EEG findings in frontal lobe epilepsies

As a group, epilepsies of frontal lobe origin are thought to be poorly localized using surface EEG recordings. This finding may depend on the specific areas of frontal lobe from which the seizures originate or the pathologic substrate. We reviewed the presurgical surface EEGs of patients with frontal lobe epilepsy who underwent epilepsy surgery. The specific area of the frontal lobe where seizures originated was determined by 1) intracranial ictal EEG recordings, or 2) the presence of a structural lesion, identified by imaging studies in patients who achieved complete seizure control following surgery. We differentiated patients whose seizures began in the dorsolateral frontal convexity from those whose seizures began in the medial frontal region, and we correlated EEG findings in the interictal, postictal, and ictal states with seizure semiology, pathologic substrate, and surgical outcome. Four of nine patients had seizures originating in the dorsolateral frontal convexity and five had medial frontal onset seizures. Patients whose seizures originated from the dorsolateral convexity had focal interictal epileptiform abnormalities that localized to the region of seizure onset. Patients whose seizures began in the medial frontal region had either no interictal epileptiform abnormality or had multifocal epileptiform discharges. Patients whose seizures began in the dorsolateral convexity showed focal electrographic seizure activity that was localizing. This rhythmic fast activity did not appear to be substrate-specific. Patients whose seizure onset localized to the medial frontal region did not show focal electrographic seizure at clinical onset. We conclude that the scalp EEG recordings of frontal lobe epilepsies contain features that enable differentiation of seizures originating from two different regions of the frontal lobe.     

Visual and quantitative ictal EEG predictors of outcome after temporal lobectomy

PURPOSE: We investigated whether visual and quantitative ictal EEG analysis could predict surgical outcome after anteromesial temporal lobectomy (AMTL) in which mesial structures, basal, and temporal tip cortex were resected. METHODS: We retrospectively reviewed 282 presurgical scalp-recorded ictal EEGs (21- to 27-channel) from 75 patients who underwent AMTL. We examined the pattern of seizure onset (frequency, distribution, and evolution) and estimated the principal underlying cerebral generators by using a multiple fixed dipole model that decomposes temporal lobe activity into four sublobar sources (Focus 1.1). We correlated findings with a 2-year postoperative outcome. RESULTS: Sixteen patients had seizures with a well-lateralized, regular 5 to 9-Hz rhythm at onset, that most often had a temporal or subtemporal distribution. All patients became seizure free after surgery. In 51 patients, seizure onset was remarkable for lateralized slow rhythms (<5 Hz), which sometimes appeared as periodic discharges, were often irregular and stable only for short periods (<5 s), and had a widespread lateral temporal distribution. Among these a favorable surgical outcome was encountered in patients with seizures having prominent anterior-tip sources ( 16 of 17 seizure free), whereas those with dominant lateral or oblique sources had a less favorable outcome (three of 14 and 13 of 18, respectively). Irregular, nonlateralized slowing characterized seizure onsets in eight patients. Three patients became seizure free after surgery. CONCLUSIONS: Both visual and quantitative sublobar source analysis of scalp ictal EEG can predict surgical outcome in most cases after AMTL and complement non-invasive presurgical evaluation.     

Variability in visual cortex activation during prolonged functional magnetic resonance imaging

OBJECTIVE: To review the EEG features of ring 20 syndrome in two patients and determine the characteristic pattern of this syndrome. The features of our cases and 24 patients reported in the literature will be discussed. SUBJECTS AND METHODS: Report of two patients and review of literature. RESULTS: The two patients had intractable epilepsy since childhood. Their clinical seizures were mostly complex partial seizures. Often the patients seizures were of prolonged duration. Ictal EEG revealed characteristic slow waves, and sharp waves. The slow waves were (1) usually synchronous high-voltage slow waves with or without a spike component predominantly in the frontal and frontopolar areas, (2) sometimes showed a change in frequency every several seconds, (3) continued for a long period, and (4) easily spread diffusely. The sharp waves were 5-6 Hz irregular and diffuse discontinuous sharp waves, and sometimes appeared predominantly in the centroparietal area. The clinical seizure pattern and EEG findings were similar in the 24 published cases. CONCLUSIONS: These EEG findings may be a characteristic feature of ring 20 syndrome and thus may be useful as a diagnostic clue.     

