Julius Korein

Lithium and chlorpromazine: A controlled crossover study of hyperactive severely disturbed young children

A controlled crossover study of lithium and chlorpromazine involving 10 severely disturbed children, 3 to 6 years of age, of which 6 were schizophrenic and 1 autistic, is reported in detail. Patients were matched for motor activity (hyper- and hypoactivity) and prognosis. More symptoms diminished on chlorpromazine than on lithium. However, improvements were only slight on both, except in one child whose autoaggressiveness and explosiveness practically ceased on lithium (nonblind evaluations). Blind ratings indicated no statistically significant difference between the two drugs as well as absence of statistically significant change from baseline to treatment with either. Lithium diminished the severity of individual symptoms, though not statistically significant, such as explosiveness, hyperactivity, aggressiveness, and psychotic speech. Its effect in adult schizophrenia is compared to responses of schizophrenic children. Also discussed is the relationship of EEG to clinical improvement and toxicity, and effect of lithium on hyperactivity and aggressiveness. It is suggested that lithium may prove of some value in treatment of severe psychiatric disorders in childhood involving aggressiveness, explosive affect and hyperactivity.

Brain death: II. Neuropathological correlation with the radioisotopic bolus technique for evaluation of critical deficit of cerebral blood flow

An innocuous intravenous portable radioisotopic test using technetium 99m pertechnetate was employed to demonstrate the deficit of cerebral blood flow associated with brain death. The results are compared to those of bilateral carotid and vertebral angiography in 20 patients. Absence of a bolus tracing from the head in the presence of a control tracing of a bolus from the femoral artery in two successive studies one hour apart reliably correlated with the clinical and electroencephalographic findings signifying cerebal death in comatose, apneic patients. Angiography indicated absence of intracranial circulation in 10 patients. Stasis filling or retrograde emptying of arterial vessels (or both) occurred in 7 patients. There was no evidence of venous filling in any of these 17 patients; all of them had either an absent head bolus or an “intermediate tracing.” Results indicate that either form of tracing represents a critical decrease of cerebral blood flow. Two other patients had evidence of severely impaired abnormal posterior fossa circulation without angiographic evidence of cerebral circulation; both of these patients had an absent head bolus. An additional patient had an unusually small head bolus, and angiography revealed extravasation of radiopaque material but no evidence of intracranial circulation. We conclude that the bolus technique is a helpful adjunct in diagnosing brain death.

ANGIOGRAPHIC FINDINGS IN BRAIN DEATH

With advances in medical techniques, “life” may be supported even though irreversible brain t damage has occurred. To avoid prolonged efforts to maintain a brain-dead patient until systemic death occurs and to conserve organs for transplantations, it is necessary to rely on a diagnostic test that would aid in conclusively determining the irreversibility and scope of the cerebral insult. Although isotopic determination of a cerebral blood-flow deficit is a rapid and reliable diagnostic adjunct to determine cerebral t death,3-sv l6, l7 there are times that in the clinical judgment of the examining neurologist, angiography is required before it can be stated with certainty that brain death has occurred. Angiography may thus be necessary when the isotopic bolus study demonstrates an “intermediate” or small bolus pattern or is technically unsatisfactory, or when the EEG is not unequivocally isoelectric. Furthermore because of technical considerations the bolus technique is primarily limited to use in adults.15 Therefore intracranial angiography may be necessary to document brain death in infants and small children. Many European authors maintain that the sine qua non of brain death rests with the demonstration of absence of intracranial circulation by angiography.?. s~ 2 3 Though serving a limited role in the diagnosis of brain death, the findings at angiography are recorded so that when this diagnostic test is used as the final confirmation of the determination of death, no confusion will result. It is our belief that when the advocates of angiography become familiar with the results obtained by the bolus technique, they will rarely resort to angiography.

