An open-label evaluation of the tolerability and safety of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease patients experiencing wearing-off.

OBJECTIVES: To evaluate the tolerability, safety and efficacy of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease (PD). BACKGROUND: Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound. DESIGN METHODS: An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments. RESULTS: 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments. CONCLUSIONS: Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.

Treatment of refractory partial status epilepticus with multiple subpial transection: case report.

Status epilepticus (SE) represents a medical emergency that annually affects 60,000--150,000 individuals in the United States. Selective neuronal loss in vulnerable areas has been pathologically demonstrated following convulsive SE primarily affecting the limbic system, thalamus and cerebellum. Morbidity in those cases that follow refractory SE (RSE) is poorly documented. There have been anecdotal reports of surgical treatment for this condition, especially secondary to brain lesions. We report a 6-year-old patient who was in RSE for 60 days, without a brain lesion documented by MRI. The patient underwent multiple subpial transection (MST) of the sensorimotor cortex, which by ictal EEG and ictal SPECT proved to be the epileptogenic zone. We conclude that MST should be considered as an alternative treatment for refractory partial SE.

Transient epileptic amnesia in dementia: a treatable unrecognized cause of episodic amnestic wandering.

The authors present two patients with dementia who displayed recurrent transient episodes of amnestic wandering and disorientation characterized by getting lost in familiar environments. At other times these patients did not wander or become disoriented. The inability to recall any information during these episodes, and the marked difference of the episodic amnesia exacerbations from the progressive amnesia characteristic of Alzheimer disease seen in these patients led to their evaluation. These clinical episodes and the bilateral interictal epileptiform electroencephalographic changes found in both patients led to the diagnosis of transient epileptic amnesia, a syndrome that can be diagnostically elusive. These transient amnestic wandering events subsided after treatment with antiepileptic drugs in both patients. The authors suggest that transient wandering of this type may be caused by ictal events or postictal confusional states. This report emphasizes the importance of recognizing transient epileptic amnesia as an easily treatable cause of episodic behavioral abnormalities responsive to antiepileptic therapy, especially in those patients who have a markedly inconsistent pattern of wandering, disorientation in familiar settings, and amnesia exacerbation manifested by no recall of the emotional stress of getting lost or of any information during these episodes. Recognition of this type of behavioral disruption and its proper treatment can lead to improved quality of life for these patients, maintain these patients in their homes and out of chronic care institutions longer, and facilitate the community's and caretaker's interactive roles with the patient.

Assessment of colour vision in epileptic patients exposed to single-drug therapy.

Diplopia, blurred vision and colour disturbances are well-known side effects associated with anti-epileptic drugs (AEDs). Farnsworth-Munsell 100-hue colour test (F-100) is an accepted and sensitive tool to detect changes in colour perception. To determine the impact of AEDs upon colour vision, we evaluated 37 consecutive patients with complex partial seizures exposed to monotherapy with phenytoin (PHT, carbamazepine (CBZ) or valproic acid (VPA). All had normal IQ and no congenital disturbances in colour vision or ocular diseases. Twenty normal controls were used for statistical analysis. Thirteen patients were exposed to PHT, 12 to CBZ and 12 to VPA. Visual colour perception was impaired in 30/37 (82%) of the study group. The most significant abnormality was detected in the blue-yellow axis in 10/13 patients exposed to PHT (p < 0.02) and in 8/12 treated with CBZ (p < 0.009). In 8/12 patients taking VPA, no significant abnormality was observed (p < 0.06). None of the studied patients complained of colour vision disturbances. Our findings strongly support the negative effect of AEDs upon colour vision discrimination, most likely due to changes at the retinal processing level. F-100 proved to be very useful to assess early toxicity due to AEDs.

Serum neuron-specific enolase in the major subtypes of status epilepticus.

