Review
Epilepsy in women with gynecologic malignancies Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 07/26/15 For personal use only.
Expert Rev. Neurother. 14(5), 503–517 (2014)
Yixue Gu, Qin Yang and Xuefeng Wang* Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China *Author for correspondence: Tel.: +86 136 2835 9876 Fax: +86 023 8901 2878 [email protected]
Women with gynecologic malignancies are a population with various risk factors for epilepsy. Gynecologic malignancies can substantially affect daily life, even if the tumor is well controlled. Gynecologic malignancies may cause brain metastasis, paraneoplastic neurological disorders, or leptomeningeal carcinomatosis, which potentially directly cause seizures and epilepsy. Moreover, metabolic disorders, central nervous system infections, cerebrovascular complications, and chemotherapeutic drugs can indirectly induce ictus. Radiotherapy of brain metastases can also lead to seizure and epilepsy. Understanding these pathogenic mechanisms may provide novel viewpoints or methods for diagnosis, prevention and treatment of epilepsy associated with gynecologic malignancies. In this article, we extensively review the related literature regarding potential aetiologies, their mechanisms, clinical features, diagnosis and treatment. KEYWORDS: antiepileptic drugs • brain metastasis • CNS infection • cerebrovascular complications • chemotherapeutic drug • epilepsy • gynecologic malignancy • leptomeningeal carcinomatosis • metabolic disorder • paraneoplastic neurological disorder
In clinical practice, seizure or epilepsy is observed in patients with gynecologic malignancies more frequently than expected by chance [1–3]; this suggests a link between the two diseases. Seizures can be a manifestation of almost every subtype of gynecologic malignancy and can affect daily life even if tumor is well controlled. To date, a systematic description of epilepsy associated with gynecologic malignancies remains lacking. Further understanding the regularity of the co-occurrence of seizure and gynecologic malignancies may lead to better disease control and improve patient outcomes. Search strategy & selection criteria
Data for this review was obtained by searches of PubMed and Medline with single or combined terms for ‘gynecologic malignancy’, ‘ovarian tumor’, ‘cervical tumor’, ‘uterine tumor’, ‘vaginal tumor’, ‘vulval tumor’, ‘fallopian tube tumor’, ‘epilepsy’, ‘seizures’, ‘brain metastasis’, ‘paraneoplastic neurological disorder’ (PND), ‘leptomeningeal metastasis’, ‘chemotherapeutic drug’, ‘metabolic disorder’, ‘cerebrovascular complications’, ‘central nervous system infection’ and ‘antiepileptic drugs’. Original research papers, clinical series, case reports and reviews were included. Our search covered all relevant data through
informahealthcare.com
10.1586/14737175.2014.906303
1 December 2013. Information on the prevalence, pathogenesis, clinical feature, treatment and prognosis was extracted from these articles. All evidences presented in the article included patients who experienced seizures or epilepsy during the course of disease. Patients with histories of seizures or epilepsy were excluded. Prevalence
The incidence of epilepsy or seizures in women with gynecologic malignancies is currently increasing [1–3]. Epilepsy or seizures may occur in patients with almost every subtype of gynecologic malignancy. Seizure incidence is associated with the histological type and degree of tumor. According to some reports, seizures occur in 11 of 1219 patients with Stage I or greater cervical cancer but were rare and unrelated to cervical cancer in Stage 0 disease [1]. Furthermore, 83 of 2050 women with ovarian cancer accepted neurological consultations; among them 7 patients exhibit seizures as their prominent neurological manifestation [2]. Various studies have also reported seizures in other gynecologic cancers such as endometrial cancer [4]. The prevalence of epilepsy in general population is around 0.5% [5], which is much lower than in patients with gynecologic malignancies. Although rare, benign gynecologic
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tumors can also cause seizures. Yumru et al. [6] presented a case report of a woman with a giant primary ovarian leiomyoma that induced seizures as the initial symptom. Recently, several researchers have reported seizures in patients with ovarian mature or immature teratoma [7–9].
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Etiologies & clinical features
Gynecologic malignancy-related seizures or epilepsy may be divided into two types: directly related to malignancy and related to complications associated with malignancy. The former mainly includes brain metastases, followed by PNDs and leptomeningeal carcinomatosis (LC). The latter includes metabolic disorders, cerebrovascular complications and CNS infections. Malignancy treatments, especially chemotherapy, can also induce seizures [10,11]. Brain metastasis Prevalence
According to statistics, 20–35% of patients with brain metastases will experience one or more seizures during their lifetime [12]. The incidence of brain metastases from all gynecological cancers is approximately 1% [13]. Choriocarcinoma comprises 35% of brain metastases ascribed to gynecologic malignancies [14]. Kazuhiko et al. [13] conducted a retrospective review of 2729 patients with gynecological cancer. Eighteen patients (0.7%) had brain metastases. The occurrence of metastasis was associated with the primary site of the tumor. According to some reports, the incidence of brain metastases originating from ovary, uterine cervix, uterine corpus and other gynecological sites were 0.3– 2.2%, 0.4–1.2, 0.3–0.9 and 1.8%, respectively. Other gynecological sites include vagina, vulva and fallopian tube [13]. Nasu et al. [15] did a retrospective study of 139 patients with brain metastasis from gynecologic malignancies, which excluded choriocarcinoma. In total, 85.7% of patients in the ovarian cancer group and 69.3% of patients in the corpus cancer group were in advanced disease stages (stage III/IV), whereas only 35.7% of patients with cervical cancer had advanced stage disease, which indicated the possibility of early brain metastasis in cervical cancer [15]. Ovarian serous adenocarcinoma, corpus endometrial adenocarcinoma and cervical endometrial adenocarcinoma are three types of tumors that most commonly cause brain metastases [15]. A recent study demonstrated increased incidence of brain metastasis from gynecological cancer, especially in ovarian cancer [15]. This may be made possible by increased patient survival due to successful treatment of extracranial tumor and the brain’s propensity to act as a tumor cell sanctuary; this may also be possible due to more effective diagnosis of intracranial lesions [2,15]. Spread & distribution
Brain metastases from gynecological cancers are always associated with disseminated extracranial tumors. They may develop anywhere in the brain although the posterior fossa may be the most likely site for these tumors [16]. However, it is hard to identify a metastasis responsible for seizures, since posterior fossa metastasis would be unlikely to result in seizures unless 504
cerebral spinal fluid (CSF) out flow from the fourth ventricle was obstructed. In general, multiple brain metastases are more often than single one to be present [15]. Hematogenous dissemination has been suggested as the primary mechanism underlying the spread of tumor cells. Detached tumor cells from the genital tract to the brain are passed through pulmonary vasculature [16]. Another possible mechanism is the Batson plexus (paravertebral venous plexus) route [16]. The supratentorial region of the brain is the most common metastatic site for cervical cancer; this may be a result of the vasculature and spatial characteristics of this region [17]. Pathogenesis
