Unexplained spikes in lamotrigine serum concentration: nonlinear elimination?

OBJECTIVES: The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic. MATERIALS AND METHODS: Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity. RESULTS: Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose. CONCLUSIONS: Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l.

Visual field defects after selective amygdalohippocampectomy and standard temporal lobectomy.

BACKGROUND: Selective amygdalohippocampectomy (SelAH) is increasingly performed in patients with mesial temporal lobe epilepsy and hippocampal sclerosis. To determine whether visual field defects are less pronounced after SelAH than after standard temporal lobectomy (StTL), we retrospectively analyzed postoperative quantitative visual fields after the 2 procedures. METHODS: Humphrey visual field analysis was obtained postoperatively in 18 patients who had undergone SelAH and in 33 patients who had undergone StTL. The SelAH was performed via a transcortical approach through the middle temporal gyrus and included the amygdala, 3 cm of the hippocampus, and the parahippocampal gyrus. The visual field pattern deviation was used for analysis. We considered a defect clinically significant if there were 3 contiguous coordinates affected at the 5% level or 2 at the 1% level. RESULTS: All but 2 of 18 patients who had undergone SelAH had homonymous superior quadrantic visual field defects contralateral to the side of the surgery. One patient had no defects by our criteria, and one had a mild defect that reached significance only in the ipsilateral eye. The averaged defect affected mostly coordinates close to the vertical meridian with relative sparing of points close to the horizontal meridian. All but 3 of the 33 patients who had undergone StTL had homonymous superior quadrantic visual field defects. One patient had no defects; 2 had defects that reached significance in only one eye. The averaged defect involved all points in the affected quadrant, but was also greater near the vertical meridian. Of 13 tested visual field coordinates, 4 were significantly less affected by SelAH in the ipsilateral eye and 3 in the contralateral eye. The coordinates close to the horizontal meridian were significantly spared by SelAH. CONCLUSIONS: Visual field defects are very common after SelAH but are significantly less pronounced than after StTL. In particular, the visual field close to the horizontal meridian is relatively spared in SelAH.

Genetic variants in the IMPA2 gene do not confer increased risk of febrile seizures in Caucasian patients.

Pathogenesis of febrile seizures (FS), causing the most common of types of seizures in children, remains unknown. Genetic factors appear to play a pivotal role and FS can be inherited as a monogenic or genetically complex disorder. Several risks factors have been proposed but many of the previously reported genetic associations were not replicated. Non-coding polymorphisms in the myo-inositol monophosphatase 2 gene (IMPA2) have been suggested as a susceptibility factor for FS in Japanese patients. It is unknown whether genetic variants in the same gene constitute a risk factor for FS in other ethnic groups because the frequency of FS is significantly higher in Japanese children than in Caucasian patients. We investigated the role of the IMPA2 gene in a cohort of 96 unrelated Caucasian subjects with a history of FS. We did not identify any significant differences in genotypes of cases and matched controls; no mutations or non-synonymous polymorphisms were detected in these individuals. Our data suggest that the genetic variants in the IMPA2 gene are not associated with a risk of FS in Caucasian patients and patients from various genetic groups are likely to have different genetic causes of FS.

Familial genetic predisposition, epilepsy localization and antecedent febrile seizures.

PURPOSE: The magnitude of genetic influence in epilepsy may vary in relation to epilepsy classification and localization and factors such as antecedent febrile seizures. We assessed this genetic influence in a large epilepsy population. METHODS: Patients with established epilepsy diagnosis evaluated in the Vanderbilt Epilepsy Program were systematically questioned about family history of epilepsy and febrile seizures, prior febrile seizures and other risk factors for epilepsy. RESULTS: A total of 1994 patients with epilepsy and reliable family history were identified. Patients with prior febrile seizures (FS) were more likely to have a family history of febrile seizures than those without prior FS (p<0.000001) and also had a greater proportion of relatives with febrile seizures. The groups did not differ with respect to family history of epilepsy. Patients with generalized epilepsy were more likely to have first and second degree relatives with epilepsy than those with partial epilepsy (40.2% versus 31.2%, p=0.001), and also had a greater proportion of affected first degree relatives (p<0.000001). The proportion of first degree relatives affected with epilepsy was higher than local published prevalence, for both groups. CONCLUSION: Susceptibility for febrile seizures with subsequent epilepsy may be genetically distinct from susceptibility for afebrile seizures alone. Although family history of epilepsy was more likely with generalized epilepsy, a familial tendency was considerable in partial epilepsy.

Biopsy results in a kindred with Lafora disease.