Recognition and classification of seizures in infants

PURPOSE: We wished to assess the reliability of the International League Against Epilepsy (ILAE) seizure classification system applied to infantile seizures and to test a proposed new classification. METHODS: We first analyzed 39 seizures in 20 infants (aged 1-26 months) recorded with simultaneous closed-circuit television and EEG (CCTV/EEG). EEGs and videotapes of all seizures were independently analyzed by two epileptologists blinded to clinical histories. Videotapes of each seizure were reviewed without simultaneous EEG (phase 1), and printouts of ictal EEGs were assessed without behavioral correlates (phase II). The observers classified seizures according to ILAE criteria. Interrater agreement was assessed by the kappa statistic. RESULTS: Agreement on EEG features (phase II) was moderate (= 0.54) in identifying focal ictal onsets and substantial (= 0.79) in identifying generalized onsets. In contrast, analysis of videotapes showed substantial disagreement between observers in terms of classifying seizures as partial or generalized. Therefore, agreement between observers for partial was slight (= 0.14) and fair for generalized seizures (= 0.26). Similarly, conclusions of the observers as compared with those of a consensus panel were divergent for both partial (= 0.18) and generalized seizures (= 0.30). We therefore developed an alternative classification scheme and retested interrater agreement in a review of 50 seizures in 25 other infants. With this classification scheme, there was substantial agreement between observers (= 0.72). CONCLUSIONS: With clinical observations and interictal EEGs, seizures in infants cannot be reliably classified by current ILAE criteria. In contrast, a proposed new classification scheme based solely on semiology showed substantial reliability.     

Electroencephalography and computerized transaxial tomography in epilepsy diagnosis

Over a 6-month period 89 patients with epileptic seizures were systematically examined by EEGs and CT. Forty-two percent of all cases showed pathological findings in CT compared to 89% with abnormal EEGs. CT is very useful in identifying organic lesions in the epileptic patient. CT identified 11 cases of supratentorial tumour which were correctly localized by EEG. In patients with seizures after trauma or encephalitis the EEG abnormalities were more than could be detected by CT. The EEG and CT findings in cerebrovascular disorders, alcoholism and other diseases are discussed. A remarkable result is the relatively high percentage of hydrocephalus (23%) in the group of cryptogenic epilepsy. Positive EEG findings as to epilepsy could be seen in 62% of the cases.     

Problematic standards: improving organizational performance through the assess and improve phases

Since 1987, we have diagnosed 10 patients, 4 males and 6 females, aged 2-11 years at the last evaluation, who all met the following criteria of severe myoclonic epilepsy in infancy (SMEI): generalized or unilateral long-lasting febrile clonic seizures in the first year of life; the subsequent appearance of myoclonic seizures and other types of seizure (partial seizures, atypical absences and convulsive status epilepticus); and neuropsychological deterioration for a certain period. Family histories of epilepsy and febrile seizures could be traced in 1 and 3 cases, respectively. None of them had previous personal history of brain insult. Electroencephalographic (EEGic) recordings in febrile seizure stage were normal; and continuous prophylaxis with phenobarbital failed to prevent the recurrence of febrile seizures. EEG studies in myoclonic stage showed generalized spike-and-waves, polyspike-and-waves, focal abnormalities and/or photosensitivity. The seizures were highly resistant to antiepileptic drugs. Our experiences suggested that comedication of valproic acid, clonazepam and carbamazepine may be most effective in treatment of the diverse seizures including myoclonic seizures, myoclonic-tonic-clonic seizures, atypical absences and partial seizures. Myoclonic seizures and atypical absences diminished in parallel to a clear-cut decrease in generalized abnormalities on EEG in 4 cases aged more than 7 years. However, the partial seizures, secondarily generalized seizures and status epilepticus were still present. Further investigations should aim to identify the underlying etiology and to search more effective treatment.     