THE PROBLEM OF BRAIN DEATH: DEVELOPMENT AND HISTORY*

Brain death is reviewed and analyzed from medical, biological, and historical perspectives. Understanding of the terminology used is imperative prior to undertaking such an endeavor. The meaning of the words construct, concept and criterion are, therefore, explicitly defined. The usage of the terms death and brain death are discussed and throughout this paper these are separated from other sets of medical problems and social issues, such as those relating to irreversible noncognitive states, organ transplantation and the “right to die.” Death is not considered an event, but rather a process related to the dissolution of a living system. The definition of a living system involves derivations from thermodynamics, information theory, control systems, value theory and the dynamics of irreversible states. The critical component of the living system may then be defined. In the human organism, the brain is the critical component. Brain death then becomes equivalent to death of a person. Development of criteria that will allow the physician to diagnose brain death, the death of an individual, is then considered within the medical and social milieu. Historically, initiation of the major events in the evolution of these criteria is considered to have begun with the allocution of Pope Pius XI1 on the prolongation of life in 1957. These events include medical studies, social critiques, and statutes, all of which reflect the initial confusion about the subject. Medical research, however, has gradually increased the specificity of terminology as well as clinical and laboratory criteria to be used, allowing the accurate and reliable diagnosis of brain death. Ancillary laboratory techniques include electroencephalography as well as studies relating to brain circulation and metabolism. No single clinical or laboratory criterion can be used to arrive at a diagnosis of brain death. Rather, it is the composite of these criteria combined with the physician’s medical judgment, etiologic and temporal factors, and consideration of the appropriate differential diagnosis that leads to the appropriate judgment and management of any given patient.

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)

Localization of action of two amnesia producing drugs in freely moving mice.

Abstract Two drugs previously shown to produce amnesia in mice, cycloheximide, a protein synthesis inhibitor, and diethyldithiocarbamate (DDC), a dopamine beta hydroxylase inhibitor, altered the electrical activity recorded from the midbrain reticular formation and parietal cortex of freely moving awake mice. Under similar circumstances, the averaged visual evoked responses were consistently altered only from the dorsal hippocampus. It is suggested that both of these drugs have similar actions and that their primary effect is on the midbrain reticular formation and the cerebral cortex.

Evaluation of the critical deficit of cerebral circulation using radioactive tracers (bolus technique).

Technological and medical advances now often make it possible to sustain life in deeply comatose patients who would previously have died. These same advances at times also make possible prolongation of life in a body when the brain of that individual has died. In as far as the brain is the essence and substance of individual human existence, the undue prolongation of life in a body with a dead brain is futile. Such efforts prolong the anguish of relatives and drain resources which could be used for individuals still able to benefit from them. The advent of transplant surgery has created a need for viable organs; these tend to deteriorate after cessation of the heartbeat. Therefore, individuals with brain death are a source of such organs if they can be removed before the heart stops. The above factors may result in a situation that requires a relatively rapid decision regarding the question of brain death. It should be clearly borne in mind that under certain circumstances, comatose states, including those that are reversible, may temporarily mimic brain death in all clinical and electroencephalographic Situations that may transiently simulate brain death may occur in patients with drug intoxication, but have also been reported in other conditions, such as induced hypothermia, encephalitis, and metabolic disorders. The Harvard criteria’ require 24 hours of observation plus the absence of drugs and hypothermia in order to make a judgment of brain death. The problem of drug intoxication is often a difficult one to deal with since there may be no detailed history available in such patients. Moreover, the laboratory search for drugs is not rapid, especially when the nature of the drug is not known.\ It is particularly noteworthy that a collaborative study on cerebral survival (CSCS),9x lo based on the study of 503 comatose and apneic patients, found a significant proportion of these patients had drug levels in the blood compatible with coma, even when other more obvious causes of coma were known.El 1

TERMINOLOGY, DEFINITIONS, AND USAGE

Criteria are a set of standards against which observations are compared to allow the individual to make a judgment. For example, one of the criteria for death is total unresponsiveness. Based on this criterion, the presence of unresponsiveness is determined by observations and tests which will allow a judgment to be made (along with the use of other criteria) as to whether the individual is dead. The use of criteria represents an operational activity in order to come to a decision about a situation. The reader should keep in mind the confusion that exists in parts of this volume, between concept and criteria especially in the discussions.

Treatment questioned in familial spasmodic torticollis.

