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Neurologic paraneoplastic syndromes occur in patients with all forms of malignancy. Their effects on the central and peripheral nervous systems are devastating. A neurologic abnormality may be the first manifestation of malignancy or can occur late in the course of the disease. Early recognition can lead to effective treatment of a paraneoplastic syndrome and a potential cure of the underlying cancer.
BACKGROUND: Hypothermic circulatory arrest is a widely used support technique during heart surgery in infants, but its effects on neurologic outcome have been controversial. An alternative method, low-flow cardiopulmonary bypass, maintains continuous cerebral circulation but may increase exposure to known pump-related sources of brain injury, such as embolism or inadequate cerebral perfusion. METHODS: We compared the incidence of perioperative brain injury after deep hypothermia and support consisting predominantly of total circulatory arrest with the incidence after deep hypothermia and support consisting predominantly of low-flow cardiopulmonary bypass in a randomized, single-center trial. The criteria for eligibility included a diagnosis of transposition of the great arteries with an intact ventricular septum or a ventricular septal defect and a planned arterial-switch operation before the age of three months. RESULTS: Of 171 patients with D-transposition of the great arteries, 129 (66 of whom were assigned to circulatory arrest and 63 to low-flow bypass) had an intact ventricular septum, and 42 (21 assigned to circulatory arrest and 21 to low-flow bypass) had a ventricular septal defect. After adjustment for diagnosis, assignment to circulatory arrest as compared with low-flow bypass was associated with a higher risk of clinical seizures (odds ratio, 11.4; 95 percent confidence interval, 1.4 to 93.0), a tendency to a higher risk of ictal activity on continuous electroencephalographic (EEG) monitoring during the first 48 hours after surgery (odds ratio, 2.5; 95 percent confidence interval, 1.0 to 6.4), a longer recovery time to the first reappearance of EEG activity (only in the group with an intact ventricular septum, P < 0.001), and greater release of the brain isoenzyme of creatine kinase in the first 6 hours after surgery (P = 0.046). Analyses comparing durations of circulatory arrest produced results similar to those of analyses comparing treatments. CONCLUSIONS: In heart surgery in infants, a strategy consisting predominantly of circulatory arrest is associated with greater central nervous system perturbation in the early postoperative period than a strategy consisting predominantly of low-flow cardiopulmonary bypass. Assessment of the effect of these findings on later outcomes awaits follow-up of this cohort.
This paper reviews research on neurological effects of low-level microwave irradiation, which was performed at the University of Washington, during the decade of the 1980s. We studied in the rat the effects of microwave exposure on the actions of various psychoactive drugs, on the activity of cholinergic systems in the brain, and on the neural mechanisms involved. Our results indicate that endogenous opioids play an important mediating role in some of the neurological effects of microwaves, and that parameters of microwave exposure are important determinants of the outcome of the microwave effects.
This study is a review of the psychiatric and neurological effects of solvent inhalation on a group of 22 patients with chronic histories of solvent abuse, primarily toluene-based solvents. The findings suggest that the chronic inhalation of toluene-based adhesives can produce a paranoid psychosis which may persist. Other findings were a high incidence of temporal lobe epilepsy and decrease in IQ. We suggest that the psychiatric and neurological sequelae of chronic solvent abuse are serious and potentially irreversible. Toluene is felt to be a major factor in the morbidity associated with chronic solvent abuse, and attention is drawn to the necessity for educational programs in this area. The burden caused by the resulting psychiatric problems resulting from solvent abuse may have implications for health care budgets.
Suriclone selectively displaces benzodiazepines from their binding sites but is structurally unrelated to benzodiazepines. Neurologic effects of suriclone were compared to those of diazepam in 54 subjects in a sequential, double-blind, single dose, randomized study (placebo; diazepam 10 mg; suriclone 0.2, 0.4, 0.6, or 0.8 mg). Data were collected on-line by microcomputer. Suriclone 0.2 mg did not differ from placebo. Suriclone 0.4 mg and 0.6 mg did not differ from diazepam 10 mg. Suriclone 0.8 mg caused significantly more decrement than diazepam 10 mg (p less than 0.05) in manual tracking, force platform stability, and Heath rail walking and in total severity of symptoms. Suriclone 0.8 mg caused nausea (p = 0.02), clumsiness (p = 0.02), and loss of balance (p = 0.01) more frequently than diazepam 10 mg. Suriclone 0.8 mg produced symptoms and signs qualitatively and quantitatively different from diazepam 10 mg, such as vomiting, unusual ocular movement effects, and difficulty walking. Possibly the differences in CNS drug binding for anxiolytics are associated with clinical differences in toxicity.
The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research.
Abnormal movements associated with the prolonged use of antipsychotic drugs (tardive dyskinesia) occur in at least 10%-20% of the patients at risk; prevalence is higher among the elderly. The casue is unknown, but increased sensitivity to dopamine in the basal ganglia may contribute to the pathophysiology. Many treatments have been evaluated; none is satisfactory. While the problem is serious, an alarmist view is unwarranted, especially since many cases are detected early and improve spontaneously. The best approach currently is to use antipsychotic drugs thoughtfully for clear indications, the best supported of which, scientifically, is chronic schizophrenia. There is a search for new agents with much less adverse neurologic effect but with adequate antipsychotic efficacy. This article summarizes an APA Task Force Report.
