Coma prognosis in children. Part I: definitional and methodological challenges.

Prediction of outcome from coma is a frequent and important task of neurologists. It is difficult enough in adult patients and even more difficult in children. Part I of this review considers some of the methodological problems and caveats besetting clinical research in this field: the very definition of coma, definition of the study population and outcome variables, study design, the fallacy of self-fulfilling prophecy, early death rate from nonneurologic causes resulting in low statistical power, and invalid attempts to compensate for that by combining outcome categories, lumping together age groups, short and inhomogeneous follow-up, and failure to provide confidence intervals. Part II reviews the clinical pediatric coma-prognosis literature, first according to etiology and then according to electrodiagnostic tests.

Postoperative seizure control and antiepileptic drug use in pediatric epilepsy surgery patients: the UCLA experience, 1986-1997.

PURPOSE: Young children with refractory symptomatic epilepsy are at risk for developing neurologic and cognitive disabilities. Stopping the seizures may prevent these disabilities, but it is unclear whether resective surgery is associated with adequate long-term seizure control. METHODS: This study determined pre- and postsurgery seizure frequency and antiepileptic drug (AED) use (6 months to 10 years) in children with symptomatic seizures from unilateral cortical dysplasia (CD; n = 64) and non-CD etiologies (i.e., ischemia, infection; n = 71), and compared them with older temporal lobe epilepsy (TLE; n = 31) patients with complex partial seizures. RESULTS: Compared with presurgery, postsurgery seizure frequencies were decreased for CD, non-CD, and TLE patients (p < 0.002), and there were no differences between the three groups from 6 to 24 months after surgery (p > 0.12). At 5 years after surgery, seizure frequencies were greater in CD compared with TLE cases (p = 0.009). Compared with presurgery, the number of AEDs declined after surgery in all three groups (p < 0.002), and positively correlated with seizure frequencies (p = 0.0001). CONCLUSIONS: This study indicates that seizure relief and AED use after resective surgery for symptomatic CD and non-CD etiologies was comparable with complex partial TLE cases up to 2 years after surgery. Furthermore, at 5 years after surgery, CD patients had outcomes better than those before surgery, but worse than TLE cases. In young children, these findings support the concept that early removal of symptomatic pathologic substrates is associated with seizure control and reduced AED use, similar to that noted in older TLE cases up to 2 years after surgery. Seizure control may reduce the risk of developing the seizure-related encephalopathy associated with severe symptomatic early-onset childhood epilepsy.

Surgery for the treatment of medically intractable infantile spasms: a cautionary case.

UNLABELLED: The most appropriate time to consider cortical resection to treat medically intractable infantile spasms has not been clearly defined. The risks that need to be reconciled to make this decision are: What is the risk of loss of developmental potential if surgery is delayed too long versus what is the risk of unnecessary surgery if it is done too soon. We propose that, in addition to evaluation of seizures, developmental assessment is a key factor in the surgical decision. The case report illustrates this concept. CASE REPORT: HC had onset of seizures at 9 days of age and developed infantile spasms due to mild right hemimegancephaly. At 19 months, she was having up to 50 seizures/day and was evaluated and approved for right hemispherectomy but surgery was delayed. Despite the seizures, her development had been much better than most patients with hemimegencephaly and infantile spasms. At 25 months her seizure control was much improved but she had several seizures/week. EcoG at the time of surgery did not demonstrate the usual abnormalities so no resection was performed. She has had only 5 seizures in the 2(1/2) year since. CONCLUSIONS: (a) Hemimegalencephaly is not always associated with severe mental retardation; (b) normal or near-normal development may, in some cases, indicate the possibility of medical control of seizures as the child grows; (c) a localized developmental brain abnormality in a child with intractable seizures should not necessarily lead to cortical resection; and (d) when a child meets developmental milestones, it may be appropriate to delay surgical intervention.

Consciousness in congenitally decorticate children: developmental vegetative state as self-fulfilling prophecy.

