Differences between mesial and neocortical magnetic-resonance-imaging-negative temporal lobe epilepsy.

OBJECTIVE: The aim of this study was to assess clinical and electrophysiological differences within a group of patients with magnetic-resonance-imaging-negative temporal lobe epilepsy (MRI-negative TLE) according to seizure onset zone (SOZ) localization in invasive EEG (IEEG). METHODS: According to SOZ localization in IEEG, 20 patients with MRI-negative TLE were divided into either having mesial SOZ-mesial MRI-negative TLE or neocortical SOZ-neocortical MRI-negative TLE. We evaluated for differences between these groups in demographic data, localization of interictal epileptiform discharges (IEDs), and the ictal onset pattern in semiinvasive EEG and in ictal semiology. RESULTS: Thirteen of the 20 patients (65%) had mesial MRI-negative TLE and 7 of the 20 patients (35%) had neocortical MRI-negative TLE. The differences between mesial MRI-negative TLE and neocortical MRI-negative TLE were identified in the distribution of IEDs and in the ictal onset pattern in semiinvasive EEG. The patients with neocortical MRI-negative TLE tended to have more IEDs localized outside the anterotemporal region (p=0.031) and more seizures without clear lateralization of ictal activity (p=0.044). No other differences regarding demographic data, seizure semiology, surgical outcome, or histopathological findings were found. CONCLUSIONS: According to the localization of the SOZ, MRI-negative TLE had two subgroups: mesial MRI-negative TLE and neocortical MRI-negative TLE. The groups could be partially distinguished by an analysis of their noninvasive data (distribution of IEDs and lateralization of ictal activity). This differentiation might have an impact on the surgical approach.

Ictal and postictal semiology in patients with bilateral temporal lobe epilepsy.

Bilateral temporal lobe epilepsy is characterized by evidence of seizure onset independently in both temporal lobes. The main aim of the present study was to determine whether patients with evidence of independent bilateral temporal lobe epilepsy (biTLE) can be identified noninvasively on the basis of seizure semiology analysis. Thirteen patients with biTLE, as defined by invasive EEG, were matched with 13 patients with unilateral temporal lobe epilepsy (uniTLE). In all 26 patients, the frequency of predefined clusters of ictal and periictal signs were evaluated: ictal motor signs (IMSs), periictal motor signs (PIMSs), periictal vegetative signs (PIVSs), the frequency of early oroalimentary automatisms (EOAs), and the duration of postictal unresponsiveness (PU). Some other noninvasive and clinical data were also evaluated. A lower frequency of IMSs was noted in the group with biTLE (patients = 46.2%, seizures = 20.7%) than in the group with uniTLE (patients = 92.3%, seizures = 61.0%) (p = 0.030; p < 0.001, respectively). The individual IMS average per seizure was significantly lower in the group with biTLE (0.14; range = 0-1.0) than in the group with uniTLE (0.80; range = 0-2.6) (p = 0.003). Postictal unresponsiveness was longer than 5 min in more patients (75.0%) and seizures (42.9%) in the group with biTLE than in the group with uniTLE (patients = 30.8%, seizures = 18.6%) (p = 0.047; p = 0.002). The frequency of EOAs, PIMSs, PIVSs, and other clinical data did not differ significantly. There is a lower frequency of ictal motor signs and longer duration of postictal unresponsiveness in patients with biTLE.

Comparing the effects of cortical resection and vagus nerve stimulation in patients with nonlesional extratemporal epilepsy.

The main purpose of this retrospective study was to compare the effects of resective surgery (RESgr-26 patients) and vagus nerve stimulation (VNSgr-35 patients) on seizure frequency (2 and 5years after surgery) in patients with nonlesional extratemporal epilepsy (NLexTLE). We analyzed hospital admission costs directly associated with epilepsy (HACE) in both groups at the same follow-up. The decrease in seizure frequency from the preoperative levels, in both VNSgr and RESgr, was statistically significant (p<0.001). The seizure frequency reduction did not differ significantly between the follow-up visits for either group (p=0.221 at 2years and 0.218 at 5years). A significantly higher number of Engel I and Engel I+II patients were found in RESgr than in VNSgr at both follow-up visits (p=0.04 and 0.007, respectively). Using McHugh classification, we did not find statistically significant differences between both groups at both follow-up visits. Hospital admission costs directly associated with epilepsy/patient/year in both RESgr and VNSgr dropped significantly at 2- and 5-year follow-up visit and this reduction was not statistically different between RESgr and VNSgr (p=0.232). Both VNS and resective surgery cause comparably significant seizure reduction in NLexTLE. Resective surgery leads to a greater number of patients with excellent postoperative outcome (Engel I+II). The HACE reduction is statistically comparable between both groups.