We studied biopsy results in a kindred with the Lafora form of progressive myoclonic epilepsy. Four members of a family with known consanguinity presented as teenagers with seizures, myoclonus, dementia, and ataxia. After the diagnosis was established by brain biopsy in the first patient, many efforts were made to obtain a tissue diagnosis in the three other patients. Lafora bodies were absent in most of the skin biopsy specimens in three patients and in liver biopsy specimens from two patients. In cases of Lafora disease, where a reasonably certain clinical diagnosis can be established, supported by biopsy proof in some family members, repeated biopsy specimens even at advanced stages of the disease may be negative. These findings suggest that negative skin or liver biopsy specimens in patients with progressive myoclonic epilepsy should not exclude the diagnosis of Lafora disease.

The course of seizure disorders in patients with malignant gliomas.

OBJECTIVE: To describe the morbidity associated with seizures and the efficacy of anticonvulsant therapy in adult patients with malignant gliomas (MGs). STUDY DESIGN: A retrospective review of charts was performed to determine the occurrence of seizures at diagnosis, the frequency and character of subsequent seizures, and the use and toxic side effects of anticonvulsants. PATIENTS: Sixty-five consecutive adult patients with supratentorial MGs who were examined in the neurooncology clinic at a university medical center were studied. The diagnosis was glioblastoma in 47 of the patients, and it was anaplastic astrocytoma in 18 patients. The mean age of the patients was 49.5 years. The median Karnofsky status score was 80. The median survival was 18 months. RESULTS: Twenty-nine patients presented with seizures, and 21 of these had subsequent (eg, "recurrent") seizures while they were receiving anticonvulsant therapy. Ten of 36 patients who were free of seizures at diagnosis experienced seizures after diagnosis (eg, "late onset") while they were being treated with anticonvulsants, including five patients who had single seizures. Long-term seizure frequency in excess of one per month was observed in 13 patients. Ten patients had episodes of partial motor status epilepticus. Most recurrent and late-onset seizures occurred despite therapeutic anticonvulsant levels, and without evidence of tumor progression. Rash associated with anticonvulsants was observed in 26% of the patients. Other clinically important toxic side effects were observed in 14% of the patients who were receiving long-term anticonvulsant therapy. CONCLUSIONS: Seizures contributed substantially to the neurologic morbidity of MGs in at least 25% of these patients. The occurrence of seizures at diagnosis was a strong predictor of subsequent seizures, and in many patients, seizures proved to be refractory to standard anticonvulsant therapy. Long-term anticonvulsant toxic side effects are relatively common in patients with MGs. The use of long-term seizure prophylaxis for patients with MGs who are free of seizures at presentation is not clearly beneficial and should be studied in a prospective trial.

Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions.

PURPOSE: A history of febrile convulsions (FC) is often obtained in patients presenting for surgical treatment of temporal lobe epilepsy (TLE), but it is not clear that preferential temporal localization of epilepsy is associated with antecedent FC. METHODS: We prospectively inquired about FC and their characteristics in all patients presenting to an epilepsy clinic through a patient questionnaire and interview. We studied the incidence of antecedent childhood febrile convulsions in relation to epilepsy diagnosis. RESULTS: FC were reported by 133 of 1005 study patients (13.2%). TLE was more likely to be preceded by FC (78/310, 25.2%) than extratemporal epilepsy (ETE) (12/216, 5.6%) (p < 0.000001) or generalized epilepsy (GE) (16/146, 11.0%) (p < 0.001). Patients with GE were more likely than patients with TLE to have had simple FC (p < 0.00005). Prolonged duration was the most common FC complex feature in TLE patients. CONCLUSIONS: We demonstrated a preferential association of FC with temporal lobe foci and a weaker association between FC and GE. FC does not appear to be a clear risk factor for ETE.

Brief antiepileptic drug withdrawal prolongs interval to next seizure.

OBJECTIVE: To evaluate the course of seizure control after reinstitution of antiepileptic drugs (AEDs) in patients whose AEDs were discontinued during inpatient EEG-video monitoring. METHODS: The authors studied prospectively patients with intractable epilepsy admitted for EEG-video monitoring with AED withdrawal. They examined seizure diaries in the 2 months preceding admission and recorded the number of seizures during hospitalization and for 2 months after discharge. They also recorded the interval between the last two seizures preceding admission (S-S pre), from the last seizure to admission (S-A), from discharge to the first seizure after discharge (D-S), and between the first and the second seizures following discharge (S-S post). RESULTS: Sixty patients qualified for the study. There was a significant decrease in seizure frequency in the 2 months after discharge compared with baseline (p = 0.02). For patients who had at least two seizures during follow-up, the mean D-S interval was significantly longer than mean S-S pre and S-S post (p < 0.005), whereas the latter two intervals were comparable. Prolongation of D-S was related to duration off AEDs and to the AED restarted, but not to the number or severity of seizures during monitoring. CONCLUSION: Seizure improvement after reinstitution of antiepileptic drugs (AEDs) is due primarily to prolongation of the interval from reinstitution of AEDs to the next seizure. This may reflect increased patient responsiveness to AED therapy after a drug "holiday" and has implications for experimental AED testing in the setting of presurgical evaluation.

