultation.
Fourteen patients had another malignancy and 3
patients had multiple malignancies. Breast carcinoma
was the most common second malignancy (n ⫽ 11); 3
patients had endometrial carcinoma and 1 patient
each had Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, renal cell carcinoma, and melanoma. Patients
with a second malignancy were more likely to have
Stage I or II ovarian carcinoma (P ⫽ 0.001). Three
patients had evidence of an active second tumor at the
time of neurology consultation.
In 38 patients, neurologic symptoms were a direct
result of treatment. Fifty percent were related to chemotherapy (n ⫽ 19), most often a peripheral neuropathy secondary to treatment with paclitaxel, cisplatin,
or combination chemotherapy. Headache, encephalopathy, and ototoxicity were less frequent complications of chemotherapy. Opiates contributed to approximately 33% of encephalopathies. Five patients
had postoperative complications (three strokes and
two lumbosacral radiculopathies).
Twenty-seven consultations resulted in a diagnosis of metastatic disease (12 brain metastases, 4 leptomeningeal metastases, 4 vertebral body metastases,
4 lumbosacral plexus metastases, and 3 bone metastases). Three of 11 patients with both breast and ovarian carcinoma developed brain metastases; in one
patient surgical pathology confirmed ovarian carcinoma. The other two patients had active, advanced
stage breast carcinoma in addition to their ovarian
carcinoma; both died within 1 month of being diagnosed with brain metastases and the pathology of the
brain metastases was unknown.
The initial symptom in ⬎ 50% of all patients with
brain metastases was altered mental status; 8 patients
underwent a nonfocal neurologic examination. Brain
metastases occurred a median of 38 months after the
initial tumor diagnosis (range, 0 –91 months), but was
the presenting site of ovarian carcinoma in 1 patient.
All but one patient had advanced stage ovarian carcinoma at initial diagnosis. Six patients had a single
supratentorial metastasis, two had multiple supratentorial metastases, and four had multiple supratentorial
and infratentorial metastases. All patients with leptomeningeal metastases had a prior diagnosis of parenchymal brain metastases. Four patients with brain
metastases were treated with surgical resection fol-
Neurologic Complications of Ovarian Carcinoma/Abrey and Dalmau
lowed by whole brain radiation, three patients received whole brain radiation alone, and one patient
received whole brain radiation followed by surgical
resection. One patient initially was treated with ifosfamide alone for her solitary brain metastasis; she had
a partial radiographic response lasting 10 months (Fig.
3) an stereotactic radiation was given at time of tumor
progression. Three patients received best supportive
care. The median survival of patients receiving active
treatment for brain metastases was 4.5 months; however, 3 of 4 patients surviving ⬎ 1 year after the diagnosis of brain metastases underwent resection and
received whole brain radiation, including 2 patients
with multiple lesions. The fourth patient was the patient treated with ifosfamide initially and stereotactic
radiosurgery at recurrence. All 4 1-year survivors had
active systemic tumor in addition to their brain metastases; 2 patients eventually died of progressive systemic tumor and 2 eventually developed leptomeningeal tumors and died of neurologic disease. The
presence of multiple versus single metastases did not
impact 1-year survival significantly (P ⫽ 0.54).
Metastases outside the central nervous system accounted for ⬎ 33% of metastatic neurologic complications. Local pelvic disease resulted in lumbosacral
plexopathy in four patients. Four patients with vertebral column metastases and three patients with other
bone metastases presented with pain. No patient had
spinal cord compression.
Thirteen patients had 14 cerebrovascular events: 4
transient ischemic attacks and 10 infarctions. The median age of these patients was 67 years. Eight patients
had cerebrovascular risk factors unrelated to their malignancy. Twelve patients had active ovarian tumor at
the time of their vascular event; all had advanced stage
disease. One patient also had metastatic breast carcinoma. Six patients were receiving chemotherapy at
the time of their cerebrovascular event; however, no
particular chemotherapy was identified in association
with these events. Three patients had a perioperative
stroke; two had concomitant deep venous thrombosis.
A 26-year-old woman developed a hypercoaguable
state and cerebrovascular symptoms as the presentation of her ovarian tumor. Nonbacterial thrombotic
endocarditis (NBTE) was diagnosed by echocardiogram in another patient. Ten of the 13 patients improved neurologically; 4 received anticoagulants. Low
molecular weight heparin was used to treat the patients with hypercoaguability and NBTE; both patients
improved neurologically and had no further cerebrovascular events.
Four patients had neurologic paraneoplastic disease; one developed dermatomyositis and three presented with subacute cerebellar degeneration. Para-
129
neoplastic markers were identified in the serum of two
patients with cerebellar degeneration; one had anti-Yo
antibodies and the other had anti-Ri antibodies. The
third patient had no detectable antibodies, but immunohistochemistry of her tumor demonstrated expression of Hu and Ri neuronal antigens.