The etiological mechanism of cerebral metastatic tumorinduced epilepsy remains poorly understood [18]. However, there are several hypotheses regarding pathogenesis of brain tumors, which may give us a better understanding. These include the theory of denervation hypersensitivity, described by Echlin et al. [18] as a theory that brain tumors can chronically cause partial isolation and differentiation of the cerebral cortex, which leads to denervation hypersensitivity and generates ictus. This theory thus explains the relationship between seizure and tumor location. However, it cannot explain why in some cases, after tumor excision, seizures return or appear for the first time [18]. A second hypothesis involves microvascular disorder; one possible causal mechanism occurs by metastatic tumorrelated reduced peritumoral perfusion pressure and local microcirculation impairment, which then causes peritumoral brain ischemia and seizures [19]. Neurotransmitter abnormalities are also hypothesized to underlying pathogenesis. Brain tumors may lead to dysfunctional metabolism of amino acids in peritumoral brain areas including deficits in alanine, ethanolamine, isoleucine, valine, taurine and glutamine metabolism. Most of these amino acids act as neurotransmitters or neuromodulators. Disturbances in amino acid levels may disrupt the balance between excitatory and inhibitory compounds, which can then lead to seizures. However, it remains unknown whether disorders of amino acid metabolism are the cause or consequence of seizures [20]. A fourth theory implicates pH and enzymatic abnormalities. Peritumoral cortex pH is more alkaline, and such changes may affect the transmembrane movement of oxygen ions, reduce the flow of potassium ions and inhibit sodium channels to increase cell excitability and cause seizures. Changes in peritumoral enzyme levels such as enhanced lactate dehydrogenase, phosphodiesterase, enolase and thymidine kinase levels can also elevate neuronal excitability and cause seizures [21,22]. Aberrant cell–cell contacts or interactions between periphery tumor cells and surrounding neuronal and glial cells may result in abnormal metabolism that directly affects neuronal network function and seizures susceptibility [23]. Finally, radiation necrosis may cause ictus; seizures can be an acute or delayed manifestation following radiotherapy of brain lesions due to complications such as radiation necrosis, edema or hemorrhage. These types of cell damage may increase the incidence of seizures, which can follow soon or several months or years after radiotherapy [24,25]. Expert Rev. Neurother. 14(5), (2014)
Epilepsy in women with gynecologic malignancies
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Clinical features
In cerebral metastasis-associated seizures, clinical manifestations depend on the location, histological type and rate of growth of the tumor. Lynam et al. [26] completed a retrospective study and found that 34% of patients (12 of 35) with CNS metastases developed seizures in their course of the disease. Of these, five had seizures at presentation and seven had delayed seizures. Alajbegovic et al. [27] conducted a retrospective study and found that single seizure occurred most often (59%); a series of seizures is relatively uncommon (38%). Status epilepticus occurred in only 3% of patients. The most common type of seizures were simple partial seizures with or without secondary generalization (66% of seizures were simple partial seizures: 44% of which occurred without generalization and 22% occurred with generalization), followed by generalized convulsive seizures (31%), and finally, the least common type, complex partial seizures (3%) [27]. Ramamurthi et al. [28] reported that partial seizures are often associated with lesions in perirolandic areas affecting M1, S1, the supplementary motor area or the secondary somatosensory cortex. Complex partial seizures were typically caused by lesions in the temporal lobe and were associated with auditory hallucinations, deja vu phenomena, epigastric, gustatory and olfactory auras. Treatment
Treatment can be divided into two aspects: the treatment of metastatic lesions and the treatment of seizures. The management of metastases includes supportive care, radiotherapy, surgical resection and chemotherapy [15]. In most of patients with brain metastasis originating from gynecological cancers, treatment is usually palliative because of the advanced primary tumor and poor general condition [13,15]. However, numerous studies have shown that multimodal treatments may provide better outcomes [13,15]. The treatment of seizures typically involves antiepileptic drugs (AEDs); however, whether they are useful to prevent seizures in patients with brain metastasis remains controversial. Prophylactic use of AEDs has been assessed in patients with brain tumor who had no history of epilepsy with negative results [29,30] The American Academy of Neurology has recommended that AEDs should not be administered routinely in new cases of brain tumor due to their ineffective prevention of initial seizures [31]. AEDs can be administered once brain metastases cause seizures [31]. To maintain seizure-free status in brain tumor patients is very difficult despite AED treatment. The mechanisms of brain metastases-associated seizures are complicated. While the effects of AEDs are almost certainly associated with blocking or inactivating Na2+ or Ca2+ channels or increasing GABAergic activity [32], this accounts for only part of various epileptogenic mechanisms. In addition, interactions with antitumor drugs may decrease the serum concentration and effectiveness of AEDs [33]. Lamotrigine, valproic acid and topiramate are first-line treatments for seizures in patients with brain tumors [33]. Wagner et al. [34] found that add-on levetiracetam can decrease seizure frequency in 50–65% of patients, while some patients informahealthcare.com
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Table 1. Alleviation of symptoms by antiepileptic drugs. Drug
Depression
Anxiety
Pain
Phenytoin
+
-
+
Carbamazepine
+
-
+
Valproic acid
+
-
+
Gabapentin
-
+
+
Pregabalin
-
+
+
Lamotrigine
+
-
+
Topiramate
+
+
+
Zonisamide
+
-
-
Oxcarbazepine
+
-
+
Tiagabine
+
+
+
Levetiracetam
-
+
+
Data taken from [37].
remain seizure free throughout their lifetime [34–36]. Some reports indicate that after add-on gabapentin, all patients achieved seizure remission, and 50% of patients were seizure free [33]. When first line or monotherapy is ineffective, double or triple combinations should be considered [33]. Other than seizures, there are many other symptoms in gynecologic malignancies such as pain, depression and anxiety. Some studies have shown that remission of one or more concomitant symptoms can be achieved with AEDs. Thus, the decision to prescribe AEDs is made according to seizure type or concomitant symptoms (TABLE 1) [37]. When surgery for metastatic lesions is necessary, prophylaxis via AEDs should be considered; however, their effect remains unclear [33]. In recent years, an increasing body of research has found that resection or cytoreductive surgery is usually followed by good outcomes, involving the remission or curing of brain metastasis-associated seizures. However, this is related to many factors including lesion location, operative approach and execution and the extent of tumor resection [28,38]. Prognosis
The median survival of patients with gynecologic malignancies who developed brain metastasis is 3–6 months [12]. The presence of seizures is associated with poorer general health and mental status. Although be treated by complex strategies, gynecological cancer patients with seizures almost always have poorer prognoses than those without seizures; however, prognostic instruments are lacking. Paraneoplastic neurological disorder Prevalence
PNDs are rare occurring in approximately 0.01% of cancer patients [39]. PNDs are a series of neurological signs and symptoms caused by a remote cancer. They are not the direct result 505
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of a primary tumor or metastases, but the result of an autoimmune attack on normal neuronal tissue by similar neuronal antigens that are ectopically produced by tumor cells. Among tumor-associated neurological symptoms, PND accounts for 10% of all nonmetastatic causes [40]. Gynecological cancers after small cell lung cancer most frequently result in PND, especially ovarian cancer [41]. Yumru et al. [6] reported a case of a patient with giant primary ovarian leiomyoma who developed epileptic seizures as the initial presenting symptom. These authors excluded all other causes of the seizures, and the patient was seizure free after tumor resection. Although they did not test neuronal antibodies, these investigators believed the seizures to be associated to PND. Dalmau et al. [7,8] successively reported a series of 60 patients with ovarian teratoma who developed seizures and other neurological and/or psychiatric symptom, believing that these symptoms resulted from ovarian teratomaassociated PND. Specific antibodies