Aphasia secondary to partial status epilepticus of the basal temporal language area.

We present a patient with aphasia of several days' duration that was secondary to spontaneous partial status epilepticus arising from the left basal temporal region. Evidence from MRI, EEG, and PET confirmed the origin of the seizures in the basal temporal area. Both the seizure discharges and the aphasia resolved after antiepileptic therapy. This case, to our knowledge, is the first documented example of epileptic aphasia secondary to spontaneous partial status epilepticus originating from the basal temporal area.

Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. METHODS: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. RESULTS: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p /=10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. CONCLUSION: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.

Visual field defects after temporal lobe resection: a prospective quantitative analysis.

OBJECTIVE: To evaluate and quantify prospectively visual field changes in patients undergoing temporal lobe resections for intractable epilepsy. BACKGROUND: Visual field abnormalities occur after temporal lobe resections for epilepsy; however, we have not encountered published reports using automated static visual field analysis. METHODS: Humphrey visual fields (program 30-2) were obtained before and after partial temporal lobe resection in 32 consecutive patients with intractable epilepsy. A quantitative point-by-point analysis was made in the affected superior quadrant, and the defects were averaged for the whole patient group. RESULTS: Thirty-one patients developed a visual field defect, but none was aware of the defect. The points nearest fixation were relatively spared. The defects were greatest in the sector closest to the vertical meridian in the eye ipsilateral to the resection. The ipsilateral and contralateral mean field defects also differed in both topography and depth. A significant correlation was found between the extent of lateral temporal lobe resection and the degree of the defect in the contralateral eye. CONCLUSIONS: There are differences in the shape and depth of the ipsilateral and the contralateral field defects not previously reported. These findings demonstrate that certain fibers from the ipsilateral eye travel more anteriorly and laterally in Meyer's loop, and support the hypothesis that visual field defects due to anterior retrogeniculate lesions are relatively incongruous because of anatomic differences in the afferent pathways. Automated perimetry is a sensitive method of evaluating and quantifying visual field defects.

Adult myoclonic epilepsy: a distinct syndrome of idiopathic generalized epilepsy.

The authors present 11 cases of idiopathic generalized epilepsy that began in adulthood at a mean age of 39 years. All patients had myoclonic jerks, five had absence seizures, and nine had infrequent generalized tonic-clonic seizures. A majority had a family history of seizures. EEG in all patients showed generalized epileptiform abnormalities, whereas neuroimaging and neurologic examination results were normal. This series appears to represent a previously undescribed idiopathic generalized epilepsy syndrome of adult myoclonic epilepsy.

Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel alpha-subunit (SCN1A) and beta1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types. METHODS: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives. RESULTS: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T). CONCLUSIONS: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.

MRI asymmetries and language dominance.

OBJECTIVE: To examine the relationship between language dominance, as measured by Wada testing, and hemispheric asymmetries on MR brain images. BACKGROUND: A previous report that did not include verification of language dominance compared the length of the planum temporale with hemispheric asymmetries seen on CT and inferred that occipital lobe asymmetry is related to language dominance. METHODS: Language dominance was identified by the Wada test in 57 patients evaluated for surgical treatment of epilepsy. Fifty-five had an MRI scan that allowed accurate measurement. In a blinded fashion, two examiners independently measured bilateral frontal, parietal, and occipital lobe lengths on MR scan for each patient. Measurements of asymmetries were compared with language dominance established by the Wada test. RESULTS: Reliability of measurement between the examiners was 97%. Asymmetry of the occipital lobe length on MR scan 10 mm above the tentorium was the only measurement significantly related to language dominance (p < 0.01). Occipital lobe length was longer on the left in 19 (40%) and on the right in 10 (21%) patients with left dominance. The right lobe was longer in six of seven (86%) patients with bilateral dominance. One patient with right hemisphere dominance had a longer left lobe. None of the measurements significantly related to handedness. CONCLUSION: Asymmetries of occipital lobe length relate to language dominance, but such dominance cannot be reliably identified by MR in an individual patient.

Pilot study of fluzinamide (N-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) in refractory partial seizures.