At last follow-up, two patients with subacute cerebellar degeneration had tumors in complete remission; both were Stage I at diagnosis, but have permanent neurologic impairment. The patient with anti-Ri
antibodies and the patient with dermatomyositis both
had advanced stage tumors and died of progressive
disease. It is interesting to note that the patient with
dermatomyositis had a disease course closely paralleling that of her tumor, improving as her tumor responded to chemotherapy and worsening at the time
of tumor recurrence.
After initial neurologic evaluation, follow-up information was available for 78 consultations; in 61.5%
there was clear neurologic improvement documented
by neurologic examination and in 32% the neurologic
findings were unchanged. In particular, 87% of patients with toxic metabolic encephalopathy, 77% with
cerebrovascular events, and 48% with metastatic disease improved.
DISCUSSION
Neurologic complications affect up to 50% of patients
with cancer over the course of their disease and its
treatment. Although prior studies of ovarian carcinoma detail specific neurologic problems such as
brain metastases or chemotherapy-induced peripheral neuropathy, to our knowledge none has sought to
elaborate the full spectrum of neurologic complications in patients with ovarian carcinoma. In this series
we found that nearly 33% of neurologic problems were
related to complications of therapy, and 25% were
related to metastatic involvement of the nervous system. Cerebrovascular disease and paraneoplastic syndromes were more common than anticipated.2,3 Definitive neurologic evaluation and diagnosis often led
to appropriate intervention and the majority of patients improved neurologically. Our observations and
patient sample may be limited by the fact that our
hospital is a major referral center for cancer and neurologic complications of cancer; wherever possible we
compared our results with prior series or reports that
either support or contradict our conclusions.
Altered mental status was the most common reason for consultation and our findings were representative of the larger population of cancer patients. The
majority of patients had a multifactorial, toxic metabolic encephalopathy with the use of opiates contributing to ⬎ 33% of cases. Encephalopathy most often is
Neurologic Complications of Ovarian Carcinoma/Abrey and Dalmau
a dose-limiting event during opiate titration, and typically is observed in older patients receiving an intravenous infusion of any opiate. The only opiate with a
particular risk of encephalopathy is meperidine; the
toxic accumulation of its metabolite, normeperidine,
occurs with chronic use and causes a florid delirium,
myoclonus, and seizures. Greater than 50% of the
patients with brain metastases presented with altered
mental status and a nonfocal neurologic examination.
Similar findings have been reported in other malignancies2; 30 –75% of patients with brain metastases
develop behavioral or cognitive abnormalities at presentation, most likely because these patients are more
prone to encephalopathy induced by opiates or other
metabolic derangements.
Complications of chemotherapy were observed
in 16% of patients. Cisplatin and paclitaxel alone or
in combination accounted for the majority of peripheral neuropathies. Cisplatin typically produces
a large fiber neuropathy with loss of vibratory and
position sense, whereas paclitaxel affects all sensory
fibers and also may cause a proximal motor neuropathy.2 Either concomitant or sequential administration of cisplatin and paclitaxel enhances neurotoxicity and can result in debilitating peripheral
neuropathy.4,5 Twenty percent of patients in this
series who received ifosfamide developed a reversible encephalopathy. Ifosfamide-related encephalopathy is reported to occur in as many as 30% of
patients treated; it typically begins within 24 hours
of infusion and usually is reversible.6
The only available intervention for chemotherapyinduced peripheral neuropathy is to discontinue the offending chemotherapy. This is frustrating for the oncologist, the neurologist, and the patient because it often
means discontinuing the optimal antitumor drug. Our
practice has been to recommend either discontinuing or
reducing the dose of the offending agent when the patient develops objective weakness or sensory loss that
results in functional impairment. An important contribution of the neurologist is to eliminate other potential
causes of peripheral neuropathy so that effective chemotherapy is not withdrawn unnecessarily. Several potential neuroprotective and therapeutic agents (Org 2766,
nerve growth factors, and ethiofus) are in different stages
of preclinical and clinical evaluation.7–9
In longitudinal studies of ovarian carcinoma,
brain metastases are estimated to occur in 0.29 – 4% of
patients.10-15 There has been concern that the im-
131
proved treatment of systemic disease may lead to an
increase in the incidence of brain metastases, either as
a result of prolonged survival and/or as a result of the
brain acting as a sanctuary site for tumor cells. Our
findings are in keeping with other reports in which the
median reported interval from the time of the diagnosis of ovarian carcinoma to brain metastases ranges
from 14.5–34 months and the median survival after
diagnosis of brain metastases ranges from 1–9
months.10 –14,16 –18 A recent report by Rodriguez et al.
suggests that aggressive treatment with a combination
of surgery, radiation, and chemotherapy leads to improved survival. In their meta-analysis patients treated
with a combination of surgery, radiation, and chemotherapy had a median survival of 16.5 months compared with 10 months for patients treated with surgery
and radiation, and 3 months for patients treated with
radiation alone.19 Similarly, we found that our long
term survivors received more aggressive, multimodality treatment with surgery, radiation, and chemotherapy.