There are classical onconeural antibodies and antimembrane antibodies associated with gynecologic malignancies. The most specific onconeural antibody related to gynecological cancer is anti-Yo. Rojas-Marcos et al. [41] retrospectively reviewed 92 patients with PND associated with gynecological cancer and breast cancer. Their assessment of serum onconeural antibodies found that 50 patients were positive for anti-Yo, 5 were positive for anti-Hu and 5 were positive for ant-Ri indicating that anti-Yo antibody is the onconeural antibody most commonly associated with gynecologic malignancies. Anti-Yo antibodies are a type of Ig-G antibody that recognize several proteins, such as cytoplasmic proteins with a helix-leucine zipper motif and attack Purkinje cells, usually leading to paraneoplastic cerebellar degeneration and seizures [42]. In 1997, Petit et al. [42] described a woman with an endometrial adenocarcinoma and metastatic evolution who developed temporal lobe epilepsy secondary to anti-Yo antibody. Another onconeural antibody is anti-Hu, which was described in 1985. The most common symptoms associated with anti-Hu were paraneoplastic limbic encephalitis, sensory neuropathy and paraneoplastic cerebellar degeneration [40]. Anti-Hu antibody is sometimes present in the serum of patients with gynecologic malignancies [41]. Regarding antimembrane antibodies, a close relationship between the antiN-methyl-D-aspartate receptor (anti-NMDAR) antibody and ovarian teratoma (mature or immature) has been found in recent years. Dalmau et al. [7] reported on a specific antiNMDAR antibody in the serum or cerebrospinal fluid of 11 patients with ovarian teratoma and 1 patient with mediastinal teratoma. The antibody mainly attacks the neuropil of the hippocampus or forebrain; in particular, the cell surface of hippocampal neurons is targeted. Most of the 12 patients described by these authors experienced seizures, with or without prominent psychiatric symptoms, amnesia, frequent dyskinesias, autonomic dysfunction and reduced levels of consciousness. They termed this disorder paraneoplastic anti-NMDAR encephalitis. One year later, Dalmau [8] and another nine investigators described 506
100 patients with encephalitis and anti-NMDAR antibodies. Among them, 53 had a teratoma (35 had mature ovarian teratoma, 14 had immature ovarian teratoma and 4 had radiographically demonstrated teratoma). Seventy-six patients developed seizures. Pathogenesis
Generally, PND is associated with all nonmetastatic neurological disorders including metabolic disorders, infections and coagulation disturbances. Our discussion of PND considers that only or mainly caused via immune-mediated mechanisms. Onconeuronal antigens are recognized by the immune system once tumor cells spontaneously undergo apoptosis and dendritic cells phagocytose antigens contained in apoptotic bodies [43]. Various immune responses then also occur. These include hormonal immune responses, in which B Cells bind to specific onconeural antigens and produce specific antibodies. Several studies have shown that the concentration of specific onconeural antibodies in the cerebrospinal fluid are much higher than in the serum, indicating that onconeural antigens can be made intrinsically in the CNS rather having to cross the blood–brain barrier (BBB) [43]. Anti-Hu antibody is a neuronal antinuclear antibody associated with an intranuclear RNAbinding protein that acts to regulate the cell cycle [44]. A previous study found that anti-Hu clearly demonstrates cytotoxicity and always results in limbic encephalitis. Anti-Yo antibody is specific to Purkinje cells and always accompanies paraneoplastic cerebellar degeneration; it may also sometimes cause limbic encephalitis [45]. Cellular immune responses also occur: most recently, cytotoxic T cells are believed to play the primary role in PND pathogenesis [46]. T cells can be found at autopsy and biopsy in patients with PND. T cells are generally found in the perivascular spaces and parenchyma. Hu-specific T-helper cells and Hu-specific cytotoxic T cells have been found to be expressed in the blood of PND patients [47]. Yospecific T-helper cells and Yo-specific cytotoxic T cells were also identified in the blood and CSF [48]. Both hormonal and cellular immune responses may lead to neuronal loss and inflammation infiltration, which progresses to cause various neurological disorders [46–48]. Patients with gynecologic malignancies can develop paraneoplastic cerebellar degeneration, limbic encephalitis, motor neuron syndrome, inflammatory myopathy and dermatomyositis. Seizures are mainly a manifestation of paraneoplastic encephalitis; they always co-occur with paraneoplastic limbic encephalitis and are sometimes associated with cortical encephalitis [40]. Closely examined teratomas may be found to contain nervous tissue, express anti-NMDAR subunits (NR1, NR2 or their heteromers) and then produce specific antibodies, which leads to anti-NMDAR encephalitis and seizures or other neurological symptoms [7]. Clinical features
Seizures in PND patients with gynecologic malignancies always appear before the diagnosis of primary tumors or several months or years after chemotherapy [10]. In patients with PND, the most common type of seizures are generalized seizures, Expert Rev. Neurother. 14(5), (2014)
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Epilepsy in women with gynecologic malignancies
complex seizures or partial status, with or without agitation, confusion or hallucination [10,43]. Gultekin et al. [45] reported on 50 patients with PND. Twenty-five patients developed seizures: 10 experienced temporal lobe of partial seizures, 6 had generalized seizures and 9 had a combination of seizure types. Abel et al. [49] reported a case of a woman with PND who presented with partial nonconvulsive status epilepticus. Shavit [50] reported a series of three patients with PND who presented with epilepsia partialis continua. These uncommon types of epilepsy may be caused by PND and should be considered. Vitaliani et al. [51] reported a series of four patients who developed PND with ovarian teratoma. Three of these patients developed generalized seizures. The investigators reviewed five previously reported patients and found that one exhibited myoclonic seizures and one demonstrated secondary generalized seizures with other symptoms such as severe behavioral and personality changes, short-term memory deficits and hallucinations. Dalmau et al. [8] described a series of 100 patients with anti-NMDAR encephalitis. Of the 76 patients who experienced seizures, 45 experienced generalized tonic–clonic seizures, 10 experienced complex–partial seizures, 8 experienced secondary generalized seizures, 6 demonstrated refractory status epilepticus, 7 experienced partial motor seizures, 7 were not classified and 2 demonstrated epilepsia partialis continua, with or without psychiatric symptoms, memory problems, dyskinesia, autonomic instability or hypoventilation. Treatment
Most patients remain seizure free after control of the primary tumor; however, a smaller group of patients experienced refractory seizures. Treatment included tumor control, immunosuppressive therapy and antiepileptic treatment. Because some AEDs interact with specific immunosuppressive drugs, careful AED selection is important. Enzyme-induced AEDs such as phenytoin, carbamazepine and phenobarbital decrease the serum concentration and effect of steroidal immunosuppressive drugs, requiring a dosage of steroid that was 150% of the normal dose to achieve the same effect [33,52]. Therefore, nonenzyme-induced AEDs are optimal; however, a clinical guideline for seizure control in PND patients with gynecologic malignancies does not exist. Prognosis
After effective control of the primary tumor, seizures typically remit in 2–6 months [53]. After excision of ovarian teratoma and immunotherapy, neurological symptoms, including seizures, in patients with anti-NMDAR encephalitis were always completely resolved [7,8]. For recurrent epilepsy, especially that associated with progressive tumors or irreversible brain damage, long-term antiepileptic treatment may be necessary.