Syncope with atypical trunk convulsions in a patient with malignant arrhythmia.

Syncope is a condition often misdiagnosed as epilepsy. Syncope caused by cardiac disturbance is a life-threatening condition and accurate diagnosis is crucial for patient outcome. We present a case study of a 71-year-old woman who was referred to our epilepsy centre with a diagnosis of refractory epilepsy. We diagnosed convulsive syncope caused by malignant cardiac arrhythmia based on the presence of cardiac asystole lasting for 20-30 seconds, which was caused by sick sinus syndrome combined with third-degree atrioventricular block. The most prominent feature of this syncope was atypical trunk (abdominal or thoracoabdominal) convulsions, which were accompanied by other motor signs (head and eye deviation and brief jerks of the extremities). In the periods between attacks, all investigations, including standard 12-lead ECG and 24-hour ECG monitoring, were normal. This case study highlights the challenge in differential diagnosis of sudden loss of consciousness. [Published with video sequences].

The role of voxel-based morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy.

PURPOSE: To determine whether voxel-based morphometry (VBM) might contribute to the detection of cortical dysplasia within the temporal pole in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS). METHODS: Eighteen patients with intractable MTLE/HS and 30 sex- and age-matched healthy controls were included in the study. All of the patients fulfilled the diagnostic criteria for MTLE/HS and underwent anteromedial temporal resection. VBM without a modulation step was applied to the magnetic resonance (MR) images of the brain. Statistical parametric maps were used to compare structural characteristics such as gray matter concentration (GMC) within the temporal pole among patients and controls separately. The acquired data were then statistically analyzed to determine the congruency between visually inspected MR imaging (MRI) scans and VBM results in the detection of morphologic abnormalities in the temporal pole compared to postoperative histopathologic findings of cortical dysplasia. KEY FINDINGS: Histopathologic examination revealed cortical dysplasia within the temporal pole in 11 patients. In detail, according to Palmini's classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. Some type of structural temporal pole abnormality was suggested by VBM in 14 patients and by visually inspected MRI scans in 11 patients. The results of VBM were in agreement with the presence/absence of cortical dysplasia in 13 patients (72.2%); this correspondence was significant (p = 0.047). In one case, VBM was false negative and in four cases it was false positive. There was congruence between the results of visual analysis and histologic proof in 55.6% of examined patients, which was not significant. SIGNIFICANCE: We found that VBM made a superior contribution to the detection of temporopolar structural malformations (cortical dysplasia) compared to visual inspection. The agreement with postoperative histopathologic proof was clearly significant for VBM results and nonsignificant for visual inspection.

Postictal psychosis and its electrophysiological correlates in invasive EEG: a case report study and literature review.

We identified two patients with medically refractory temporal lobe epilepsy, from whom intracranial EEG recordings were obtained at the time of postictal psychosis. Both patients had mesial temporal epilepsy associated with hippocampal sclerosis. In both patients, the postictal psychosis was associated with a continual "epileptiform" EEG pattern that differed from their interictal and ictal EEG findings (rhythmical slow wave and "abortive" spike-slow wave complex activity in the right hippocampus and lateral temporal cortex in case 1 and a periodic pattern of triphasic waves in the contacts recording activity from the left anterior cingulate gyrus). Some cases of postictal psychosis might be caused by the transient impairment of several limbic system structures due to the "continual epileptiform discharge" in some brain regions. Case 2 is the first report of a patient with TLE in whom psychotic symptoms were associated with the epileptiform impairment of the anterior cingulate gyrus.

Do the basal ganglia inhibit seizure activity in temporal lobe epilepsy?

There is substantial evidence in the literature that the basal ganglia (BG), namely the striatum and pallidum, are involved in temporal lobe epilepsy (TLE). The BG are probably not involved in elaborating clinical seizures, as they do not produce specific epileptiform activity and there is no evident change in the electrical activity in the BG immediately after seizure onset. The data we obtained by direct ictal recording in the BG [1,2], as well as a large body of experimental and clinical evidence reported by other groups, suggest an inhibitory role of the BG during temporal lobe seizures. The BG may have a remote influence on cortical oscillatory processes related to control of epileptic seizures via their feedback pathways to the cortex.