Adult-onset temporal lobe epilepsy associated with smoldering herpes simplex 2 infection

A 40-year-old man with chronic genital herpes simplex infection developed partial complex temporal lobe seizures of insidious onset, with EEG and MRI evidence of a unilateral temporal lobe destructive, atrophic process. Extensive workup did not reveal an infectious etiology. Three years of escalating number and severity of daily seizures with memory loss led to temporal lobectomy. Histologic study revealed active, low-level viral infection in the resected hippocampus and temporal lobe cortex, with immunohistochemical evidence for infection by herpes simplex 2, principally in neurons. In situ hybridization confirmed the presence of herpes simplex virus in neurons. Anticonvulsant-resistant seizure episodes began to recur several times daily soon after surgery, but the addition of acyclovir to the treatment regimen resulted in a substantial reduction in seizure occurrence, maintained for the subsequent 2.5 years.     

Scalp-recorded, ictal focal DC shift in a patient with tonic seizure

PURPOSE: We recorded focal ictal DC shifts from scalp electrodes in a 9-year-old boy with intractable, clinically generalized tonic seizures. The patient had a high intensity signal abnormality of the left temporal cortex with thickening of the gyri on T2-weighted MRI. METHODS: Scalp digital EEGs were recorded using electrodes made of silver/silver chloride. The low frequency filter (LFF) was set at 0.016 Hz. Recorded seizures were subsequently analyzed with LFF settings of 1.0, 0.016 and 0.03 Hz. RESULTS: All recorded seizures initially showed diffuse, low voltage, high frequency activity (electrodecremental pattern) followed 10-20 s later by quasirhythmic activity over the left frontotemporal region. In two seizures, LFF of 0.016-0.03 Hz revealed a slow negative shift over the left frontotemporal area simultaneously with onset of the bilateral electrodecremental pattern. However, in the other seizures, this initial slow negative shift was obscured by artifacts. Subsequent electrocorticography (ECoG) delineated frequent epileptiform discharges in the left temporal as well as frontal cortex. CONCLUSIONS: Scalp-recorded ictal DC shifts may help identify focal epileptogenic brain area in patients with clinically generalized seizures although the technique is vulnerable to artifact.     

Repair of traumatic orbital wall defects with nasal septal cartilage: report of five cases

PURPOSE: Arachnoid cysts are sometimes encountered in MRIs performed for a variety of reasons. In patients with epilepsy, particularly those with refractory epilepsy, arachnoid cysts are often assumed to be related to their seizure focus. We conducted a study to investigate this putative relationship. METHODS: A retrospective study on the incidence of arachnoid cysts was performed in patients seen in our Epilepsy Clinic who had CT or MRI scans, interictal EEGs or ictal EEGS. Locations of seizure foci in these patients were defined from clinical and electrophysiologic data. RESULTS: Seventeen of 867 patients had arachnoid cysts. Twelve patients had temporal lobe cysts and only 3 of them had temporal lobe seizures. Four patients had frontal lobe cysts and only 1 had frontal lobe seizures ipsilateral to the cyst. One patient had a cerebello-pontine angle cyst and frontal lobe seizures. Thus, clinical manifestations of seizures and EEG findings (interictal and/or ictal) indicated that the seizure focus was adjacent to the cysts in only 4 patients (23.5%). CONCLUSIONS: Our findings suggest that arachnoid cysts are often an incidental finding in patients with epilepsy and do not necessarily reflect the location of the seizure focus.     

Clinical and electrographic manifestations of lesional neocortical temporal lobe epilepsy