The concept of the sea as a source of noxious agents is perhaps not a familiar one to clinical neurologists, judging by the lack of reference to these agents in standard textbooks. Chemical, physiologic, and pharmacologic laboratories are increasingly investigating the properties of marine toxins, finding in them compounds with interesting and novel structures or unusual physiologic effects. Such substances are seen as possible agents for biologic and, more particularly, physiologic research, and as possible sources of new pharmaceuticals. These include hormone-like substances and antiviral or antitumor agents. Despite these specialized developments, which are in large measure a consequence of the technological advances of the present century, the clinician is at times directly concerned with the effects of marine toxic substances. For example, in Japan, puffer fish or tetrodotoxic poisoning is one of the major causes of deaths from food poisoning. Another marine toxin that has caused many explosive outbreaks of food poisoning. with many deaths in various parts of the world, comes from clams or mussels. This toxin, saxitoxin, is produced by species of marine protozoa including Gonyaulax, and is concentrated in filter-feeding molluscs. These two examples were of significant interest in medicine long before the technologic developments of the twentieth century. In the last few decades, entirely new problems of marine intoxication have arisen as a result of marine pollution from the disposal of industrial wastes in the sea. The most striking example of a man-made marine intoxication has been the outbreak of Minamata disease. In Minamata, Japan, the disposal of mercury-contaminated industrial wastes from a plastics factory into an enclosed bay, followed by human consumption of the contaminated fishes, crabs, or shellfish, led to many instances of acute cerebral degeneration. With the increasing exploration of the sea for both pleasure and economic exploitation, which is a feature of the second half of the twentieth century, it may be expected that the frequency and variety of human intoxications by marine creatures will be increased. This chapter reviews the neurologic effects of noxious substances of marine biologic origin. The subject is now developing so rapidly that overall surveys, such as this, of the general animal life of theocens will soon be beyond the scope of a single review. Nevertheless, it is hoped that the references given will enable the interested reader to pursue particular aspects further.
We studied the effect of thiopental loading during resuscitation of 53 patients following cardiopulmonary arrest and compared the outcome with that found in 54 patients treated conventionally in the 30 previous months. Thiopental therapy (10 mg/kg i.v.) was begun within 30 min of the arrest once hemodynamic stability had been established. Thiopental infusion (20 mg/kg over 6 h) was followed by phenobarbital sodium (125 mg every 12 h), tolerance to the initial dose having been assessed. The in-hospital mortality rate for both groups was similar. In patients with ischemic heart disease, the mortality rate within the first 6 h was significantly higher in the thiopental group (p less than 0.05), although for the remaining patients there were more survivors among the thiopental treated patients (p less than 0.05). Excluding the patients who died within the first 6 h, 61% of the patients in the thiopental group survived cardiac arrest with normal cerebral performance, whereas only 37% in the standard treatment group showed normal functional outcome (p less than 0.03). These results suggest a favorable neurologic effect of thiopental loading during resuscitation of patients without ischemic heart disease. In patients with ischemic heart disease, an initial hemodynamic deterioration may contribute to minimising the beneficial effect of barbiturate therapy.
Reports of neurologic impairment of children following recovery from acute lead encephalopathy have raised questions concerning the effects of chronic low-level lead exposure on the central nervous system. Behavioral toxicologic techniques have been employed to assess the effects of lead on the central nervous system in sheep. Mature sheep receiving daily doses of 100 mg lead/kg showed a significant decrease in performance on an auditory signal detection task. Daily oral doses of 120 and 230 mg lead/sheep for 27 weeks did not alter the performance of mature sheep on a fixed-interval schedule of reinforcement behavioral task. Prenatal exposure to maternal blood lead levels of 16 or 34 mug/100 ml during gestation and postnatal daily ingestion of 16, 8, 4, or 2 mg lead/kg did not alter performance of lambs on a closed-field maze task. Slowed learning was demonstrated in lambs prenatally exposed to maternal blood lead levels of 34 mug/100 ml during gestation when tested on nonspatial, two-choice visual discrimination problems at 10-15 months of age.
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A double-blind withdrawal trial in 41 chronic schizophrenic outpatients was carried out over 6 months. Depot neuroleptics (fluphenazine decanoate or flupenthixol decanoate) were compared with placebo to evaluate neurological side effects during continued therapy and during withdrawal. The drugs were significantly more effective than placebo in preventing relapse and rehospitalization. In the placebo group 62% relapsed compared to 27% in the drug group. A difference was observed in the occurrence of extrapyramidal symptoms (EPS) between the neuroleptics in the study. Akathasia was observed in 9/38 (23.7%) cases, significantly more frequent in the fluphenazine decanoate group. Tardive dyskinesia (TD) was observed in six cases (15.8%); four cases existed at the start of the study and two others were observed after 3-6 weeks of withdrawal. There was no relation between TD symptoms and relapse. There was a significant decrease in the EPS scores during the placebo treatment and also a significant weight decrease.