Review
Prevalence
LM occurs in nearly 5% of all cancer patients. LM caused by gynecologic malignancies is commonly associated with ovarian cancer; the most frequent pathological finding is undifferentiated or poorly differentiated carcinomas of the serous histological subtype [11,55]. The incidence of LM increases with effective tumor treatment local control of the tumor site; this allows for more time to develop LM. According to statistics, 1–5% of LM patients develop seizures [54]. Palma et al. [55] reported a series of 50 patients with LM and found that 2 patients developed seizures as their chief complaint at presentation. Nuria et al. [11] conducted a MEDLINE search of patients with LC resulting from cervical cancer, which returned 12 case reports. Of these cases, two had developed seizures. The histopathological findings of these patients were adenosquamous carcinoma and squamous cell carcinoma; all were poorly differentiated. Pathogenesis
Although LM was first described in 1869 by Eberth [56], little progress has been made to better understand the pathogenesis, therapy and prognosis of LM. The mechanism of LM from gynecologic malignancy is still unknown. Hypothetical mechanisms of LM from malignancy are currently under investigation. Tumor cells spreading to the meninges mainly include hematogenous meningeal seeding from previous brain metastases, which extended into the ventricles or subarachnoid space, infiltration via arachnoid veins or choroid plexus extension, along the nerves, perineural or perivascular lymphatics and sheaths, etc. [57,58]. The posterior fossa, basilar cisterns and cauda equina appear to be the areas that are most heavily seeded. The slowing of the CSF flow and the effect of gravity in these area may underlie these findings [59]. Hypotheses regarding epileptogenesis include multiple mechanisms. Irritation of the adjacent corresponding brains area may lead to paradoxical discharge and seizure [54]. Invasion by tumors of the basal cisterns often leads to increased intracranial pressure and hydrocephalus by interfering with the flow of CSF in the ventricular system and basal cisterns [60]; continuous increased intracranial pressure and progressive hydrocephalus can be a cause of epilepsy. Neovascularization may form around the tumor, and the new vessels are fenestrated capillaries that allow drugs or contrast material to infiltrate the brain, which leads to seizures [60]. Similarly, infiltration of the Virchow–Robin spaces of the penetrating vessels often results in ischemia by perivascular tumor cuffing. Arteriography may indicate narrowing and beading vessels, and secondary ischemia or infarction may lead to seizures [54,61]. Finally, hydrocephalus or tumor nodules may cause compression of various brain structures and alter brain structure, which can cause seizures [54]. Clinical features
Leptomeningeal metastasis
Leptomeningeal metastasis (LM) is the dissemination of malignant cells to the leptomeninges or CSF that is distant from the primary tumor [54]. informahealthcare.com
The clinical signs and symptoms of LM are variable because LM can affect almost all levels of the CNS [62]. Seizures associated with LM can appear at any stage of the disease [10]. William et al. [62] analyzed a series of 90 LC patients and 507
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found that 5 patients (5.56%) had seizures at first clinical presentation. Among these five patients, three (3.33%) experienced generalized seizures and two (2.22%) experienced partial seizures. Eventually, 13 LC patients (21%) developed seizures. Eight patients (8.89%) experienced generalized seizures and five (5.56%) experienced partial seizures.
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Treatment
Present treatments include those that target LC and those that target seizures. LC treatments are always palliative, and there are no clinical trials to guide treatment [63]. Treatments mainly consist of intrathecal chemotherapy or systemic (iv. or oral) chemotherapy, which are combined with radiotherapy when macroscopic lesions are present [63]. Methotrexate is the recommended drug for intrathecal chemotherapy [64]. It is, however, worth noting that high doses of intrathecally injected methotrexate can lead to a variety of irreversible complications including aseptic meningitis, leukoencephalopathy, encephalopathy and opportunistic intracranial infection. These complications can induce seizures [54,65]. AEDs prescription should take potential interaction with chemotherapeutic agents into account.
Clinical features
Seizures often appear during or after chemotherapy administration [10]. This includes serious type of seizures; generalized tonic– clonic seizures are the most commonly occurring type [10]. Steeghs et al. [66] reported a series of 3 patients and reviewed 21 patients who received cisplatin chemotherapy and developed encephalopathy with seizures. Twelve patients experienced generalized tonic–clonic seizures, 7 experienced partial seizures, 3 demonstrated status epilepticus and 2 patients experienced unspecified seizures. Cisplatin-induced seizures are often accompanied by cortical blindness, aphasia, hemiparesis and acute psychosis [64,66]. Most of the patients of this series made a complete recovery; however, a small group of patients experienced ongoing seizures that were resistant to antiepileptic treatment [66]. Paclitaxel
Paclitaxel is an anticancer agent of the taxanes family, which is widely used to treat solid tumors such as gynecological cancer and breast cancer. Peripheral neurotoxicity is one of the main adverse effects of paclitaxel, while CNS toxicity is relatively rare [65,67]. Both acute and delayed encephalopathy has been described in patients treated to paclitaxel [65].
Prognosis
The prognosis of LC patients is poor. Median survival of LC patients is 4–6 weeks. After effective treatment, survival is approximately 4–6 months [55]. Therefore, the outcome of LCrelated seizures is unknown. Drug-induced seizures
Epilepsy is a typical form of dose-limiting toxicity in Phases I and II clinical trials of some cancer drugs. Epilepsy can occur in patients undergoing treatment for cancer, especially at high drug doses. Additionally, renal or hepatic disorders may affect drug clearance and lead to epilepsy. Among these drugs, chemotherapeutic drugs are a frequent cause of drug-induced seizures in cancer patients. Cisplatin
Cisplatin is an effective and widely used agent for gynecological cancer patients, especially patients with ovarian carcinoma and cervical carcinoma. Pathogenesis
Cisplatin-induced seizures are a typical manifestation of acute toxic encephalopathic syndrome, which usually occurs with a combination of cortical blindness, aphasia, hemiparesis or acute confused state [66]. Cisplatin-induced seizures are a doselimiting clinical manifestation. In adults, CNS toxicity usually occurs in patients given more than 200 mg/m2 cisplatin doses [64]. Seizures are associated with cisplatin-induced electrolyte disturbances, in particular, hypokalemia, hyponatremia and hypomagnesaemia. All of these factors can cause the seizure threshold to decrease and cause seizures [66]. Cisplatin may also lead to posterior leukoencephalopathy syndrome and focal neurological disorders which are always accompanied by seizures [66]. 508
Pathogenesis
Direct effects of paclitaxel: It is generally believed that paclitaxel does not cross the BBB and is in negligible concentrations in CSF. However, a previous study demonstrated that a low concentration of paclitaxel was found in the brain of nude mice after tail vein injection, indicating that a trace amount of paclitaxel may actually cross the BBB [68]. Additionally, brain metastases, previous brain surgery, or whole-brain irradiation may cause damage to the small- and medium-sized brain vessels or oligodendroglia and disrupt the BBB, which can facilitate seizures or encephalopathy [65,67]. Toxicity of the carrier
Tracey et al. [69] reported on one patient who was treated by paclitaxel formulated using Cremophor EL and who then developed delayed onset of seizures 4 days after drug infusion. There was no history of seizures, and no metabolic lesion was present. These researchers believed that the seizures were caused by paclitaxel or its carrier [69]. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Each milliliter of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol. Cremophor EL is considered to be a neurotoxicity agent and its half-life at doses of 70–110 mg/m2 ranges from 70 to 77 h. Thus, the carrier may have caused delayed seizures, and it is difficult to discriminate whether Cremophor EL and paclitaxel causes CNS side effects [69]. Clinical features