We conducted a pilot study of fluzinamide in 15 adults with refractory partial seizures. After a baseline period, fluzinamide was added to the existing regimen of phenytoin and carbamazepine and increased to maximum tolerated dose. Common side effects included dizziness, diplopia, ataxia, headache, nausea, and rash, resulting in patient withdrawal in six cases. Seizures became less frequent in four of the nine patients who completed the 8-week trial.

Differences between lateral and mesial temporal metabolism interictally in epilepsy of mesial temporal origin.

We performed interictal [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in 17 patients with well-defined unilateral anterior mesial temporal epileptogenic foci as determined by EEG procedures. Sixteen of these patients subsequently underwent surgical resection of the epileptogenic focus. We measured local cerebral metabolic rates for glucose in mesial and lateral temporal structures and compared them with metabolic rates for analogous regions in 16 healthy normal volunteers and the contralateral hemisphere of the epileptic patients. We found relative hypometabolism ipsilateral to the seizure focus more frequently and to a greater degree in the lateral than in the mesial temporal cortex. Since the physiologic abnormalities involved mesial temporal structures, this observation suggests that functional pathways exist between mesial and lateral temporal cortex normally and that these pathways are altered in epilepsy of mesial temporal origin. Hypometabolism did not correlate well with histologic abnormalities in the surgical specimens.

Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.

This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).

Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group.

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). BACKGROUND: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. DESIGN: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30-46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. METHODS: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. RESULTS: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. CONCLUSION: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Postsurgical outcome of patients with uncontrolled complex partial seizures and temporal lobe hypometabolism on 18FDG-positron emission tomography.

RATIONAL AND OBJECTIVE: The purpose of this study is to evaluate the relation between a focus of temporal lobe hypometabolism, including comparison between mesial and lateral asymmetry on fluorine-18-labeled-deoxyglucose-positron emission tomography (18FDG-PET) and surgical outcome in patients with uncontrolled partial seizures. METHODS: Case histories, electroencephalogram (EEG) findings, radiographic findings, and surgical outcome (36 +/- 11 months of follow-up) were reviewed in 38 consecutive patients who had a interictal 18FDG-PET scan and subsequent temporal resection. RESULTS: Among the 36 patients who had a temporal lobe focus of hypometabolism (more than 15% asymmetry to contralateral side), 61% (22 of 36) became seizure-free, 33% (12 of 36) markedly improved and 6% (2 of 36) did not improve. The focus of hypometabolism on PET was in agreement with the epileptic focus on the noninvasive EEG in 30 of 36 patients and in 19 of the 22 patients who underwent an invasive EEG. The asymmetry index for the mesial temporal lobe was significantly higher in the group of patients who became seizure-free compared with the other patients. CONCLUSION: This study confirms that a focus of interictal temporal hypometabolism on PET is associated with marked improvement of seizure control after surgery in 94% (34 of 36) of the patients. Hypometabolism in the mesial temporal lobe appears to be associated with a seizure-free outcome.

Evidence for the presynaptic localization of opiate binding sites on striatal efferent fibers.

Using quantitative receptor autoradiography, [3H]D-Ala-D-Leu-enkephalin (DADL) and [3H]naloxone binding were studied in rat striatum and striatal projection areas (globus pallidus (GP) and substantia nigra pars reticulata (SNr] after unilateral striatal kainic acid lesions. [3H]DADL and [3H]naloxone binding were each examined by two methods. Initially, [3H]DADL binding was performed in 50 mM Tris-HCl (pH 7.4), 30 mM NaCl, 3 mM manganese acetate and 2 microM GTP; [3H]naloxone binding was carried out in 50 mM Tris-HCl (pH 7.4) and 100 mM NaCl. Subsequent studies were carried out in 150 mM Tris-HCl (pH 7.4) and either [3H]DADL plus 500 nM morphiceptin (to block [3H]DADL binding to mu receptors) or [3H]naloxone plus 10 nM delta receptor peptide (to block [3H]naloxone binding to delta receptors). At one and eight weeks in the lesioned striatum, [3H]DADL binding was reduced by 70% and 82%, respectively, when compared to the control side. [3H]Naloxone binding was reduced by 35% and 20%. In GP and SNr, [3H]DADL binding was reduced by 31% and 41%, respectively, at one week and 27% and 26% at eight weeks. [3H]Naloxone binding was reduced 19% in GP at eight weeks. A parsimonious explanation of these results is that opiate binding sites are located on presynaptic terminals of striatal efferent fibers to globus pallidus and substantia nigra pars reticulata as well as on local striatal axon collaterals. Since opiate peptides have recently been found to coexist with GABA in some striatal neurons, opiate peptides may play a role in striatal function by controlling GABA release from striatal efferent fibers. It is possible that pallidal and nigral opiate binding could be utilized as a marker for striatal terminals.