According to traditional neurophysiological theory, consciousness requires neocortical functioning, and children born without cerebral hemispheres necessarily remain indefinitely in a developmental vegetative state. Four children between 5 and 17 years old are reported with congenital brain malformations involving total or near-total absence of cerebral cortex but who, nevertheless, possessed discriminative awareness: for example, distinguishing familiar from unfamiliar people and environments, social interaction, functional vision, orienting, musical preferences, appropriate affective responses, and associative learning. These abilities may reflect 'vertical' plasticity of brainstem and diencephalic structures. The relative rarity of manifest consciousness in congenitally decorticate children could be due largely to an inherent tendency of the label 'developmental vegetative state' to become a self-fulfilling prophecy.

Spinal shock and brain death': somatic pathophysiological equivalence and implications for the integrative-unity rationale.

The somatic pathophysiology of high spinal cord injury (SCI) not only is of interest in itself but also sheds light on one of the several rationales proposed for equating 'brain death' (BD) with death, namely that the brain confers integrative unity upon the body, which would otherwise constitute a mere conglomeration of cells and tissues. Insofar as the neuropathology of BD includes infarction down to the foramen magnum, the somatic pathophysiology of BD should resemble that of cervico-medullary junction transection plus vagotomy. The endocrinologic aspects can be made comparable either by focusing on BD patients without diabetes insipidus or by supposing the victim of high SCI to have pre-existing therapeutically compensated diabetes insipidus. The respective literatures on intensive care for BD organ donors and high SCI corroborate that the two conditions are somatically virtually identical. If SCI victims are alive at the level of the 'organism as a whole', then so must be BD patients (the only significant difference being consciousness). Comparison with SCI leads to the conclusion that if BD is to be equated with death, a more coherent reason must be adduced than that the body as a biological organism is dead.

Incidence of death in patients with intractable epilepsy during nitrazepam treatment.

PURPOSE: Increased risk of death has been reported in patients with intractable epilepsy (IE) taking nitrazepam (NZP). METHODS: Between January 1983 and March 1994, 302 patients with IE were entered into a NZP compassionate-plea protocol. NZP was discontinued if there was < 50% seizure reduction or significant side effects. In some patients with > 50% reduction, it also was discontinued for lack of sufficient effect. At the end of follow-up for this study, 62 patients remained taking NZP. Patients took NZP from 3 days to 10 years. RESULTS: Twenty-one of 302 patients died after institution of NZP. Fourteen of 21 of these were taking NZP at death, and in five of 21, the NZP had been discontinued. Two patients were excluded from analysis, because it is unclear whether NZP had been discontinued before death. Six other patients were lost from follow-up. Of the 14 deaths with NZP, seven were sudden, six were of pneumonia, and one was of cystinosis. Nine had at least one contributing factor, such as dysphagia, gastroesophageal reflux, or recurrent aspirations. The 294 patients took NZP for a total of 704 patient years (ptyrs), and were discontinued for a total of 856 ptyrs. There were 1.98 deaths/ 100 ptyrs on NZP compared with 0.58 deaths/100 ptyrs without NZP, most of the former being associated with side effects of NZP. Mortality in patients younger than 3.4 years was 3.98 with NZP compared with 0.26 deaths/100 ptyrs without NZP (p = 0.0002). Corresponding figures in patients 3.4 years or older were 0.50 and 0.86 deaths/100 ptyrs, respectively. CONCLUSIONS: NZP therapy for epilepsy apparently increases the risk of death, especially in young patients with IE. This should be considered in antiepileptic drug (AED) management decisions.

Chronic "brain death": meta-analysis and conceptual consequences.