To determine whether lesional neocortical temporal lobe epilepsy (NTLE) can be differentiated from mesial temporal lobe epilepsy (MTLE) during the noninvasive presurgical evaluation, we compared the historical features, seizure symptomatology, and surface EEG of 8 patients seizure free after neocortical temporal resection with preservation of mesial structures and 20 patients after anterior temporal lobectomy for MTLE. Seizure symptomatology of 107 seizures (28 NTLE, 79 MTLE) was analyzed. One hundred one ictal EEGs (19 NTLE, 82 MTLE) were reviewed for activity at seizure onset; presence, distribution, and frequency of lateralized rhythmic activity (LRA); and distribution of postictal slowing. Seizure symptomatology and EEG data were compared between groups, and sensitivity, specificity, and positive and negative predictive values were determined for variables that differed significantly. Multiple logistic regression was used to determine whether patients could be correctly classified as having MTLE or NTLE. MTLE patients were younger at onset of habitual seizures and more likely to have a prior history of febrile seizures, CNS infection, perinatal complications, or head injury. NTLE seizures lacked features commonly exhibited in MTLE, including automatisms, contralateral dystonia, searching head movements, body shifting, hyperventilation, and postictal cough or sigh. NTLE ictal EEG recordings demonstrated lower mean frequency of LRA that frequently had a hemispheric distribution, whereas LRA in MTLE seizures was maximal over the ipsilateral temporal region. We conclude that it may be possible to differentiate lesional NTLE from MTLE on the basis of historical features, seizure symptomatology, and ictal surface EEG recordings. This may assist in the identification of patients with medically refractory nonlesional NTLE who frequently require intracranial monitoring and more extensive or tailored resections.     

The evolution of neurophysiological features in holoprosencephaly

The evolution of EEG, visual and auditory evoked responses (VER and AER) and sleep is described in three cases of semilobar holoprosencephaly. During the neonatal period, the waking EEG was characterized by almost continuous high amplitude rhythmic alpha-theta activity in case 1 and 2, which became discontinuous during quiet sleep. Moderate amplitude rhythmic alpha-theta waves were seen in case 3. This rhythmic alpha-theta activity gradually disappeared with increasing age, being replaced by non-specific slow dysrhythmia. In case 3, the subsequent EEGs were characterized by focal spikes at 4 months, multifocal spikes at 5 and 6 months, hypsarrhythmia at 8 months and bisynchronous diffuse sharp and slow wave discharges at 2 years and 7 months. Ictal EEGs were characterized by desynchronization and/or rapid synchronization, epileptic recruiting rhythm and postical high amplitude slow waves. Definite but mostly abnormal VERs or AERs were obtained in all three cases. In two cases, the evoked responses showed a progressive decrease in amplitude and VERs were abolished finally. No sleep cycle could be identified during the neonatal period probably because of frequent seizures. In two cases no circadian rhythm of sleep developed, although almost normal REM-NREM sleep cycle was present.     

Semiological seizure classification

We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.     

Effects of intracerebroventricular injection of histamine on memory deficits induced by hippocampal lesions in rats

This review was conducted to evaluate the long-term prognosis of children responding to vigabatrin by examining the incidence of increased seizure frequency, loss of efficacy, and appearance of new seizures in a cohort of 196 children (mean age, 68.2 months; range, 2 months to 19 years) with drug-resistant epilepsy, who had received vigabatrin as add-on treatment in clinical trials. The results indicate that an increase in seizure frequency was uncommon, occurring in only 10% of children with highly drug-resistant epilepsy and that it usually appears shortly after the initiation of treatment. It was clearly not dose-dependent and most often occurred in patients with nonprogressive myoclonic epilepsy. No specific seizure type was specially involved and usually the problem reversed on discontinuing vigabatrin. Loss of efficacy was also uncommon (12% of patients), and again no specific seizure type was found to be associated. Epilepsy syndrome does seem to be a better predictor of loss of efficacy because it occurred most often in symptomatic generalized epilepsies and cryptogenic infantile spasms. A total of 21 patients (11%) developed genuinely new types of seizures. Fifteen of these patients developed new partial seizures that had little impact on the patients' overall clinical improvement. The new partial seizures were better tolerated than the initial seizure type which in most cases had disappeared. Approximately 3% of patients experienced new generalized seizures that aggravated their initial condition. These occurred most often in patients with nonprogressive myoclonic epilepsy; therefore vigabatrin should be used with particular caution in such patients.     