Depression as a prominent cause of sexual dysfunction in women with epilepsy.

The etiology of sexual dysfunction in patients with epilepsy is perceived as multifactorial, with seizure and medication effects being the most often discussed and analyzed factors. We used common statistical methods to evaluate the impact of type of epilepsy, antiepileptic medication, hormones, seizure control, and symptoms of depression and anxiety on sexual function in a group of 78 women with epilepsy. To assess sexual function, we used the Female Sexual Function Index (FSFI). To assess symptoms of depression and anxiety, we used the Beck Depression and Anxiety Inventories (BDI, BAI). Of all the observed factors, only BDI score was significantly correlated with FSFI score. There was no correlation between FSFI, hormonal levels, seizure frequency, and symptoms of anxiety. No differences were found between patients with focal and those with generalized epilepsies; between seizure-free and non-seizure-free patients; or in relation to the number and type of antiepileptic medications.

Ictal and peri-ictal oscillations in the human basal ganglia in temporal lobe epilepsy.

Preictal, ictal, and postictal oscillations in the basal ganglia were analyzed. Five persons with temporal lobe epilepsy who were candidates for surgery had diagonal depth electrodes implanted in the basal ganglia: four of them in the putamen, and one in the pallidum and caudate. Time-frequency and power spectral analyses were used to analyze the EEG. Significant frequency components of 2-10 Hz were consistently observed in the basal ganglia. The frequency of this component slowed during seizures. There was a significant ictal increase in power spectral density in all frequency ranges. The changes in the basal ganglia were consistent while seizure activity spread over the cortex, and partially persisted after the clinical seizure ended. They were inconsistent in the period after seizure onset. Seizures originating in the mesiotemporal structures can affect physiological rhythms in the basal ganglia. The basal ganglia did not generate epileptiform EEG activity. An inhibitory role for the basal ganglia during temporal lobe seizures is suggested.

"MRI-negative PET-positive" temporal lobe epilepsy: invasive EEG findings, histopathology, and postoperative outcomes.

The aim of this retrospective study was to analyze invasive EEG findings, histopathology, and postoperative outcomes in patients with MRI-negative, PET-positive temporal lobe epilepsy (TLE) (MRI-/PET+TLE) who had undergone epilepsy surgery. We identified 20 patients with MRI-/PET+TLE (8.4% of all patients with TLE who had undergone surgery; 11 men, 9 women). Of the 20 patients, 16 underwent invasive EEG. The temporal pole and hippocampus were involved in the seizure onset zone in 62.5% of the patients. We did not identify a lateral temporal or extratemporal seizure onset in any patient. Of the 20 patients, 17 had follow-up periods >1 year (mean follow-up=3.3 years). At the final follow-up, 70.6% patients were classified as Engel I, 5.8% of patients as Engel II, and 11.8% of patients as Engel III and IV (11.8%). Histopathological evaluation showed no structural pathology in any resected hippocampus in 58% of all evaluated temporal poles. The most common pathology of the temporal pole was focal cortical dysplasia type IA or IB. MRI-/PET+TLE should be delineated from other "nonlesional TLE." The ictal onset in these patients was in each case in the temporal pole or hippocampus, rather than in the lateral temporal neocortex. Standard surgery produced a good postoperative outcome, comparable to that for patients with lesional TLE. Histopathological findings were limited: the most common pathology was focal cortical dysplasia type I.

Peri-ictal yawning lateralizes the seizure onset zone to the nondominant hemisphere in patients with temporal lobe epilepsy.

The main aim of this retrospective study was to investigate the incidence and lateralizing value of peri-ictal yawning in patients with temporal lobe epilepsy (TLE) who underwent successful surgery for epilepsy (Engel class I outcome at the 2-year follow-up visit). We reviewed a total of 97 patients (59 men and 38 women). Fifty-three patients had TLE arising from the nondominant temporal lobe, and 44 had TLE arising from the dominant temporal lobe. In total, we reviewed 380 seizures. Of those, 202 seizures arose from the nondominant temporal lobe and 178 from the dominant one. Peri-ictal yawning was observed in 4 of 97 patients (4.1%) and in 7 of 380 seizures (1.8%), in the postictal period in all cases. Peri-ictal yawning occurred only in patients with right-sided, nondominant TLE. It may have a lateralizing value.