OBJECTIVE: One rationale for equating "brain death" (BD) with death is that it reduces the body to a mere collection of organs, as evidenced by purported imminence of asystole despite maximal therapy. To test this hypothesis, cases of prolonged survival were collected and examined for factors influencing survival capacity. METHODS: Formal diagnosis of BD with survival of 1 week or longer. More than 12,200 sources yielded approximately 175 cases meeting selection criteria; 56 had sufficient information for meta-analysis. Diagnosis was judged reliable if standard criteria were described or physicians made formal declarations. Data were analyzed by means of Kaplan-Meier curves, with treatment withdrawals as "censored" data, compared by log-rank test. RESULTS: Survival probability over time decreased exponentially in two phases, with initial half-life of 2 to 3 months, followed at 1 year by slow decline to more than 14 years. Survival capacity correlated inversely with age. Independently, primary brain pathology was associated with longer survival than were multisystem etiologies. Initial hemodynamic instability tended to resolve gradually; some patients were successfully discharged on ventilators to nursing facilities or even to their homes. CONCLUSIONS: The tendency to asystole in BD can be transient and is attributable more to systemic factors than to absence of brain function per se. If BD is to be equated with death, it must be on some basis more plausible than loss of somatic integrative unity.

"Brainstem death," "brain death" and death: a critical re-evaluation of the purported equivalence.

The author challenges brain-based diagnoses of death by re-examining the concept of death, its definition, the anatomical criterion, and the clinical signs or tests. Dr. Shewmon challenges the fundamental assumptions underlying brain death: (1) that the brain is the body's "critical system"; and (2) that the body even has a localized "critical system." He does not redefine death, but shifts the anatomical criterion from a single focus (the brain) to the entire body. The clinical tests correspondingly shift from those implying loss of brain function to those implying thermodynamically supracritical microstructural damage diffusely throughout the body. He concludes that the notion of "brain death" as bodily death is logically and physiologically incoherent, and that its replacement by something scientifically more credible would promote not only the sanctity of life, but ironically even transplantation as well.

Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms.

Two-year postsurgical developmental outcomes were assessed in 24 children with infantile spasms who underwent resective surgery. The mean age of onset of infantile spasms was 12.0 weeks and the mean age at surgery was 20.8 months. Developmental outcomes were assessed using the Vineland Adaptive Behavior Scales (VABS). There was a significant increase in developmental level at 2 years postsurgery compared with presurgical levels. At 2 years postsurgery only one of the children in this series was severely retarded. The developmental outcomes of patients in the series were better than those in prior studies of symptomatic patients receiving medical treatment for infantile spasms. It is surprising that the children in the UCLA series frequently had developmental outcomes equal to and sometimes superior to other groups of children with infantile spasms, since all the UCLA patients were symptomatic, had neurologic deficits and had failed to respond to adrenocorticotrophic hormone (ACTH) and antiepileptic drugs. The 2-year postsurgery developmental outcomes were best for the children who received surgery when they were relatively young and who had the highest level of developmental attainments presurgically.

Global brain dysfunction in an infant with pyridoxine dependency: evaluation with EEG, evoked potentials, MRI, and PET.

Pyridoxine dependency often presents with intractable seizures in neonates and infants. We describe an infant with pyridoxine-dependent seizures and report the first PET and evoked potential results and EEG and MRI findings. All studies show either diffuse structural or functional abnormality. Our data suggest this coenzyme deficiency causes a generalized disease process.

Hemispherectomy for intractable seizures in children: a report of 58 cases.

Fifty-eight children who underwent anatomical, functional, or modified anatomical hemispherectomy for intractable seizures from 1986 to 1995 were evaluated for seizure control, motor function, and complications. Age at surgery ranged from 0.3 to 17.3 years (median 2.8 years). Twenty-seven anatomical, 27 functional, and 4 modified anatomical hemispherectomies were performed. Seizure control and motor function in the 50 patients with more than 1 year follow-up revealed a 90% or better reduction in seizure frequency in 44/50 (88%) overall: 19/22 (86%) anatomical, 23/26 (89%) functional, and 2/2 modified anatomical. Motor function of the preoperatively hemiparetic extremities was improved or unchanged postoperatively in 38/50 (76%) of the patients. Complications included one intraoperative death, one late death from shunt obstruction managed elsewhere, late postoperative seizure breakthrough requiring reoperation and further disconnection in 5/27 functional hemispherectomy patients, mild cerebrospinal fluid infections in 3/27 anatomical hemispherectomy patients, and hydrocephalus requiring shunting in 3/27 functional hemispherectomy patients. A review of the literature and comparison of techniques is presented.

