The Declaration of Sydney on human death.

On 5 August 1968, publication of the Harvard Committee's report on the subject of "irreversible coma" established a standard for diagnosing death on neurological grounds. On the same day, the 22nd World Medical Assembly met in Sydney, Australia, and announced the Declaration of Sydney, a pronouncement on death, which is less often quoted because it was overshadowed by the impact of the Harvard Report. To put those events into present-day perspective, the authors reviewed all papers published on this subject and the World Medical Association web page and documents, and corresponded with Dr A G Romualdez, the son of Dr A Z Romualdez. There was vast neurological expertise among some of the Harvard Committee members, leading to a comprehensible and practical clinical description of the brain death syndrome and the way to diagnose it. This landmark account had a global medical and social impact on the issue of human death, which simultaneously lessened reception of the Declaration of Sydney. Nonetheless, the Declaration of Sydney faced the main conceptual and philosophical issues on human death in a bold and forthright manner. This statement differentiated the meaning of death at the cellular and tissue levels from the death of the person. This was a pioneering view on the discussion of human death, published as early as in 1968, that should be recognised by current and future generations.

Recognizing a mother's voice in the persistent vegetative state.

We studied an 8-year-old boy after a near-drowning left him in a vegetative state (VS) for 4 years before the study. Findings fulfilled all clinical criteria for the diagnosis of VS. The purpose of this study was to investigate whether there was significant differential activation of the brain in response to hearing his mother's voice compared with the voices of unknown women. The data were assessed using quantitative electric tomography (QEEGt), a technique that combines anatomical information of the brain by MRI with EEG patterns to estimate the sources of the EEG within the brain. We found significant differences for EEG frequencies from 14-58 Hz, with a peak at 33.2 Hz (gamma band). The 3D reconstruction showed that these statistical differences were localized in the lateral and posterior regions of the left hemisphere. No significant differences were found between unknown women vs. basal conditions. These results demonstrate recognition of the mother's voice and indicate high-level residual linguistic processing in a patient meeting clinical criteria for VS. These findings launch new ethical and practical implications for the management of VS patients.

Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity.

Classical Maple Syrup Urine Disease (MSUD) is a disease of infancy which is an inherited disorder of metabolism of branched-chain amino acids (BCAA). The BCAA are normally transaminated to branched-chain keto acids (BCKA). However, the enzyme required to metabolize the BCKA is deficient, resulting in elevation of both, the BCAA and the BCKA. One of the BCAA (isoleucine) produces a metabolite that causes the urine to smell like maple syrup. The elevations of the BCAA and BCKA are associated with an acute, critical neurotoxic condition often prior to the age of two weeks. The clinical state, the electroencephalogram-(EEG), and plasma BCAA levels were evaluated in 26 patients with classical and variant MSUD. Patients were seen from the time of diagnosis, often within a week after birth, and some were followed clinically for more than 20 years while on specific diet therapy. They were monitored by plasma BCAA (leucine, isoleucine and valine) levels and a total of 101 EEGs were performed during different phases of their illness. During periods of acute metabolic decompensation, there were marked clinical symptoms of neurotoxicity including opisthotonos, seizures, and coma with elevated BCAA plasma levels. The EEGs revealed spikes, polyspikes, spike-wave complexes, triphasic waves, severe slowing and bursts of periodic suppression. Occasionally paradoxical EEG arousal was noted while the patient was lethargic. During asymptomatic periods when the plasma BCAA were at low or normal levels, EEG abnormalities occurred in patients with and without residual neurological deficit. These observations included rolandic sharp waves (comb-like rhythm) which were observed in 7 of 15 patients less than two months of age. Additionally, paroxysmal spike and spike-wave response to photic stimuli were observed in 9 of 17 patients. Loading tests were performed on three patients. Clinical and EEG changes were most marked after leucine. Less dramatic EEG changes also occurred with the other two BCAA loads but without clinical manifestations. Elevation of the appropriate BCAA plasma level occurred after each load. These studies and a review of the literature suggest that one component of the pathophysiological mechanism for the acute neurotoxic effects in this disorder is related to a defect in glutamate, glutamine and gamma-aminobutyric acid (GABA) production. The BCAAs are transaminated to BCKAs. Further metabolism of the BCKAs are blocked because of enzyme deficiency required for decarboxylation.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuropathological findings in the brain of Karen Ann Quinlan. The role of the thalamus in the persistent vegetative state.

BACKGROUND: Karen Ann Quinlan had a cardiopulmonary arrest in 1975 and died 10 years later, having never regained consciousness. Her story prompted a national debate about the appropriateness of life-sustaining treatment in patients who are in a persistent vegetative state and led to the development of medicolegal guidelines for the care of such patients. This report describes the neuropathologic features of Quinlan's brain. METHODS: The entire brain and spinal cord were systematically sampled for histologic examination. The brain stem and central cerebrum were embedded en bloc and serially sectioned. Three-dimensional computer reconstructions helped visualize the topographic features of the lesions. RESULTS: Contrary to expectation, the most severe damage was not in the cerebral cortex but in the thalamus, and the brain stem was relatively intact. The neuropathological findings included extensive bilateral thalamic scarring, bilateral cortical scars primarily in the occipital pole and parasagittal parieto-occipital region, and bilateral damage to cerebellar and focal-basal-ganglia regions. The brain stem and basal forebrain and the hypothalamic components of the ascending arousal systems and brainstem regions critical to cardiac and respiratory control were undamaged. The lesions were consistent with hypoxia-ischemia after the cardiopulmonary arrest. CONCLUSIONS: Although the neuropathological findings in the case of Karen Ann Quinlan were complex, the disproportionately severe damage in the thalamus as compared with the cerebral cortex supports the hypothesis that the thalamus is critical for cognition and awareness and may be less essential for arousal.