Seizures appear often during or soon after paclitaxel administration although delayed seizure may occur. Generalized Expert Rev. Neurother. 14(5), (2014)
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Epilepsy in women with gynecologic malignancies
tonic–clonic seizures are the most common type of seizure [10,69]. There are a few case reports regarding seizures related to paclitaxel infusion. William et al. [70] reported that 1 of 51 patients with epithelial ovarian cancer experienced two grand mal seizures after the first few hours of her paclitaxel treatment, which was two-times the standard dose. There was no metastatic lesion, and the lumbar puncture results were normal. The EEG findings indicated nonspecific changes. Michelle et al. [71] described a patient who experienced a generalized tonic–clonic seizure 5 min after paclitaxel infusion was initiated. The patient’s neurological examination and EEG and MRI were normal. The authors believed that these seizures may have been caused by paclitaxel-induced CNS toxicity. 5-Fluorouracil
The pyrimidine antimetabolite and antineoplastic 5-fluorouracil (5-FU) are widely used as a chemotherapeutic agent to treat gynecological cancers such as cervical cancer, vaginal cancer and vulvar cancer. Furthermore, 5-FU-induced neurotoxicity is uncommon, occurring in
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Expert Rev. Neurother. 14(5), 503–517 (2014)
Yixue Gu, Qin Yang and Xuefeng Wang* Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China *Author for correspondence: Tel.: +86 136 2835 9876 Fax: +86 023 8901 2878 [email protected]
Women with gynecologic malignancies are a population with various risk factors for epilepsy. Gynecologic malignancies can substantially affect daily life, even if the tumor is well controlled. Gynecologic malignancies may cause brain metastasis, paraneoplastic neurological disorders, or leptomeningeal carcinomatosis, which potentially directly cause seizures and epilepsy. Moreover, metabolic disorders, central nervous system infections, cerebrovascular complications, and chemotherapeutic drugs can indirectly induce ictus. Radiotherapy of brain metastases can also lead to seizure and epilepsy. Understanding these pathogenic mechanisms may provide novel viewpoints or methods for diagnosis, prevention and treatment of epilepsy associated with gynecologic malignancies. In this article, we extensively review the related literature regarding potential aetiologies, their mechanisms, clinical features, diagnosis and treatment. KEYWORDS: antiepileptic drugs • brain metastasis • CNS infection • cerebrovascular complications • chemotherapeutic drug • epilepsy • gynecologic malignancy • leptomeningeal carcinomatosis • metabolic disorder • paraneoplastic neurological disorder
In clinical practice, seizure or epilepsy is observed in patients with gynecologic malignancies more frequently than expected by chance [1–3]; this suggests a link between the two diseases. Seizures can be a manifestation of almost every subtype of gynecologic malignancy and can affect daily life even if tumor is well controlled. To date, a systematic description of epilepsy associated with gynecologic malignancies remains lacking. Further understanding the regularity of the co-occurrence of seizure and gynecologic malignancies may lead to better disease control and improve patient outcomes. Search strategy & selection criteria
Data for this review was obtained by searches of PubMed and Medline with single or combined terms for ‘gynecologic malignancy’, ‘ovarian tumor’, ‘cervical tumor’, ‘uterine tumor’, ‘vaginal tumor’, ‘vulval tumor’, ‘fallopian tube tumor’, ‘epilepsy’, ‘seizures’, ‘brain metastasis’, ‘paraneoplastic neurological disorder’ (PND), ‘leptomeningeal metastasis’, ‘chemotherapeutic drug’, ‘metabolic disorder’, ‘cerebrovascular complications’, ‘central nervous system infection’ and ‘antiepileptic drugs’. Original research papers, clinical series, case reports and reviews were included. Our search covered all relevant data through
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10.1586/14737175.2014.906303
1 December 2013. Information on the prevalence, pathogenesis, clinical feature, treatment and prognosis was extracted from these articles. All evidences presented in the article included patients who experienced seizures or epilepsy during the course of disease. Patients with histories of seizures or epilepsy were excluded. Prevalence
The incidence of epilepsy or seizures in women with gynecologic malignancies is currently increasing [1–3]. Epilepsy or seizures may occur in patients with almost every subtype of gynecologic malignancy. Seizure incidence is associated with the histological type and degree of tumor. According to some reports, seizures occur in 11 of 1219 patients with Stage I or greater cervical cancer but were rare and unrelated to cervical cancer in Stage 0 disease [1]. Furthermore, 83 of 2050 women with ovarian cancer accepted neurological consultations; among them 7 patients exhibit seizures as their prominent neurological manifestation [2]. Various studies have also reported seizures in other gynecologic cancers such as endometrial cancer [4]. The prevalence of epilepsy in general population is around 0.5% [5], which is much lower than in patients with gynecologic malignancies. Although rare, benign gynecologic
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tumors can also cause seizures. Yumru et al. [6] presented a case report of a woman with a giant primary ovarian leiomyoma that induced seizures as the initial symptom. Recently, several researchers have reported seizures in patients with ovarian mature or immature teratoma [7–9].
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Etiologies & clinical features
Gynecologic malignancy-related seizures or epilepsy may be divided into two types: directly related to malignancy and related to complications associated with malignancy. The former mainly includes brain metastases, followed by PNDs and leptomeningeal carcinomatosis (LC). The latter includes metabolic disorders, cerebrovascular complications and CNS infections. Malignancy treatments, especially chemotherapy, can also induce seizures [10,11]. Brain metastasis Prevalence
According to statistics, 20–35% of patients with brain metastases will experience one or more seizures during their lifetime [12]. The incidence of brain metastases from all gynecological cancers is approximately 1% [13]. Choriocarcinoma comprises 35% of brain metastases ascribed to gynecologic malignancies [14]. Kazuhiko et al. [13] conducted a retrospective review of 2729 patients with gynecological cancer. Eighteen patients (0.7%) had brain metastases. The occurrence of metastasis was associated with the primary site of the tumor. According to some reports, the incidence of brain metastases originating from ovary, uterine cervix, uterine corpus and other gynecological sites were 0.3– 2.2%, 0.4–1.2, 0.3–0.9 and 1.8%, respectively. Other gynecological sites include vagina, vulva and fallopian tube [13]. Nasu et al. [15] did a retrospective study of 139 patients with brain metastasis from gynecologic malignancies, which excluded choriocarcinoma. In total, 85.7% of patients in the ovarian cancer group and 69.3% of patients in the corpus cancer group were in advanced disease stages (stage III/IV), whereas only 35.7% of patients with cervical cancer had advanced stage disease, which indicated the possibility of early brain metastasis in cervical cancer [15]. Ovarian serous adenocarcinoma, corpus endometrial adenocarcinoma and cervical endometrial adenocarcinoma are three types of tumors that most commonly cause brain metastases [15]. A recent study demonstrated increased incidence of brain metastasis from gynecological cancer, especially in ovarian cancer [15]. This may be made possible by increased patient survival due to successful treatment of extracranial tumor and the brain’s propensity to act as a tumor cell sanctuary; this may also be possible due to more effective diagnosis of intracranial lesions [2,15]. Spread & distribution
Brain metastases from gynecological cancers are always associated with disseminated extracranial tumors. They may develop anywhere in the brain although the posterior fossa may be the most likely site for these tumors [16]. However, it is hard to identify a metastasis responsible for seizures, since posterior fossa metastasis would be unlikely to result in seizures unless 504
cerebral spinal fluid (CSF) out flow from the fourth ventricle was obstructed. In general, multiple brain metastases are more often than single one to be present [15]. Hematogenous dissemination has been suggested as the primary mechanism underlying the spread of tumor cells. Detached tumor cells from the genital tract to the brain are passed through pulmonary vasculature [16]. Another possible mechanism is the Batson plexus (paravertebral venous plexus) route [16]. The supratentorial region of the brain is the most common metastatic site for cervical cancer; this may be a result of the vasculature and spatial characteristics of this region [17]. Pathogenesis