Long-term electroencephalographic monitoring for diagnosis and management of seizures

Long-term electroencephalographic (EEG) monitoring is the process of recording an EEG for a prolonged period in order to document epileptic seizures or other episodic disturbances of neurologic function. Indications for long-term EEG monitoring include diagnosis of a seizure disorder (epilepsy), classification of seizure types in patients with epilepsy, and localization of the epileptogenic region of the brain. Methods used for long-term EEG monitoring include prolonged analog or digital EEG, prolonged analog or digital ambulatory EEG, and prolonged analog or digital video-EEG monitoring with telemetry. Each of these methods has distinct advantages and disadvantages, particularly relative to storage, retrieval, and manipulation of data. Long-term EEG monitoring is useful in the management of patients with epilepsy and in the diagnosis of a seizure disorder. For most patients, inpatient long-term EEG monitoring is best performed in a specialized epilepsy-monitoring unit, which can provide a safe environment and both educational and psychosocial support. The choice of the most appropriate method of long-term monitoring for a specific clinical situation is best made by an epileptologist or a neurologist at an epilepsy center.     

A case of pneumoconiosis (welder''s lung) suspected to be lung cancer

PURPOSE: Seizures provoked by television viewing may be triggered by patterns in the television image or by flicker from the display itself. We examined the incidence of EEG abnormalities elicited by patterns displayed on television sets with two different frame rates to evaluate the likely contribution of photosensitive and pattern-sensitive mechanisms to television- and video-game epilepsy. METHODS: Televisions with frame rates of 50 and 100 Hz were used to present 35 patients who were photosensitive or pattern-sensitive with grating patterns. These patterns comprised vertical square-wave and sine-wave gratings of 90% contrast, and the spatial frequency was varied between 0.25-7 cycles/degree. EEGs were analysed for laboratory sensitivity to patterned and unpatterned intermittent photic stimulation (IPS). RESULTS: Significantly fewer EEG abnormalities were elicited by patterns displayed on the 100 Hz frame-rate television than on the 50-Hz frame-rate television. No abnormalities were observed in response to the blank screens of either television. Thirty-three patients showed abnormalities in response to patterned IPS but only 15 in response to diffuse flash. Two patients showed no laboratory evidence of photosensitivity. Patients who were sensitive to patterned IPS at 50 Hz were significantly more likely to demonstrate abnormalities to patterns displayed on the 100-Hz frame-rate television than were patients who were not sensitive to 50-Hz patterned IPS. CONCLUSIONS: We suggest that for many patients, the combination of high-contrast patterns and screen flicker may elicit the observed EEG abnormalities. For patients with sensitivity to screen flicker, the use of a high frame-rate television may be beneficial in reducing the risk of seizures.     

Unverricht-Lündborg disease: clinical and electrophysiologic study of 19 Maghreb families

We describe clinical, electrophysiological and genetic features in 44 patients with Unverricht-Lündborg disease from 19 families living in North African countries (Tunisia, Algeria and Morocco). The mean age of patients was 25.3 years; mean age was at onset 11.3 years. The disease began more frequently with seizures (91 per cent) or myoclonus (80 p. 100) than ataxia (16 p. 100). Subsequently myoclonus and generalized seizures were present in all patients, cerebellar signs were absent in four cases. EEG findings included normal background activity (90 p. 100), spontaneous fast generalized spikes (93 p. 100) and photosensitivity (70 p. 100). Antiepileptic polytherapy (clonazepam and/or phenobarbital and/or valporic acid) was used in 84 per cent of cases. Antiepileptic drugs were more effective in controlling epileptic seizures (less than one seizure/month in 60 p. 100) than myocloni which persisted daily in 64 p. 100 of cases. Mean duration of the disease was 13.5 years. One patient died of status epilepticus. Consanguinity was noted in 17 families (first degree in 15 families). Linkage to chromosome 21q 22.3 was confirmed in 11 families. We noted an inter and intrafamilial variability of clinical signs and disease course.     