Electroencephalogram and treatment of hospitalized aggressive children with haloperidol or lithium.

Electroencephalograms (EEGs) of 48 children ages 5.2 to 12.9 years were examined on baseline placebo and on optimal dosages of haloperidol, lithium, or placebo. These children represent a subgroup of 61 hospitalized aggressive and explosive patients diagnosed as Conduct Disorder, undersocialized, aggressive who completed a double-blind study comparing the efficacy of haloperidol, lithium, and placebo. EEGs were correlated across treatment groups with behavioral ratings, ratings of untoward effects, and optimal dosages of medication. During the baseline placebo period 58.3% of the children had abnormal EEGs. Children receiving haloperidol or lithium had a significant probability that their EEGs on optimal dose would worsen, and would be more likely to show paroxysmal or focal abnormalities than those children treated with placebo. It was possible to identify children treated with haloperidol, lithium, or placebo on the basis of EEG alone. Thus, despite limitations, visual evaluation of EEGs is of value. No statements can be made with confidence regarding associations between baseline EEGs and behavioral changes, side effects, or optimal dosages of haloperidol or lithium.

Human leukocyte anitgen in torticollis and other idiopathic dystonic syndromes.

Two groups totaling 67 patients with idiopathic focal, segmental, and generalized dystonia, including torticollis, were compared with normal controls to determine whether there was a difference in the frequency of A, B, and C locus human leukocyte (HLA) antigens. The results indicated no statistically significant deviations in HLA antigen frequencies between the patients and the normal controls. Thirteen of the patients with idiopathic torsion dystonia were compared with normal controls for DR locus antigens. A trend of increased DR3 antigens observed in the patients may be significant. HLA genotyping of parents and children in nine families was also studied to determine if an HLA-linked factor could be related to the dystonic syndrome in the children. The results were indeterminate, suggesting that further family studies are required to resolve this issue.

Effect of L-glutamine and isoniazid on torticollis and segmental dystonia.

Fourteen patients with spasmodic torticollis and other segmental dystonic syndromes, who were refractory to previous forms of therapy, were selected for treatment with drugs intended to elevate brain gamma-aminobutyric acid (GABA) levels. These patients were simultaneously given diazepam, isoniazid, pyridoxine, and large doses of L-glutamine. Involuntary spasmodic activity improved to varying degrees in 7 patients; in 2 the dyskinesia became worse. Transient alteration of renal or hepatic function occurred in 6 patients and mild euphoria unrelated to neurological improvement in 8. Two patients are still being treated. Deficiency of GABA may be a factor in some patients with these disorders.

Iris pigmentation (melanin) in idiopathic dystonic syndromes including torticollis.

Iris pigmentation was evaluated in 153 Caucasian patients with torticollis and other focal, segmental, or generalized dystonias of unknown cause. Since these disorders are rare in non-Caucasians, it was hypothesized that a relationship might exist between decreased melanin metabolism, reflected by iris pigmentation, and a genetic predisposition to these disorders of voluntary movement. Patients were separated into two groups on the basis of iris pigmentation. Compared to control groups, there was a statistically significant reversal in the ratio of patients with light eyes versus dark eyes. Further comparisons were made in two groups of patients with drug-induced nonparkinsonian dyskinesias; no significant correlation was found between their dyskinetic syndrome and iris pigmentation. Data concerning race, ethnic origin, and other disorders of the basal ganglia support the hypothesis that there may be genetic predilection in individuals whose metabolic pathways produce less systemic melanin.

Evaluation of Parkinson's disease.

An examination was developed for patients with PD. The four major signs--rigidity, tremor, bradykinesia, and gait disorder--were assessed through a series of specific maneuvers. Each sign was allocated a number of points reflecting its relative value. The scores for each of the major signs were added to yield a total score. There was a correlation between total score and stage of PD. Involuntary movements, functional disability, and dementia were assessed separately. The examination could be performed rapidly without special equipment and was particularly useful in evaluating patients exhibiting the "on-off" effect.

Dementia in Parkinson Disease.

In 520 patients with parkinsonism seen over eight years, 168 (32%) had moderate to marked dementia. Although the demented patients were older than the nondemented patients (70.4 versus 65.5 years), the incidence of dementia in Parkinson's disease (PD) was tenfold higher than among controls (similarly aged spouses of PD patients), and dementia is held to be related more to the disease than to age. Demented patients, in addition to being older, developed PD later, were more severely involved in a shorter time, and responded less well to levodopa. It is suggested that PD with dementia may represent a different disorder from PD without dementia.

Helping hemiparetics to help themselves. Sensory feedback therapy.

Despite the presence of some voluntary movement, the loss of discrete control impairs functioning of the arm and hand in most hemiparetics. Seventy hemiparetic patients, aged 12 to 78 years, were treated and followed up for six months to three years. Electromyographic activity monitored from dysfunctional primary movers during attempted movement was displayed to the patients as a continuous oscilloscopic trace, reflecting generated muscle activity and allowing its quantification. Coupled with operant conditioning techniques, these displays were modified gradually by reinforcing the patient's effort with auditory feedback during successive approximations to a desired level. Such therapeutic use of electromyographic displays often resulted in a progressive improvement of voluntary movement. More than half the patients acquired and retained purposive movements that meaningfully improved their functional capabilities.

A controlled crossover study of triiodothyronine in autistic children.

A placebo-controlled crossover study of behavioral effects of triiodothyronine (T3) was conducted in 30 young clinically euthyroid autistic children. Multiple independent raters and multiple rating scales were used. Except for a few symptoms that were reduced on T3, the drug did not differ from placebo. Time itself accounted for most of the improvement in the whole sample. As a group, the lower IQ children responded to T3. The individual children who were responders could not be defined by any parameter.