Asymmetric and asynchronous infantile spasms.

Infantile spasms most commonly show symmetric behavioral and electroencephalogram (EEG) manifestations. Asymmetric and asynchronous behavioral spasms occur occasionally, but their relationship to ictal EEG and to other localizing studies has not received much attention. We reviewed 75 consecutive video-EEG recordings, done at UCLA from 1982 to 1992, that contained infantile spasms; 8,680 spasms were scored for behavioral and EEG asymmetry and asynchrony. Of the recorded spasms, 25% were asymmetric and 7% were asynchronous. Most asymmetric of asynchronous spasms were associated with an ictal EEG discharge that was contralateral to the behaviorally more involved side. In 12 of the 60 patients (20%), more than half of the recorded spasms were asymmetric of asynchronous. Baseline EEG, magnetic resonance imaging, positron emission tomography, and neurological examination revealed structural and functional brain abnormalities that involved the contralateral central region significantly more often in the children with > 50% spasm asymmetry or asynchrony than in the other children. Partial seizures with lateralized motor behavior also occurred frequently in these children. The findings suggest that asymmetric and asynchronous spasms are generated by a cortical epileptogenic region that involves the primary sensorimotor area. The combination of asymmetric and asynchronous infantile spasms, partial motor seizures involving the same side of the body, and pathology in the contralateral central region may represent a unique subset of symptomatic localization-related infantile epilepsy.

Microscopic cortical dysplasia in infantile spasms: evolution of white matter abnormalities.

PURPOSE: To determine whether microscopic cortical lamination defects in patients with infantile spasms, not initially identifiable on MR, may be inferred from evolving changes in the adjacent white matter. METHODS: Three infants between 3 and 6 months of age presented with infantile spasms. Based on negative metabolic assessment and normal MR findings, they were classified as cryptogenic. Despite therapy the children deteriorated with seizure recurrence and the advent of lateralizing clinical and neurophysiologic findings. MR studies were repeated and positron emission tomography was done. RESULTS: The second MR studies demonstrated abnormalities of myelination, corresponding to localized clinical and neurophysiologic findings. Positron emission tomography findings did not show a strong correlation; one was normal, one showed no abnormality in the major area of MR abnormality, and one showed significantly less abnormality than on MR. Two patients have undergone surgery, both with good response. DISCUSSION: Subtle lamination defects may be identifiable on positron emission tomography but are usually not detectable on MR. White matter abnormality on MR images is usually attributable to primary disease. We suggest that in certain cases progressive white matter changes may be induced as a secondary phenomenon by overlying microscopic cortical lamination defects. Serial MR imaging may be beneficial in children with infantile spasms in whom signs of laterality evolve.

Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women.

Data in the literature suggest that circulating levels of lipoprotein(a) [Lp(a)] and insulinlike growth factor I (IGF-I) respond similarly to therapy with growth hormone, estrogen, or tamoxifen. To more clearly document these relations, we designed a randomized, double-blind, placebo-controlled study of the effects of tamoxifen and continuous estrogen on circulating levels of Lp(a), IGF-I, and IGF binding protein 3 (IGFBP-3) in healthy postmenopausal women. Both estrogen and tamoxifen decreased serum levels of IGF-I to 30% below baseline during the 3 months of treatment, while IGFBP-3 levels were unchanged. Plasma Lp(a) levels decreased to 24% below baseline after 1 month of treatment with either estrogen or tamoxifen (P < .05 for estrogen only); after 3 months Lp(a) decreased to 34% below baseline with tamoxifen therapy (P < .05) but returned to only 16% below baseline with estrogen. The correlation between Lp(a) and IGF-I was highly significant (P < .0001). We conclude that (1) tamoxifen lowers plasma Lp(a) levels in healthy postmenopausal women, (2) the suppressive effects of tamoxifen and estrogen on circulating Lp(a) concentration diverge after the first month of therapy, and (3) circulating levels of Lp(a) and IGF-I are strongly correlated with each other, an indication that they may share regulatory influences.