The etiological mechanism of cerebral metastatic tumorinduced epilepsy remains poorly understood [18]. However, there are several hypotheses regarding pathogenesis of brain tumors, which may give us a better understanding. These include the theory of denervation hypersensitivity, described by Echlin et al. [18] as a theory that brain tumors can chronically cause partial isolation and differentiation of the cerebral cortex, which leads to denervation hypersensitivity and generates ictus. This theory thus explains the relationship between seizure and tumor location. However, it cannot explain why in some cases, after tumor excision, seizures return or appear for the first time [18]. A second hypothesis involves microvascular disorder; one possible causal mechanism occurs by metastatic tumorrelated reduced peritumoral perfusion pressure and local microcirculation impairment, which then causes peritumoral brain ischemia and seizures [19]. Neurotransmitter abnormalities are also hypothesized to underlying pathogenesis. Brain tumors may lead to dysfunctional metabolism of amino acids in peritumoral brain areas including deficits in alanine, ethanolamine, isoleucine, valine, taurine and glutamine metabolism. Most of these amino acids act as neurotransmitters or neuromodulators. Disturbances in amino acid levels may disrupt the balance between excitatory and inhibitory compounds, which can then lead to seizures. However, it remains unknown whether disorders of amino acid metabolism are the cause or consequence of seizures [20]. A fourth theory implicates pH and enzymatic abnormalities. Peritumoral cortex pH is more alkaline, and such changes may affect the transmembrane movement of oxygen ions, reduce the flow of potassium ions and inhibit sodium channels to increase cell excitability and cause seizures. Changes in peritumoral enzyme levels such as enhanced lactate dehydrogenase, phosphodiesterase, enolase and thymidine kinase levels can also elevate neuronal excitability and cause seizures [21,22]. Aberrant cell–cell contacts or interactions between periphery tumor cells and surrounding neuronal and glial cells may result in abnormal metabolism that directly affects neuronal network function and seizures susceptibility [23]. Finally, radiation necrosis may cause ictus; seizures can be an acute or delayed manifestation following radiotherapy of brain lesions due to complications such as radiation necrosis, edema or hemorrhage. These types of cell damage may increase the incidence of seizures, which can follow soon or several months or years after radiotherapy [24,25]. Expert Rev. Neurother. 14(5), (2014)
Epilepsy in women with gynecologic malignancies
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Clinical features
In cerebral metastasis-associated seizures, clinical manifestations depend on the location, histological type and rate of growth of the tumor. Lynam et al. [26] completed a retrospective study and found that 34% of patients (12 of 35) with CNS metastases developed seizures in their course of the disease. Of these, five had seizures at presentation and seven had delayed seizures. Alajbegovic et al. [27] conducted a retrospective study and found that single seizure occurred most often (59%); a series of seizures is relatively uncommon (38%). Status epilepticus occurred in only 3% of patients. The most common type of seizures were simple partial seizures with or without secondary generalization (66% of seizures were simple partial seizures: 44% of which occurred without generalization and 22% occurred with generalization), followed by generalized convulsive seizures (31%), and finally, the least common type, complex partial seizures (3%) [27]. Ramamurthi et al. [28] reported that partial seizures are often associated with lesions in perirolandic areas affecting M1, S1, the supplementary motor area or the secondary somatosensory cortex. Complex partial seizures were typically caused by lesions in the temporal lobe and were associated with auditory hallucinations, deja vu phenomena, epigastric, gustatory and olfactory auras. Treatment
Treatment can be divided into two aspects: the treatment of metastatic lesions and the treatment of seizures. The management of metastases includes supportive care, radiotherapy, surgical resection and chemotherapy [15]. In most of patients with brain metastasis originating from gynecological cancers, treatment is usually palliative because of the advanced primary tumor and poor general condition [13,15]. However, numerous studies have shown that multimodal treatments may provide better outcomes [13,15]. The treatment of seizures typically involves antiepileptic drugs (AEDs); however, whether they are useful to prevent seizures in patients with brain metastasis remains controversial. Prophylactic use of AEDs has been assessed in patients with brain tumor who had no history of epilepsy with negative results [29,30] The American Academy of Neurology has recommended that AEDs should not be administered routinely in new cases of brain tumor due to their ineffective prevention of initial seizures [31]. AEDs can be administered once brain metastases cause seizures [31]. To maintain seizure-free status in brain tumor patients is very difficult despite AED treatment. The mechanisms of brain metastases-associated seizures are complicated. While the effects of AEDs are almost certainly associated with blocking or inactivating Na2+ or Ca2+ channels or increasing GABAergic activity [32], this accounts for only part of various epileptogenic mechanisms. In addition, interactions with antitumor drugs may decrease the serum concentration and effectiveness of AEDs [33]. Lamotrigine, valproic acid and topiramate are first-line treatments for seizures in patients with brain tumors [33]. Wagner et al. [34] found that add-on levetiracetam can decrease seizure frequency in 50–65% of patients, while some patients informahealthcare.com
Review
Table 1. Alleviation of symptoms by antiepileptic drugs. Drug
Depression
Anxiety
Pain
Phenytoin
+
-
+
Carbamazepine
+
-
+
Valproic acid
+
-
+
Gabapentin
-
+
+
Pregabalin
-
+
+
Lamotrigine
+
-
+
Topiramate
+
+
+
Zonisamide
+
-
-
Oxcarbazepine
+
-
+
Tiagabine
+
+
+
Levetiracetam
-
+
+
Data taken from [37].
remain seizure free throughout their lifetime [34–36]. Some reports indicate that after add-on gabapentin, all patients achieved seizure remission, and 50% of patients were seizure free [33]. When first line or monotherapy is ineffective, double or triple combinations should be considered [33]. Other than seizures, there are many other symptoms in gynecologic malignancies such as pain, depression and anxiety. Some studies have shown that remission of one or more concomitant symptoms can be achieved with AEDs. Thus, the decision to prescribe AEDs is made according to seizure type or concomitant symptoms (TABLE 1) [37]. When surgery for metastatic lesions is necessary, prophylaxis via AEDs should be considered; however, their effect remains unclear [33]. In recent years, an increasing body of research has found that resection or cytoreductive surgery is usually followed by good outcomes, involving the remission or curing of brain metastasis-associated seizures. However, this is related to many factors including lesion location, operative approach and execution and the extent of tumor resection [28,38]. Prognosis
The median survival of patients with gynecologic malignancies who developed brain metastasis is 3–6 months [12]. The presence of seizures is associated with poorer general health and mental status. Although be treated by complex strategies, gynecological cancer patients with seizures almost always have poorer prognoses than those without seizures; however, prognostic instruments are lacking. Paraneoplastic neurological disorder Prevalence
PNDs are rare occurring in approximately 0.01% of cancer patients [39]. PNDs are a series of neurological signs and symptoms caused by a remote cancer. They are not the direct result 505