A study was made of the frequency and duration of neurological disorders after cranio-caudal irradiation of rats with doses of 7.5-500 Gy delivered to the head. As the mean effective dose increased the neurological disorders occurred in the following order: tremor, rotatory movements hyperkinesia, opisthotonos, and convulsions. The neurophysiological disorders observed were subjected to a pathophysiological analysis.
To define the utility of high-dose barbiturate therapy following an episode of complete global cerebral ischemia, we investigate the effects of 60 mg/kg of thiopental given to cats five minutes after resuscitation from 12, 14, or 16 min of electrically induced ventricular fibrillation (VF). All aspects of the arrest, resuscitation, with post-arrest care were carefully controlled, with the EEG becoming isoelectric 20-25 s after the onset mean resuscitation time of 2.5 +/- 0.2 (SEM) min. For any given duration of VF, there were no differences (control vs thiopental) in any pre- or post-arrest parameters (blood pressure, blood gases, electrolytes, etc.) A total of 68 resuscitated cats were entered into various treatment and control groups, and all but one group received 20-24 h of post-resuscitation paralysis, mechanical ventilation, and ICU support before being extubated. Cats received an additional six days of aggressive nursing care, and daily examinations were performed with the assignment of a neurologic deficit score (NDS) between 0 (normal) and (brain dead). Autopsies were performed to determine the cause of death in animals which died before the end of the seven-day observation period. The early post-arrest period was marked by the occurrence of repetitive, rhythmic bursts of high-frequency electroencephalographic (EEG) activity (? seizures) in 38 per cent of control animals (16/42, all arrest times combined). Ten of these animals died as a result of severe neurologic injuries. By contrast, only 12 per cent of treated cats (3/26) developed similar EEG patterns (P less than 0.05) and there were no neurologic deaths in the thiopental groups. The differences in the incidence of neurologic deaths (control vs. thiopental) was significant (P less than 0.02). The change in overall mortality did not quite reach significance (36 per cent vs. 21 per cent), and treatment had no effect on the incidence of deaths due to cardiovascular causes (e.g., myocardial infarctions). In spite of the effects on mortality, treatment had no effect on the neurologic function of survivors (assessed by NDS). These findings suggest that thiopental improved survival rates by suppressing an unusual post-arrest EEG pattern (? anticonvulsant effect), but had no additional cerebral protective effects.
Alcoholism, a worldwide disorder, is the cause of a variety of neurologic disorders. In this article we discuss the cellular pathophysiology of ethanol addition and abuse as well as evidence supporting and refuting the role of inheritance in alcoholism. A genetic marker for alcoholism has not been identified, but neurophysiologic studies may be promising. Some neurologic disorders related to longterm alcoholism are due predominantly to inadequate nutrition (the thiamine deficiency that causes Wernicke's encephalopathy), but others appear to involve the neurotoxicity of ethanol on brain (alcohol withdrawal syndrome and dementia) and peripheral nerves (alcoholic neuropathy and myopathy).
BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or ≥10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8·5 years (SD 1·9) in the eDSP group and 8·6 years (2·3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.
Using a standard battery of medical surveillance questions, a study was undertaken to determine if an increase in reported neurologic symptoms was resulting from solvent exposure at a pharmaceutical research, development, and manufacturing site. The prevalence of positive responses to 13 interval history questions pertaining to neurological symptoms was compared between those enrolled in exposed surveillance programs (n = 840) and those enrolled in other, non-solvent exposed surveillance programs (n = 1,042). The ratio of positive responders between the exposed and unexposed groups was used to generate a relative prevalence ratio (RPR). No significantly elevated RPRs were seen when the analysis was adjusted for the confounding factors of age, sex, smoking, alcohol use, noise exposure, and number of interval histories. These results suggest that workplace solvent exposures in the employees studied did not appear to result in obvious neurologic symptoms. However, low-level neurotoxic exposures can cause asymptomatic or sub-clinical disorders. Therefore, more sensitive neurotoxic surveillance systems need to be developed.
Metoclopramide hydrochloride is now commonly prescribed for a variety of gastrointestinal disorders. Over a 2-year period 18 patients with neurologic disorders induced by metoclopramide were assessed at the Parkinson's disease clinic of the Ottawa Civic Hospital. During metoclopramide therapy acute transient dystonic reactions were seen in 4 patients, and parkinsonism, which was frequently misdiagnosed and treated as classic Parkinson's disease, was seen in 12 patients. After treatment with metoclopramide was stopped, tardive dyskinesia appeared in seven patients and has persisted for up to 15 months in three patients. Parkinsonism and tardive dyskinesia occurred in older patients undergoing long-term therapy with metoclopramide. This experience, therefore, suggests that such treatment, especially in older patients, should be avoided.