Lateralized ictal dystonia of upper and lower limbs in patients with temporal lobe epilepsy.

PURPOSE: To perform a retrospective study to determine the incidence and lateralizing value of ictal dystonia in patients with temporal lobe epilepsy. METHODS: The study included 142 patients (76 males, 66 females) with temporal lobe epilepsy, aged from 19 to 58 years with an average age of 33.1 +/- 8.7 years. Overall, 454 seizures were analysed. The seizure onset zone was mesial in 112 patients (78.8%), and "non-mesial" in 30 patients (21.2%). RESULTS: Ictal dystonia was present in 68 of the 142 patients (47.9%), and in 186 of 454 total seizures (40.9%). Upper limb dystonia was present in 94 seizures (50.5%) of 32 patients; hemidystonia in 84 seizures (45.2%) of 30 patients; and lower limb dystonia in eight seizures (4.3%) of six patients. For all cases, all types of ictal dystonia were contralateral to the seizure onset zone. Ictal dystonia was significantly more frequent in patients with a mesial seizure onset zone than in "non-mesial" patients (58.1% vs 7.7%; p < 0.001). Within the mesial group, ictal dystonia was significantly more frequent in patients with hippocampal sclerosis than in those patients with other lesions (66.1% vs 41.1%; p = 0.023). CONCLUSION: Ictal dystonia in temporal lobe epilepsy is a reliable lateralizing ictal sign. During almost half of the seizures studied, ictal dystonia was present in the form of hemidystonia, and isolated involvement of the lower limbs also occurred. Combined data obtained from both noninvasive and invasive EEG showed that ictal dystonia tended to occur more often in mesial onset temporal lobe epilepsy, especially when hippocampal sclerosis was the epileptogenic lesion.

Correlation study of optimized voxel-based morphometry and (1)H MRS in patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: : To assess whether structural and metabolic brain abnormalities are correlated in MTLE/HS syndrome. METHODS: : Optimized voxel-based morphometry (VBM) of gray matter concentration (GMC) and gray matter volume (GMV) and proton magnetic resonance spectroscopy measurements from both-sided hippocampal and thalamic regions were performed in 20 MTLE/HS patients and 20 sex- and age-matched healthy controls. The local GMC and GMV values were calculated in both the affected and unaffected hippocampi and ipsilateral and contralateral thalami in patients and healthy subjects, and these were compared. VBM variables and NAA, NAA/Cr and NAA/(Cr+Cho) values from the investigated brain regions were correlated. RESULTS: : (1) Analysis revealed significantly more extensive GMV reduction than GMC reduction in patients' affected hippocampus. In addition, significant GMV reduction was observed in the ipsilateral thalamus in MTLE/HS patients. (2) Significant decreases in all VBM and MRS variables were revealed in the affected hippocampus. Whilst practically normal GMC values were revealed in patients' both-sided thalamic regions, a significant decrease in local GMV and metabolic measurements were found in the patients' ipsilateral thalamus. (3) Pearson's correlations between structural and metabolic abnormalities were significant for the ipsilateral thalamus only. CONCLUSION: : Structural and metabolic abnormalities as detected by optimized voxel-based morphometry and (1)H MRS in hippocampal and thalamic regions are only partially correlated in MTLE/HS patients. It seems therefore reasonable that both methods reflect different aspects of brain pathology, which, at least to some degree, might be independently ongoing.

Secondary generalization in seizures of temporal lobe origin: Ictal EEG pattern in a stereo-EEG study.

OBJECTIVE: We tested the hypothesis that secondary generalized seizures (SGS) are not truly generalized and may involve selective regions. METHODS: The spread from focal to generalized seizures in temporal lobe epilepsy (TLE) was studied in 20 SGS recorded via stereo-EEG (SEEG) in 15 candidates for surgery. Electrodes were assigned to fronto-orbital, prefrontal, and temporal cortex, cingulate, hippocampus, and amygdala. The onset of SGS was ascertained by behavioral analysis of the video recordings. EEG recordings were evaluated using the rating scale developed by Blumenfeld [Blumenfeld H, Rivera M, McNally KA, Davis K, Spencer DD, Spencer SS. Ictal neocortical slowing in temporal lobe epilepsy. Neurology 2004;63:1015-21]. The seizure rating in each region was compared with the rating in the hippocampus. RESULTS: Ranking significantly differed in the cingulate and fronto-orbital cortex; there was a trend toward significance in the prefrontal cortex. In these regions, slow activity dominated. CONCLUSION: The onset of secondary generalization, when the head, face and all limbs are involved, does not implicate global cortical involvement.

Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years.

We performed a retrospective, multicenter, open-label study to evaluate the efficacy of vagus nerve stimulation (VNS) in all patients in the Czech Republic who have received this treatment for at least 5 years (n=90). The mean last follow-up was 6.6+/-1.1 years (79+/-13 months). The median number of seizures among all patients decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at 5 years follow-up visit. The mean percentage of seizure reduction was 55.9%. The responder rate in these patients is in concordance with the decrease of overall seizure frequency. At 1 year after beginning the stimulation, 44.4% of patients were responders; this percentage increased to 58.7% after 2 years. At the 5 years last follow-up 64.4% of patients were responders, 15.5% experienced > or = 90% seizure reduction, and 5.5% were seizure-free. A separate analysis of patients younger than 16 years of age showed lower efficacy rates of VNS in comparison to the whole group. Complications and chronic adverse effects occurred in 13.3% of patients. VNS is an effective and safe method to refractory epilepsy in common clinical practice.

Sexual functions in women with focal epilepsy. A preliminary study.

We analyzed sexual function in 29 women suffering from focal epilepsy using the Female Sexual Function Index, Beck Depression Inventory, Beck Anxiety Inventory and a battery of laboratory tests were performed to find possible correlations and differences. A total FSFI score lower than the predefined cut-off score was found in 20.7% women and the presence of at least one subtype of sexual dysfunction was found in 51.7% of them. The most frequent dysfunction was lack of lubrication, which occurred in 34.5% of patients. A higher depression score was significantly correlated with a worse total score of Female Sexual Function Index and with decreased score of lubrication, satisfaction and pain. Patients who were seizure-free had better total score of Female Sexual Function Index and score of lubrication, orgasm and pain in comparison to patients who were not seizure-free. A higher anxiety scale was correlated only with lower satisfaction. We found a statistically significant correlation of reduced desire and use of carbamazepine and with lower dehydroepiandrosterone sulphate and free-androgene index. Reduced arousal was also correlated with the use of carbamazepine and lower dehydroepiandrosterone sulphate. Patients with a combination of complex partial and generalized tonic-clonic seizures had a worse total sexual function score and pain score than those with complex partial and generalized tonic-clonic seizures only. Sexual dysfunctions are relatively common problems in epileptic women with focal epilepsy. Prospective studies, including a control group, are needed.

Magnetic resonance spectroscopy of the thalamus in patients with typical absence epilepsy.

PURPOSE: To investigate possible neuronal dysfunction of the thalamus in patients suffering from typical absence epilepsy, using magnetic resonance spectroscopy (MRS). Special attention was paid to levels of N-acetylaspartate (NAA) and creatine (Cr), and to the NAA/Cr ratio. METHODS: MRS was performed over the right and left thalamus in nine patients suffering from typical absence epilepsy, and in nine sex- and age-matched healthy controls. All patients and controls were examined using a standard MRS-CSI (chemical shift imaging) technique. RESULTS: Statistical analysis of the obtained data demonstrated a significantly lower thalamic NAA/Cr ratio in patients with typical absence epilepsy when compared to the healthy controls. Our MRS data showed symmetrical distribution of NAA/Cr ratio in the right and left thalamus within both the patient group and the group of healthy controls. No significant correlation between the patients' thalamic NAA/Cr values and the duration of the epilepsy or seizure frequency was revealed. CONCLUSIONS: The present MRS data clearly indicate neuronal dysfunction in the thalami of patients with typical absence epilepsy. In agreement with other recent MRS findings in different idiopathic generalized epilepsy syndromes, our results confirm the role of the thalamus as an important structure in the pathogenesis of typical absence epilepsy.

Dropped head syndrome in severe intractable epilepsies with mental retardation.