Prior studies have reported a predilection of
pelvic tumors to metastasize to the posterior fossa.20
Our small series does not support this predilection.
All solitary metastases were located in the cerebral
hemispheres and all patients with multiple metastases had supratentorial lesions. The presence of
solitary versus multiple metastases had no impact
on patient survival; even patients with multiple lesions benefited from an aggressive combination of
surgical resection or chemotherapy followed by radiation.
Cerebrovascular disease was common in this series, accounting for 12% of consultations. Large retrospective series indicate that 15% of cancer patients
have cerebrovascular lesions at autopsy; only approximately 50% are ever symptomatic and the etiology of
cerebrovascular symptoms usually is cancer-related.3
Our patients with cerebrovascular events were older
than the overall patient group and the majority had
risk factors for stroke that were not related to their
cancer. However, all these patients had active, advanced stage tumor and in at least 43% the etiology of
the cerebrovascular event was related to the tumor or
its treatment. Dehydration, electrolyte abnormalities,
and alteration in baseline blood pressure are all potential side effects of abdominal surgery and chemotherapy, and may increase the risk of stroke in patients
with preexisting cerebrovascular risk factors. Hyper-
Š
FIGURE 3. Coronal T1-weighted magnetic resonance imaging of the brain with gadolinium demonstrating response of a solitary brain metastasis to treatment
with ifosfamide. (a and b) Scans taken prior to treatment. (c and d) Scans taken after five cycles of ifosfamide.
132
CANCER January 1, 1999 / Volume 85 / Number 1
coaguable states and NBTE are complications of disseminated malignancy and are independent cerebrovascular risk factors. It is interesting to note that no
patient had a hemorrhagic stroke or cerebral sinus
thrombosis.
Paraneoplastic syndromes are rare, and considered to occur in 1–3% of patients with cancer. The
incidence of subacute cerebellar degeneration associated with ovarian carcinoma is estimated to be
0.1%.2 Paraneoplastic dermatomyositis is even more
uncommon and some authors question whether its
association with cancer is coincidental rather than a
true paraneoplastic event. However, in patients
age ⬎ 50 years, dermatomyositis appears to have a
higher than expected association with malignancy,
among which ovarian carcinoma is a common offender.21 Anti-Yo antibodies are the most common
paraneoplastic marker in patients with subacute
cerebellar degeneration and ovarian carcinoma and
these were identified in one of our three patients
with cerebellar degeneration. Anti-Ri antibodies,
found in another patient, develop in association
with breast and ovarian carcinoma; these patients
have a syndrome characterized by opsoclonus and
truncal ataxia. The fact that one patient had no
detectable paraneoplastic antibody in her serum but
her tumor expressed both Hu and Ri antigens is
unusual. A prior study comparing the tumors of
patients with and without paraneoplastic cerebellar
degeneration demonstrated that only the tumors of
patients with paraneoplastic cerebellar degeneration expressed neural antigens.22
This study has several limitations. First, selection bias may have affected our patient population
and may account for the high rate of multiple malignancies. The frequency of multiple tumors illustrates the importance of considering a second malignancy in patients with one cancer diagnosis;
those patients with diagnoses of breast and ovarian
carcinoma may harbor a BRCA gene mutation. The
presence of multiple malignancies also complicates
the neurologic evaluation. The toxicity of cumulative treatments may be additive or synergistic, and
metastases have more than one possible tumor of
origin. Because only a few patients had more than
one active tumor at time of neurologic consultation,
we did not exclude them from our analysis, but
sought to clarify their etiology or pathology when
possible.
Second, this group of patients was selected retrospectively from a departmental database and we
cannot exclude the possibility that some patients
with ovarian carcinoma and neurologic complications were not included. Particularly in the instance
of chemotherapy-induced peripheral neuropathy,
the neurology service often is consulted only for
severe or unremitting cases. Also, many patients
may come to our institution for a single consultation, but receive their care elsewhere, thus artificially inflating the total number of ovarian carcinoma patients seen over the 3-year period.
Therefore, although we can describe the range of
neurologic complications observed in this ovarian
carcinoma population, we cannot predict the incidence of specific complications accurately.
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