Ictal patterns of cerebral glucose utilization in children with epilepsy.

To determine seizure propagation patterns, we analyzed ictal positron emission tomography (PET) studies of regional cerebral glucose utilization in 18 children (11 male and 7 female aged 2 weeks to 16 years) with epilepsy (excluding infantile spasms IS). Three major metabolic patterns were determined based on degree and type of subcortical involvement: Nine children had type I; asymmetric glucose metabolism of striatum and thalamus. Of these, the 7 oldest children showed unilateral cortical hypermetabolism (always including frontal cortex) and crossed cerebellar hypermetabolism. Two infants (aged < 1 year) had a similar ictal PET pattern but no cerebellar asymmetry, presumably owing to immaturity of corticopontocerebellar projections. Five children had type II, symmetric metabolic abnormalities of striatum and thalamus; this pattern was accompanied by hippocampal or insular cortex hypermetabolism, diffuse neocortical hypometabolism, and absence of any cerebellar abnormality. Four children had type III, hypermetabolism restricted to cerebral cortex. This classification can accommodate ictal PET and single photon emission computed tomography (SPECT) patterns described by other investigators. Future studies should be directed at the clinical relevance of this classification, particularly with regard to epilepsy surgery.

Lipids, atherosclerosis, and the postmenopausal woman. A clinical perspective.

Gynecologists are often responsible for the primary care of postmenopausal women. In this role, they become responsible for the assessment and subsequent management issues surrounding the prevention of atherosclerotic disease. The effects of estrogen upon the physiology of lipoproteins can be simplified to include an increased flux of apo B-100 particles out of and then back into the liver, an inhibition of hepatic lipase activity, and an apparent decrease in the hepatic secretion of lipoprotein(a) particles. In clinical practice, the lipoprotein picture is best thought of as one of a group of risk factors that need to be assessed and modified as needed, based upon the overall estimation of risk. The only caveat to this approach is that one should consider patients with proven heart disease for more aggressive therapy (to achieve an LDL cholesterol of less than 100 mg/dL), as long as there is no overriding morbidity from other causes.

Tamoxifen decreases lipoprotein (a) in patients with breast cancer.

An elevated concentration of lipoprotein(a) [Lp(a)] is a potent risk factor for coronary atherosclerosis. Recently, several hormonal agents including estrogen have been reported to decrease serum Lp(a) concentrations. We found that the antiestrogen tamoxifen also decreased Lp(a) concentrations approximately 40% in six patients with breast cancer, an effect that was achieved by 1 month of therapy and that was stable in five of six patients. If the Lp(a)-lowering effect of tamoxifen can be replicated in women without breast cancer, tamoxifen might be considered as an alternative to niacin for the treatment of elevated Lp(a) levels.

Surgery for intractable infantile spasms: neuroimaging perspectives.

Twenty-three infants and children underwent cortical resection (n = 15) or hemispherectomy (n = 8) for intractable infantile spasms. Infantile spasms were present at the time of surgery in 17 of the 23 patients; in six, spasms had evolved to other seizure types during surgical evaluation. Children with a remote history of infantile spasms were excluded from this study. Focal or hemispheric lesions were identified by magnetic resonance imaging in seven children; an additional two showed focal atrophy without a discrete lesion. Positron emission tomography (PET) showed lateralized or localized abnormalities of cerebral glucose utilization in all patients; in 14, PET was the only neuroimaging modality to identify the epileptogenic cortex. When this occurred, neuropathological examination of resected brain tissue typically showed malformative and dysplastic cortical lesions. Focal interictal and/or ictal electrographic abnormalities were present in all patients, and corresponded well with localization from neuroimaging. None of the patients were subjected to chronic invasive electrographic monitoring with intracranial electrodes. At follow-up (range 4-67 months; mean 28.3 months), 15 children were seizure-free, three had 90% seizure control, one had 75% seizure control, and four failed to benefit from surgery with respect to seizure frequency.