To the Editor: Dr. Gordon J . Gilbert (NEUROLOGY 27:l 1-13, January, 1977), in his article on familial spasmodic torticollis, discusses the familial occurrence of torticollis. In the case reports, he mentions the treatment of a small group of patients with apparently excellent results. Ln our experience with 80 patients with focal dystonia and torticollis, 12 of the 69 patients with torticollis had a family history of dyskinesia, most often torticollis or torticollis associated with other components of focal dy~ ton ia . ’ -~ The familial incidence also has been discussed by other authors. 4 ,5 Two aspects of the article as presented infer a conclusion in terms of treatment. This is indicated in the case reports, stating that all patients e i ther improved markedly or became asymptomatic on combinations of drug therapy including haloperidol, amantadine, trihexyphenidyl, and/or diazepam with EMG feedback. There is no discussion or follow-up indicating the duration ofthe patients’ improvement. Since it has been our experience that 40 to 50 percent of patients with torticollis may be treated with integrated EMG feedback alone with significant results, one must question the contribution of the drug therapy. We have followed patients treated with EMG feedback for up to 4 years in whom there has been persistent improvement without medication. In contrast, many patients treated with the drugs mentioned often not only fail to respond but develop a progressive worsening of their symptomatology or stiffer unpleasant side effects of a parkinson-like syndrome or other dyskinesia. The limited value of drug therapy in the treatment of spasmodic torticollis is discussed in the recent communica t ion by Dr . H . H . West ( N E U R O L O G Y 37:198-199, 1977) tising a double-blind study. He notes the spontaneous fluctuations occurring early in the course of the disease that limit the value of single case reports. The complexity of the problem may be illustrated by two siblings whom we have observed for a prolonged period. The brother, who is 40 years old, developed torticollis to the right at the age of 26. There was gradual progression with a left sided segmental dystonia over the next 2 years. He underwent bilateral cryothalamectomy with limited results and subsequent speech impairment. He received pimozide in 1974, which resulted in immediate but transient improvement of all symptomatology . Subsequent drug therapy was ineffective. In the patient’s sister, 37 years old, torticollis developed to the right when she was 33. The symptoms remained focal and treatment with a variety of drugs including pimozide was ineffective. Diazepam was of marginal benefit. Two trials of EMG feedback were ineffective. During the next year and a half, following the hypothesis that depletion of gamma aminobutyric acid (GABA) in the basal ganglia was a probable etiologic factor in this disorder,4 the patient was treated with a series of pharmaceutically available agents that might act to increase central nervous system GABA. 627After many trials, she was startedon acombinationof L-gltitamine in massive doses (40 gm per day in six divided doses) with isoniazid 150 mg, vitamin Bti 150mg, anddiazepam 30 mg per day. Within 4 weeks, all symptoms diminished. She has been maintained on this regimen for over 2 months and is essentially symptom free with full range of head motion and normal activities. Her brother was then treated in a similar manner with no significant effect. The only side effects noted in both siblings were increased “energy,” appetite, and sexual drive. This limited study is sufficient only to warrant speculation about the efficacy and mechanism of the treatment. A statistically significant group of patients must be treated and followed for an appropriate period. Then performance of a double blind study is required, as suggested by Dr. West. The study of the efficacy of isoniazid and large doses of L-glutamine is now in progress.

Computer processing of neuroradiologic reports by variable-field-length format. II. Utilization of the technic to evaluate cerebral angiograms in a series of patients with head trauma.

The variable-field-length format is a data-recording technic which allows the reporting of narrative radiologic data in a form acceptable for computer storage and retrieval. Most methods that apply computer technics to verbal medical data utilize inputs into the computer by means of punch cards and check lists. These “fixed-field” methods are time-consuming, incomplete, and restricted in terms of data which may be stored. The variable-field technic enables the radiologist to dictate reports in his own words without altering his usual word patterns. The entire report is then stored in the computer and is available for subsequent analysis and retrieval. There is theoretically no limit to the amount or type of data that can be included in the report. Data Collection The method of data collection has been previously described in detail (1–4). The radiologist designs a “master” format consisting of several paragraph headings to be followed in sequence (Fig. 1). A typist uses a special punched paper tape in a p...