PURPOSE: Dropped head syndrome is characterized by a gradual forward sagging of the head due to the isolated weakness of the neck extensor muscles. The syndrome has a relatively benign clinical course. To date, there have been no reports of dropped head syndrome in epileptic patients. METHODS: Nine patients with intractable epilepsy (mean age, 33.6+/-9.91 years), each presenting with apparent dropped head, were evaluated. The duration of the drooping head symptom varied from 3 to 15 years (mean, 7.4+/-4.06 years), with a slowly progressing weakness in most of the patients. In all of the patients, extensive clinical, laboratory, electrophysiological, histopathological, and neuroimaging examinations were performed. RESULTS: The weakness in all of the subjects was strictly limited to the cervical paraspinal muscles. Laboratory studies produced normal results from all subjects. EMG and muscle biopsy were normal or revealed subtle nonspecific myopathic changes without inflammation in the cervical paraspinal muscles. Polymyographic investigation revealed that none of the patients had convincing dystonic spasms of the anterior neck muscles. No atrophy or fatty changes of the neck extensor muscles were observed on CT or MRI. In most of the patients (7/9), altered L-carnitine concentrations were observed (four patients displayed a marked decrease in plasma carnitine concentrations, and three other patients showed abnormalities in urinary excretion of carnitine). CONCLUSIONS: These findings seem to suggest that a secondary carnitine deficiency, induced by antiepileptic drugs (principally valproic acid), represents a plausible pathogenetic mechanism for the development of dropped head in some epileptic patients.

Long-term outcomes in patients after epilepsy surgery failure.

PURPOSE: The primary aim of this study was to analyze the long-term outcomes of patients who were classified as Engel IV one year after resective epilepsy surgery. The secondary objectives were to evaluate the effectiveness of different treatment options and to examine the reasons that the patients did not undergo resective reoperation. METHODS: Our study was designed as a retrospective open-label investigation of the long-term outcomes of 34 patients (12% of all surgically treated patients) who were classified as Engel IV one year after epilepsy surgery. RESULTS: At the last follow-up visit (average of 7.6 ± 4.2 years after surgery), 12 of the 34 examined patients (35.3%) were still classified as Engel IV; 22 of the 34 patients (64.7%) were improved (Engel I-III). Of the 34 patients, 8 (23.5%) achieved an excellent outcome, classified as Engel I, 3 patients (8.8%) were classified as Engel II, and 11 patients (32.4%) as Engel III. The seizure outcome in the patients classified as Engel I was achieved by resective reoperation in 4; by a change in antiepileptic medication in 3 patients; and by vagus nerve stimulation (VNS) in 1 patient. The seizure outcome of Engel II was achieved by a change in antiepileptic medication in all 3 patients. Of the 34 patients, a total of 6 (17.6%) underwent resective reoperation only. The major reasons for this were the absence of a plausible hypothesis for invasive re-evaluation, the risk of postoperative deficit, and multifocal epilepsy in the rest of patients. CONCLUSION: Although the reoperation rate was relatively low in our series, we can achieve better or even excellent seizure outcomes using other procedures in patients for whom resective surgery initially failed.

A new approach to the in vivo and in vitro investigation of drug release from locoregionally delivered microspheres.

The purpose of this work was to determine the in vivo release profile of doxorubicin (Dox) delivered locoregionally by dextran-based microspheres (MS) and to develop an in vitro method for predicting in vivo drug release from MS-- in vitro-in vivo correlation (IVIVC). For the determination of in vivo Dox release, drug-loaded MS were placed into hollow fibers (HF) and implanted subcutaneously into C3H mice. Samples were retrieved at various times following implantation, MS removed from HF, and the amount of Dox remaining determined via ultraviolet/visible (UV/Vis) spectrophotometry. Various in vitro systems were designed and investigated for their ability to link in vivo and in vitro release profiles, including an open system (e.g. a column) with continuous flow of release medium at different flow rates and closed systems (e.g. a cuvette) using different release media and conditions. About 34% of loaded Dox was released from MS in vivo at 48 h. Only an incremental release was observed over the ensuing 72 h. The release kinetics of Dox from MS using three of the investigated in vitro systems, column system and HF immersed in a buffer solution or growth medium gave release profiles that were highly correlated with the in vivo release profile (r(2)>0.9). The relationships, both linear and non-linear, suggest that Level A IVIVC models can be developed for Dox release from locoregionally delivered MS using specially designed release systems.