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of a primary tumor or metastases, but the result of an autoimmune attack on normal neuronal tissue by similar neuronal antigens that are ectopically produced by tumor cells. Among tumor-associated neurological symptoms, PND accounts for 10% of all nonmetastatic causes [40]. Gynecological cancers after small cell lung cancer most frequently result in PND, especially ovarian cancer [41]. Yumru et al. [6] reported a case of a patient with giant primary ovarian leiomyoma who developed epileptic seizures as the initial presenting symptom. These authors excluded all other causes of the seizures, and the patient was seizure free after tumor resection. Although they did not test neuronal antibodies, these investigators believed the seizures to be associated to PND. Dalmau et al. [7,8] successively reported a series of 60 patients with ovarian teratoma who developed seizures and other neurological and/or psychiatric symptom, believing that these symptoms resulted from ovarian teratomaassociated PND. Specific antibodies
There are classical onconeural antibodies and antimembrane antibodies associated with gynecologic malignancies. The most specific onconeural antibody related to gynecological cancer is anti-Yo. Rojas-Marcos et al. [41] retrospectively reviewed 92 patients with PND associated with gynecological cancer and breast cancer. Their assessment of serum onconeural antibodies found that 50 patients were positive for anti-Yo, 5 were positive for anti-Hu and 5 were positive for ant-Ri indicating that anti-Yo antibody is the onconeural antibody most commonly associated with gynecologic malignancies. Anti-Yo antibodies are a type of Ig-G antibody that recognize several proteins, such as cytoplasmic proteins with a helix-leucine zipper motif and attack Purkinje cells, usually leading to paraneoplastic cerebellar degeneration and seizures [42]. In 1997, Petit et al. [42] described a woman with an endometrial adenocarcinoma and metastatic evolution who developed temporal lobe epilepsy secondary to anti-Yo antibody. Another onconeural antibody is anti-Hu, which was described in 1985. The most common symptoms associated with anti-Hu were paraneoplastic limbic encephalitis, sensory neuropathy and paraneoplastic cerebellar degeneration [40]. Anti-Hu antibody is sometimes present in the serum of patients with gynecologic malignancies [41]. Regarding antimembrane antibodies, a close relationship between the antiN-methyl-D-aspartate receptor (anti-NMDAR) antibody and ovarian teratoma (mature or immature) has been found in recent years. Dalmau et al. [7] reported on a specific antiNMDAR antibody in the serum or cerebrospinal fluid of 11 patients with ovarian teratoma and 1 patient with mediastinal teratoma. The antibody mainly attacks the neuropil of the hippocampus or forebrain; in particular, the cell surface of hippocampal neurons is targeted. Most of the 12 patients described by these authors experienced seizures, with or without prominent psychiatric symptoms, amnesia, frequent dyskinesias, autonomic dysfunction and reduced levels of consciousness. They termed this disorder paraneoplastic anti-NMDAR encephalitis. One year later, Dalmau [8] and another nine investigators described 506
100 patients with encephalitis and anti-NMDAR antibodies. Among them, 53 had a teratoma (35 had mature ovarian teratoma, 14 had immature ovarian teratoma and 4 had radiographically demonstrated teratoma). Seventy-six patients developed seizures. Pathogenesis
Generally, PND is associated with all nonmetastatic neurological disorders including metabolic disorders, infections and coagulation disturbances. Our discussion of PND considers that only or mainly caused via immune-mediated mechanisms. Onconeuronal antigens are recognized by the immune system once tumor cells spontaneously undergo apoptosis and dendritic cells phagocytose antigens contained in apoptotic bodies [43]. Various immune responses then also occur. These include hormonal immune responses, in which B Cells bind to specific onconeural antigens and produce specific antibodies. Several studies have shown that the concentration of specific onconeural antibodies in the cerebrospinal fluid are much higher than in the serum, indicating that onconeural antigens can be made intrinsically in the CNS rather having to cross the blood–brain barrier (BBB) [43]. Anti-Hu antibody is a neuronal antinuclear antibody associated with an intranuclear RNAbinding protein that acts to regulate the cell cycle [44]. A previous study found that anti-Hu clearly demonstrates cytotoxicity and always results in limbic encephalitis. Anti-Yo antibody is specific to Purkinje cells and always accompanies paraneoplastic cerebellar degeneration; it may also sometimes cause limbic encephalitis [45]. Cellular immune responses also occur: most recently, cytotoxic T cells are believed to play the primary role in PND pathogenesis [46]. T cells can be found at autopsy and biopsy in patients with PND. T cells are generally found in the perivascular spaces and parenchyma. Hu-specific T-helper cells and Hu-specific cytotoxic T cells have been found to be expressed in the blood of PND patients [47]. Yospecific T-helper cells and Yo-specific cytotoxic T cells were also identified in the blood and CSF [48]. Both hormonal and cellular immune responses may lead to neuronal loss and inflammation infiltration, which progresses to cause various neurological disorders [46–48]. Patients with gynecologic malignancies can develop paraneoplastic cerebellar degeneration, limbic encephalitis, motor neuron syndrome, inflammatory myopathy and dermatomyositis. Seizures are mainly a manifestation of paraneoplastic encephalitis; they always co-occur with paraneoplastic limbic encephalitis and are sometimes associated with cortical encephalitis [40]. Closely examined teratomas may be found to contain nervous tissue, express anti-NMDAR subunits (NR1, NR2 or their heteromers) and then produce specific antibodies, which leads to anti-NMDAR encephalitis and seizures or other neurological symptoms [7]. Clinical features
Seizures in PND patients with gynecologic malignancies always appear before the diagnosis of primary tumors or several months or years after chemotherapy [10]. In patients with PND, the most common type of seizures are generalized seizures, Expert Rev. Neurother. 14(5), (2014)
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Epilepsy in women with gynecologic malignancies
complex seizures or partial status, with or without agitation, confusion or hallucination [10,43]. Gultekin et al. [45] reported on 50 patients with PND. Twenty-five patients developed seizures: 10 experienced temporal lobe of partial seizures, 6 had generalized seizures and 9 had a combination of seizure types. Abel et al. [49] reported a case of a woman with PND who presented with partial nonconvulsive status epilepticus. Shavit [50] reported a series of three patients with PND who presented with epilepsia partialis continua. These uncommon types of epilepsy may be caused by PND and should be considered. Vitaliani et al. [51] reported a series of four patients who developed PND with ovarian teratoma. Three of these patients developed generalized seizures. The investigators reviewed five previously reported patients and found that one exhibited myoclonic seizures and one demonstrated secondary generalized seizures with other symptoms such as severe behavioral and personality changes, short-term memory deficits and hallucinations. Dalmau et al. [8] described a series of 100 patients with anti-NMDAR encephalitis. Of the 76 patients who experienced seizures, 45 experienced generalized tonic–clonic seizures, 10 experienced complex–partial seizures, 8 experienced secondary generalized seizures, 6 demonstrated refractory status epilepticus, 7 experienced partial motor seizures, 7 were not classified and 2 demonstrated epilepsia partialis continua, with or without psychiatric symptoms, memory problems, dyskinesia, autonomic instability or hypoventilation. Treatment
Most patients remain seizure free after control of the primary tumor; however, a smaller group of patients experienced refractory seizures. Treatment included tumor control, immunosuppressive therapy and antiepileptic treatment. Because some AEDs interact with specific immunosuppressive drugs, careful AED selection is important. Enzyme-induced AEDs such as phenytoin, carbamazepine and phenobarbital decrease the serum concentration and effect of steroidal immunosuppressive drugs, requiring a dosage of steroid that was 150% of the normal dose to achieve the same effect [33,52]. Therefore, nonenzyme-induced AEDs are optimal; however, a clinical guideline for seizure control in PND patients with gynecologic malignancies does not exist. Prognosis
After effective control of the primary tumor, seizures typically remit in 2–6 months [53]. After excision of ovarian teratoma and immunotherapy, neurological symptoms, including seizures, in patients with anti-NMDAR encephalitis were always completely resolved [7,8]. For recurrent epilepsy, especially that associated with progressive tumors or irreversible brain damage, long-term antiepileptic treatment may be necessary.