OBJECTIVES: To determine the relative magnitudes of neuron-specific enolase (NSE) levels after complex partial status epilepticus (SE), absence SE, generalized convulsive SE, and subclinical generalized convulsive SE (frequently referred to as acute symptomatic myoclonic status epilepticus). BACKGROUND: NSE is a marker of acute brain injury and blood-brain barrier dysfunction, which is elevated in SE. METHODS: Serum NSE levels were drawn in 31 patients 1, 2, 3, and 7 days after SE. Patients were classified as acute symptomatic or remote symptomatic, and the duration and outcome of SE were determined and correlated with the peak NSE level. RESULTS: NSE was elevated significantly in all four subtypes of SE, but NSE levels were highest in complex partial and subclinical SE. The mean peak NSE level for the complex partial SE group was 23.88 ng/mL (n = 12), 21.5 ng/mL for absence SE (n = 1), 14.10 ng/mL for the generalized convulsive SE group (n = 12), and 37.83 ng/mL for the subclinical SE group (n = 6), all of which was significantly higher than normal control subjects (5.02 ng/mL). Outcome was significantly different between the three groups (p = 0.0007), and was significantly worse for subclinical SE (p = 0.0005, subclinical versus generalized convulsive SE). CONCLUSION: Serum NSE levels were highest in complex partial and subclinical generalized convulsive SE. The extremely high levels of NSE in subclinical SE reflect the severity of the acute neurologic insults and poor outcome common to subclinical SE. High NSE levels in complex partial SE reflects the long duration of SE in this subgroup, and potential for brain injury.

Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier.

Neuron-specific enolase (NSE) is a sensitive marker of brain damage in stroke, global ischemia, and coma. Serum NSE is also correlated with the duration and outcome of status epilepticus (SE). CSF-NSE levels have not been previously reported in SE. We report the CSF concentrations of NSE in 11 patients with cryptogenic/remote symptomatic SE. CSF obtained within 24 hours of SE showed increased concentrations of NSE in 9 of 11 patients. The mean CSF-NSE for the group was elevated compared with the levels for normal control subjects (30.8 +/- 18.33 versus 10.76 +/- 3.08 ng/mL; p = 0.002). Further, CSF-NSE levels were elevated compared with simultaneous serum levels in the same group of patients (p = 0.01). In addition, the CSF/serum albumin ratio (QAlb), a measure of the integrity of the blood-brain barrier, was increased in SE patients compared with control individuals (33.4 versus 4.79 x 10(-3); p = 0.0001). An increase of QAlb correlated with CSF-NSE (rs = 0.66, p = 0.04) and serum NSE levels (rs = 0.83, p = 0.004). CSF-NSE is a promising in vivo marker for brain injury after SE.

Use of antiepileptic drugs in nontraumatic neurosurgical procedures. Is there any best route and time of administration?

We assessed in 15 consecutive patients the best route and time of administration for phenytoin (PHT) prophylaxis in neurosurgical procedures. We also correlated PHT levels in serum and cerebrospinal fluid after oral and parenteral loading doses. The mean PHT level was 13.9 micrograms/ml in serum and 2.03 micrograms/ml in cerebrospinal fluid (CSF), with a significant correlation between levels in both compartments (r = 0.73, p < 0.01). Mean PHT levels among the different groups were not statistically significant. We conclude that therapeutic levels of PHT in CSF can be achieved independently of the route of administration, as long as accepted loading doses are used.

Time distribution of epileptic seizures during video-EEG monitoring. Implications for health insurance systems in developing countries.

An attempt was made to identify guidelines to help establish epilepsy monitoring units in developing countries. We assessed the time distribution of seizures during video-EEG monitoring and we also estimated the minimum time required for such a procedure and the impact of these variables upon the health insurance system. Mean time for recording five stereotyped clinical events was 72 hours, with a significant number of events recorded between midnight and 0600 hours (P < 0.05). This pilot study may help to establish local policies that will warrant an adequate work-up for our patients.

Changes in regional cerebral blood flow beyond the temporal lobe in unilateral temporal lobe epilepsy.