Surgical outcome in patients with epilepsy with occult vascular malformations treated with lesionectomy

PURPOSE: This retrospective study reports the long-term surgical outcome of patients with medically refractory epilepsy and vascular malformations who were treated with lesionectomy. A detailed analysis of surgical failures had been performed in an attempt to define predictors of surgical success and failure. METHODS: Fifteen patients with medically intractable epilepsy and angiographically occult vascular malformations (AOVMs) were treated surgically with lesionectomy at Duke University Medical Center. Lesionectomy consisted of removal of the AOVM and surrounding hemosiderin-stained brain only, without the use of electrocorticography (ECoG) to guide resection. RESULTS: Eleven (73%) patients are seizure free after lesionectomy. Three showed no significant improvement, and one patient died, presumably after a seizure. Age of onset, duration of seizures, age at resection, and gender did not affect outcome. All patients with neocortical AOVMs in whom EEG findings correlated with the site of the lesion were seizure free after lesional resection. Treatment failures were associated with the presence of multiple intracranial lesions, poorly localized or diffuse EEG findings, discordant positron emission tomography (PET) imaging, or with a lesion in close proximity to the limbic system. CONCLUSIONS: Lesionectomy, with removal of surrounding hemosiderin-stained brain, can be considered the procedure of choice in carefully selected patients with epilepsy with occult vascular malformations.     

Electroencephalographic findings in Tanzanian epileptic patients

Electroencephalogram (EEG) of 524 Tanzanian epileptic patients seen between 1985 and 1987 were reviewed. Over two thirds were young patients between the ages of five and thirty. Four hundred and fifty (86%) had abnormal records. Eighty nine per cent of abnormal records had focal abnormality and 11% had centrencephalic abnormality. Grand mal seizures did not imply centrencephalic abnormality, only 13% had such abnormality. Petit mal seizures are rare, over one third of these had temporal focal abnormality. Partial seizures were associated highly with focal abnormality. However, complex partial seizures did not imply temporal focal abnormality. Implications of EEG findings to correlation with epileptic seizures is discussed.     

Altered relationships between rCBF in different brain regions of never-treated schizophrenics

AIM: of this study was to investigate the relations between regional cerebral blood flow (rCBF) of different brain regions in acute schizophrenia and following neuroleptic treatment. METHODS: Twenty-two never-treated, acute schizophrenic patients were examined with HMPAO brain SPECT and assessed psychopathologically, and reexamined following neuroleptic treatment (over 96.8 days) and psychopathological remission, rCBF was determined by region/cerebellar count quotients obtained from 98 irregular regions of interest (ROIs), summed up to 11 ROIs on each hemisphere. In acute schizophrenics, interregional rCBF correlations of each ROI to every other ROI were compared to the interregional correlations following neuroleptic treatment and to those of controls. RESULTS: All significant correlations of rCBF ratios of different brain regions were exclusively positive in controls and patients. In controls, all ROIs of one hemisphere except the mesial temporal ROI correlated significantly to its contralateral ROI. Each hemisphere showed significant frontal-temporal correlations, as well as cortical-subcortical and some cortico-limbic. In contrast, in acute schizophrenics nearly every ROI correlated significantly with every other ROI, without a grouping or relation of the rCBF of certain ROIs as in controls. After neuroleptic treatment and clinical improvement, this diffuse pattern of correlations remained. CONCLUSIONS: These results indicate differences in the neuronal interplay between regions in schizophrenic and healthy subjects. In never-treated schizophrenics, diffuse interregional rCBF correlations can be seen as a sign of change and dysfunction of the systems regulating specificity and diversity of the neuronal functions. Neuroleptic therapy and psychopathologic remission showed no normalizing effect on interregional correlations.     

Comparative assessment of treatment efficacy with lamotrigine (Lamictal) together with valproate and/or carbamazepine in patients with refractory epilepsy

For the study 17 patients aged 26-55 years were qualified after ineffective treatment with carbamazepine and/or valproate for simple partial, complex partial or secondary generalized seizures. The criterion of resistance to treatment was the occurrence of four or more seizures monthly. The treatment with lamotrigine was successful in 9 (52%) cases, with reduction of seizures by at least 50%. In 2 cases the seizure activity in EEG became normal. In 8 cases the addition of lamotrigine was ineffective and the drug was discontinued (in one case due to allergic rash and in one the cause was toxic hepatocellular damage).