Review
Prevalence
LM occurs in nearly 5% of all cancer patients. LM caused by gynecologic malignancies is commonly associated with ovarian cancer; the most frequent pathological finding is undifferentiated or poorly differentiated carcinomas of the serous histological subtype [11,55]. The incidence of LM increases with effective tumor treatment local control of the tumor site; this allows for more time to develop LM. According to statistics, 1–5% of LM patients develop seizures [54]. Palma et al. [55] reported a series of 50 patients with LM and found that 2 patients developed seizures as their chief complaint at presentation. Nuria et al. [11] conducted a MEDLINE search of patients with LC resulting from cervical cancer, which returned 12 case reports. Of these cases, two had developed seizures. The histopathological findings of these patients were adenosquamous carcinoma and squamous cell carcinoma; all were poorly differentiated. Pathogenesis
Although LM was first described in 1869 by Eberth [56], little progress has been made to better understand the pathogenesis, therapy and prognosis of LM. The mechanism of LM from gynecologic malignancy is still unknown. Hypothetical mechanisms of LM from malignancy are currently under investigation. Tumor cells spreading to the meninges mainly include hematogenous meningeal seeding from previous brain metastases, which extended into the ventricles or subarachnoid space, infiltration via arachnoid veins or choroid plexus extension, along the nerves, perineural or perivascular lymphatics and sheaths, etc. [57,58]. The posterior fossa, basilar cisterns and cauda equina appear to be the areas that are most heavily seeded. The slowing of the CSF flow and the effect of gravity in these area may underlie these findings [59]. Hypotheses regarding epileptogenesis include multiple mechanisms. Irritation of the adjacent corresponding brains area may lead to paradoxical discharge and seizure [54]. Invasion by tumors of the basal cisterns often leads to increased intracranial pressure and hydrocephalus by interfering with the flow of CSF in the ventricular system and basal cisterns [60]; continuous increased intracranial pressure and progressive hydrocephalus can be a cause of epilepsy. Neovascularization may form around the tumor, and the new vessels are fenestrated capillaries that allow drugs or contrast material to infiltrate the brain, which leads to seizures [60]. Similarly, infiltration of the Virchow–Robin spaces of the penetrating vessels often results in ischemia by perivascular tumor cuffing. Arteriography may indicate narrowing and beading vessels, and secondary ischemia or infarction may lead to seizures [54,61]. Finally, hydrocephalus or tumor nodules may cause compression of various brain structures and alter brain structure, which can cause seizures [54]. Clinical features
Leptomeningeal metastasis
Leptomeningeal metastasis (LM) is the dissemination of malignant cells to the leptomeninges or CSF that is distant from the primary tumor [54]. informahealthcare.com
The clinical signs and symptoms of LM are variable because LM can affect almost all levels of the CNS [62]. Seizures associated with LM can appear at any stage of the disease [10]. William et al. [62] analyzed a series of 90 LC patients and 507
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found that 5 patients (5.56%) had seizures at first clinical presentation. Among these five patients, three (3.33%) experienced generalized seizures and two (2.22%) experienced partial seizures. Eventually, 13 LC patients (21%) developed seizures. Eight patients (8.89%) experienced generalized seizures and five (5.56%) experienced partial seizures.
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Treatment
Present treatments include those that target LC and those that target seizures. LC treatments are always palliative, and there are no clinical trials to guide treatment [63]. Treatments mainly consist of intrathecal chemotherapy or systemic (iv. or oral) chemotherapy, which are combined with radiotherapy when macroscopic lesions are present [63]. Methotrexate is the recommended drug for intrathecal chemotherapy [64]. It is, however, worth noting that high doses of intrathecally injected methotrexate can lead to a variety of irreversible complications including aseptic meningitis, leukoencephalopathy, encephalopathy and opportunistic intracranial infection. These complications can induce seizures [54,65]. AEDs prescription should take potential interaction with chemotherapeutic agents into account.
Clinical features
Seizures often appear during or after chemotherapy administration [10]. This includes serious type of seizures; generalized tonic– clonic seizures are the most commonly occurring type [10]. Steeghs et al. [66] reported a series of 3 patients and reviewed 21 patients who received cisplatin chemotherapy and developed encephalopathy with seizures. Twelve patients experienced generalized tonic–clonic seizures, 7 experienced partial seizures, 3 demonstrated status epilepticus and 2 patients experienced unspecified seizures. Cisplatin-induced seizures are often accompanied by cortical blindness, aphasia, hemiparesis and acute psychosis [64,66]. Most of the patients of this series made a complete recovery; however, a small group of patients experienced ongoing seizures that were resistant to antiepileptic treatment [66]. Paclitaxel
Paclitaxel is an anticancer agent of the taxanes family, which is widely used to treat solid tumors such as gynecological cancer and breast cancer. Peripheral neurotoxicity is one of the main adverse effects of paclitaxel, while CNS toxicity is relatively rare [65,67]. Both acute and delayed encephalopathy has been described in patients treated to paclitaxel [65].
Prognosis
The prognosis of LC patients is poor. Median survival of LC patients is 4–6 weeks. After effective treatment, survival is approximately 4–6 months [55]. Therefore, the outcome of LCrelated seizures is unknown. Drug-induced seizures
Epilepsy is a typical form of dose-limiting toxicity in Phases I and II clinical trials of some cancer drugs. Epilepsy can occur in patients undergoing treatment for cancer, especially at high drug doses. Additionally, renal or hepatic disorders may affect drug clearance and lead to epilepsy. Among these drugs, chemotherapeutic drugs are a frequent cause of drug-induced seizures in cancer patients. Cisplatin
Cisplatin is an effective and widely used agent for gynecological cancer patients, especially patients with ovarian carcinoma and cervical carcinoma. Pathogenesis
Cisplatin-induced seizures are a typical manifestation of acute toxic encephalopathic syndrome, which usually occurs with a combination of cortical blindness, aphasia, hemiparesis or acute confused state [66]. Cisplatin-induced seizures are a doselimiting clinical manifestation. In adults, CNS toxicity usually occurs in patients given more than 200 mg/m2 cisplatin doses [64]. Seizures are associated with cisplatin-induced electrolyte disturbances, in particular, hypokalemia, hyponatremia and hypomagnesaemia. All of these factors can cause the seizure threshold to decrease and cause seizures [66]. Cisplatin may also lead to posterior leukoencephalopathy syndrome and focal neurological disorders which are always accompanied by seizures [66]. 508
Pathogenesis
Direct effects of paclitaxel: It is generally believed that paclitaxel does not cross the BBB and is in negligible concentrations in CSF. However, a previous study demonstrated that a low concentration of paclitaxel was found in the brain of nude mice after tail vein injection, indicating that a trace amount of paclitaxel may actually cross the BBB [68]. Additionally, brain metastases, previous brain surgery, or whole-brain irradiation may cause damage to the small- and medium-sized brain vessels or oligodendroglia and disrupt the BBB, which can facilitate seizures or encephalopathy [65,67]. Toxicity of the carrier
Tracey et al. [69] reported on one patient who was treated by paclitaxel formulated using Cremophor EL and who then developed delayed onset of seizures 4 days after drug infusion. There was no history of seizures, and no metabolic lesion was present. These researchers believed that the seizures were caused by paclitaxel or its carrier [69]. Because paclitaxel is insoluble in water, it is formulated with the micelle-forming Cremophor EL. Each milliliter of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor EL (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol. Cremophor EL is considered to be a neurotoxicity agent and its half-life at doses of 70–110 mg/m2 ranges from 70 to 77 h. Thus, the carrier may have caused delayed seizures, and it is difficult to discriminate whether Cremophor EL and paclitaxel causes CNS side effects [69]. Clinical features
Seizures appear often during or soon after paclitaxel administration although delayed seizure may occur. Generalized Expert Rev. Neurother. 14(5), (2014)
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Epilepsy in women with gynecologic malignancies
tonic–clonic seizures are the most common type of seizure [10,69]. There are a few case reports regarding seizures related to paclitaxel infusion. William et al. [70] reported that 1 of 51 patients with epithelial ovarian cancer experienced two grand mal seizures after the first few hours of her paclitaxel treatment, which was two-times the standard dose. There was no metastatic lesion, and the lumbar puncture results were normal. The EEG findings indicated nonspecific changes. Michelle et al. [71] described a patient who experienced a generalized tonic–clonic seizure 5 min after paclitaxel infusion was initiated. The patient’s neurological examination and EEG and MRI were normal. The authors believed that these seizures may have been caused by paclitaxel-induced CNS toxicity. 5-Fluorouracil
The pyrimidine antimetabolite and antineoplastic 5-fluorouracil (5-FU) are widely used as a chemotherapeutic agent to treat gynecological cancers such as cervical cancer, vaginal cancer and vulvar cancer. Furthermore, 5-FU-induced neurotoxicity is uncommon, occurring in