PURPOSE: Single photon emission computed tomography (SPECT) is widely used to evaluate functional abnormalities during the epileptic event. Changes in regional cerebral blood flow (rCBF) are well defined in patients with temporal lobe epilepsy (TLE) undergoing surgical resection. Nonetheless, the interpretation of ictal abnormalities in CBF beyond the temporal lobes has not been carefully addressed. METHODS: We assessed 4 patients with pathologically proven unilateral TLE who had significant ipsilateral frontal hypoperfusion in ictal studies with no other abnormalities but chronic epilepsy accounting for such findings. Patients were assessed as candidates for surgery by interictal EEG, neuropsychological studies, brain magnetic resonance imaging, scalp electrode video-EEG monitoring, and ictal SPECT. RESULTS: Characteristic hyperperfusion was evident over the temporal lobe ipsilateral to the EEG focus, with significant hypoperfusion over the frontal region in 3 patients. In patient 4, frontal hypoperfusion was not statistically significant. CONCLUSIONS: SPECT demonstrated relative rCBF changes beyond the epileptogenic zone in unilateral TLE. Our findings provide further insight into the pathophysiological changes underlying this condition.

Neuron-specific enolase, a marker of acute neuronal injury, is increased in complex partial status epilepticus.

PURPOSE: To determine whether complex partial status epilepticus (CPSE) causes brain injury in humans. Serum neuron-specific enolase (s-NSE) is an accepted marker of acute brain injury, and increases in s-NSE have been correlated with the duration and outcome of generalized convulsive status epilepticus. s-NSE levels in CPSE are unknown. Increase in s-NSE in CPSE would provide new information about the degree of brain injury in CPSE and would help confirm that CPSE is a medical emergency. METHODS: This was a pilot prospective study of serial levels of s-NSE and outcome in CPSE. Eight patients with confirmed CPSE and no acute neurologic deficit were identified prospectively. Results were compared with those of normal and epileptic control groups, and outcome was assessed at hospital discharge or at 7 days with the Glasgow Oucome Scale (GOS). RESULTS: The mean peak s-NSE was 21.81 ng/ml, which for the 8 patients with CPSE was four times higher than that of normal controls (mean s-NSE = 5.36 SD = 1.66, p = 0.0003) and epileptic controls (mean s-NSE = 4.61 SD = 1.74, p. = 0.001). CONCLUSION: The increase in s-NSE provides new evidence that CPSE causes brain injury in humans.

Neuron-specific enolase is increased after single seizures during inpatient video/EEG monitoring.

Neuron-specific enolase (NSE) is a marker of brain injury after acute neurologic insults. We report changes in serum NSE (s-NSE) in 25 patients (15 with epilepsy and 10 patients with nonepileptic events) during continuous inpatient video/EEG monitoring. s-NSE was significantly increased as compared with baseline and normal controls after the first ictal event in the epileptic group, especially in patients with secondarily generalized tonic-clonic seizures (p = 0.01), but s-NSE was not increased in patients with nonepileptic events. These preliminary data indicate that s-NSE may be increased after complex partial seizures--and generalized tonic-clonic seizures (GTCS).

Cerebral neurocytoma: an unusual cause of refractory epilepsy. Case report and review of the literature.

We report a patient with medically refractory complex partial seizures (CPS) caused by a cerebral neurocytoma located near the amygdala. Neurocytoma represents an important addition to the differential diagnosis and, in particular, must be differentiated from oligodendroglioma and dysembryoplastic neuroepithelial tumor. Accurate pathological differential has therapeutic and prognostic implications.

Serum neuron-specific enolase in human status epilepticus.

Neuron-specific enolase (NSE) is a sensitive marker of brain injury after stroke, global ischemia, and coma. We report changes in serum NSE (s-NSE) in 19 patients who sustained status epilepticus. s-NSE peaked within 24 to 48 hours after status epilepticus. The mean peak s-NSE level for the entire group was elevated compared with the levels for normal controls (24.87 ng/ml versus 5.36 ng/ml, p = 0.0001) and for epileptic controls (24.87 ng/ml versus 4.61 ng/ml, p = 0.0001). The mean peak s-NSE level for the 11 subjects without an acute neurologic insult (15.44 ng/ml) was also significantly increased compared with levels for normal and epileptic controls. Further, s-NSE was significantly correlated with outcome and duration. We conclude that s-NSE is a promising in vivo marker of brain injury in status epilepticus and warrants further study in larger populations.

Limited efficacy of experimental anti-epileptic drugs in refractory temporal lobe epilepsy: implications for patient management and study recruitment.

Patients with refractory temporal lobe epilepsy (TLE) are commonly recruited for investigational anti-epileptic drug (XAED) studies. However, the long-term outcome of TLE after exposure to XAEDs is poorly documented. In this pilot study, we report the USC Epilepsy Center's experience of 19 patients with TLE enrolled in three XAED trials. The data reinforce that TLE is a drug-resistant epilepsy, and referral of good surgical candidates for surgery rather than XAED trials is more likely to result in remission.

Neuron-specific enolase is increased after nonconvulsive status epilepticus.

Serum neuron-specific enolase (s-NSE), a marker of brain injury and acute seizures, was increased in 2 patients with nonconvulsive SE. Neither patient had an acute neurologic insult other than nonconvulsive SE (NCSE) accounting for s-NSE changes. Increase in s-NSE provides further in vivo evidence of transient brain injury after NCSE.

High-dose tamoxifen in treatment of brain tumors: interaction with antiepileptic drugs.

The incidence of seizures related to primary brain tumors is 20-80%. High-dose tamoxifen was recently reported as a novel treatment for patients with malignant gliomas who have failed standard therapies. Tamoxifen inhibits protein kinase C (PKC) in vitro and thus may regulate glioma cell growth by modulating intracellular signal transduction. We report a patient with a recurrent supratentorial pilocytic astrocytoma who had an untoward interaction between high-dose tamoxifen therapy and phenytoin (PHT), drugs that share a common enzyme for metabolism, therefore emphasizing the need to monitor concomitant antiepileptic drug (AED) levels when high-dose tamoxifen therapy is instituted.

CSF neuron-specific enolase after methohexital activation during electrocorticography.

We report changes in CSF and serum neuron-specific enolase (NSE) before and after methohexital infusion during electrocorticography in three patients undergoing epilepsy surgery. NSE is a critical enzyme for energy metabolism that accounts for 1.5% of all soluble brain protein and is an accepted marker of neuronal injury. CSF NSE rose three- to fourfold from baseline within 60 minutes after methohexital activation. Serum NSE was unchanged. This report supports evidence that CSF NSE rises acutely after induction of epileptiform activity and suggests that CSF NSE is a marker of seizure activity.

Predictive value of P300 event-related potentials compared with EEG and somatosensory evoked potentials in non-traumatic coma.

Developments in ethical decision making are increasing demand for more accurate predictions of outcome in coma. New neurophysiologic tests are needed to improve the ability to predict awakening as well as poor outcome. We have recently reported that the P300 event-related potential (P300) correlates with awakening and depth of nontraumatic coma. In this companion study, the predictive value of the P300 was compared with median nerve somatosensory evoked potentials (SEP) and EEG in 20 patients in non-traumatic coma. We also evaluated the predictive value of a simplified grading scale for both the EEG and SEP (the USC SEP scale and USC EEG scale). The presence of a P300 was significantly associated with higher Glasgow coma scores (GCS) and awakening. Severe abnormalities of the somatosensory evoked potentials significantly correlated with the absence of awakening and a low GCS. Moderate abnormalities of the SEP were significantly associated with awakening and higher GCS scores. The EEG was significantly associated with GCS score and severe abnormalities of the EEG were predictive of the absence of awakening and very low GCS scores. The data indicates that the P300 and SEP are more effective than the EEG in predicting awakening, and that the SEP and EEG are more effective than the P300 in predicting poor outcome. We conclude that, in addition to EEG and SEP, the P300 should be considered in the prognostic evaluation of patients in nontraumatic coma. Further, simplified scales for the EEG and SEP are predictive of depth of coma and outcome.