Paraneoplastic limbic encephalitis: neuropsychiatric presentation.

Limbic encephalitis as a distinct clinicopathological entity is becoming increasingly familiar to neurologists. However, despite its classical clinical presentation of mental status changes and behavioral abnormalities, the disorder is not well known in the psychiatric literature and premortem diagnosis is rare. We recently participated in the care of a patient who spent two months on a psychiatric service and in whom a medical disorder was consistently suspected but not confirmed until autopsy revealed paraneoplastic limbic encephalitis and two primary systemic malignancies. A detailed neuropsychiatric description of this clinical entity is provided from presentation to autopsy with review of the literature.

An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders.

This paper reviews the clinical and experimental literature on patients with multiple adverse responses to chemicals (Multiple Chemical Sensitivity Syndrome-MCS) and develops a model for MCS based on olfactory-limbic system dysfunction that overlaps in part with Post's kindling model for affective disorders. MCS encompasses a broad range of chronic polysymptomatic conditions and complaints whose triggers are reported to include low levels of common indoor and outdoor environmental chemicals, such as pesticides and solvents. Other investigators have found evidence of increased prevalence of depression, anxiety, and somatization disorders in MCS patients and have concluded that their psychiatric conditions account for the clinical picture. However, none of these studies has presented any data on the effects of chemicals on symptoms or on objective measures of nervous system function. Synthesis of the MCS literature with large bodies of research in neurotoxicology, occupational medicine, and biological psychiatry, suggests that the phenomenology of MCS patients overlaps that of affective spectrum disorders and that both involve dysfunction of the limbic pathways. Animal studies demonstrate that intermittent repeated low level environmental chemical exposures, including pesticides, cause limbic kindling. Kindling (full or partial) is one central nervous system mechanism that could amplify reactivity to low levels of inhaled and ingested chemicals and initiate persistent affective, cognitive, and somatic symptomatology in both occupational and nonoccupational settings. As in animal studies, inescapable and novel stressors could cross-sensitize with chemical exposures in some individuals to generate adverse responses on a neurochemical basis. The olfactory-limbic model raises testable neurobiological hypotheses that could increase understanding of the multifactorial etiology of MCS and of certain overlapping affective spectrum disorders.

Sensitization to early life stress and response to chemical odors in older adults.

This study examined the hypothesis that older persons who currently report illness from environmental chemical odors (cacosmia) may have experienced higher levels of stress early in life than did noncacosmic controls. The hypothesis derives from a time-dependent sensitization (TDS) model for cacosmia (Bell et al 1992) that predicts a relative interchangeability of stress and chemicals in inducing and eliciting sensitized responses in vulnerable individuals. Subjects were selected from those in the top 24% (cacosmic) and bottom 27% (noncacosmic) of a sample of 192 older adults (mean age 73.8 years) for self-reported frequency of illness form the odors of pesticide, car exhaust, paint, perfume, and new carpet. As in previous investigations, cacosmics were younger, more depressed, and more shy; cacosmics also included a higher proportion of women (83% versus 61%). As predicted, cacosmics rated themselves higher in stress for the first four decades of their lives, but not the recent past or present, even after controlling for depression, anxiety, hostility, shyness, age, and gender. Cacosmics reported increased prevalence of physician-diagnosed nasal allergies, breast cysts, hypothyroidism, sinusitis, food sensitivities, irritable bowel, and migraine headache. Only 4% of the overall sample (including 9% of the cacosmics) acknowledged the controversial physician diagnosis of "chemical sensitivity." The replicated observation of greater shyness in cacosmics is consistent with the ability of hyperreactivity to novelty to predict enhanced susceptibility to TDS from low levels of pharmacological agents in animals. The findings support a TDS model for cacosmia and suggest that cacosmia as a symptom identifies a large subset of the nonindustrial population with significant psychophysiological health problems that merit further objective examination.

Differential resting quantitative electroencephalographic alpha patterns in women with environmental chemical intolerance, depressives, and normals.

BACKGROUND: Previous research suggests that a subset of individuals with intolerance to low levels of environmental chemicals have increased levels of premorbid and/or comorbid psychiatric disorders such as depression, anxiety, and somatization. The purpose of this study was to evaluate the psychological profiles and quantitative electroencephalographic (qEEG) profiles at baseline of women with and without chemical intolerance (CI). METHODS: Participants were middle-aged women who reported illness from the odor of common chemicals (CI, n = 14), depressives without such intolerances (D, n = 10), and normal controls (N, n = 11). They completed a set of psychological scales and underwent two separate qEEG recording laboratory sessions spaced 1 week apart, at the same time of day for each subject. RESULTS: CI were similar to D with increased lifetime histories of physician-diagnosed depression (71% vs. 100%), Symptom Checklist 90 (revised) (SCL-90-R) somatization scores, Barsky Somatic Symptom Amplification, and perceived life stressfulness, although D had more distress than either CI or N on several other SCL-90-R subscales. CI scored significantly higher on the McLean Limbic Symptom Checklist somatic symptom subscale than did either D or N. On qEEG, CI exhibited significantly greater overall resting absolute alpha activity with eyes closed, especially at the parietal midline site (Pz), and increased (sensitized) frontal alpha from session 1 to 2, in contrast with the D and N groups. D showed right frontal asymmetry in both sessions, in comparison with CI. CONCLUSIONS: The data indicate that CI with affective distress diverge from both D without chemical intolerance and N in qEEG alpha patterns at resting baseline. Although CI descriptively resemble D with increased psychological distress, the CI's greater alpha suggests the possibility of a) central nervous system hypo-, not hyper-, activation; and/or b) an overlap with EEG alpha patterns of persons with positive family histories of alcoholism.

Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption.

Twenty narcoleptic patients and ten age-matched normals were polygraphically monitored for 58 consecutive hours. All subjects were on regimented sleep (hours between 2230 and 0700). Group A (11 patients and 10 normals) had enforced wakefulness during the day whereas Group B (9 patients) were permitted to sleep (mean = 2 1/2 hr.). On day 2, all subjects were permitted to sleep for 15-min periods every 2 hr. In narcoloptics, sleep recordings demonstrated a reduction of sleep latency, an increase of stage 1, and a decrease in stages 3 and 4 compared to normals, but total REM time and percentage of REM sleep were similar. Groups A and B showed no difference in the incidence of nocturnal awakenings. REM cyclic periodicity was larger in narcoleptics who also demonstrated a REM-sleep fragmentation. This fragmentation became more pronounced as time passed, with several shifts from REM to wakefulness and stage 1. Narcoleptics present REM onset sleep period but also show an inability to remain in REM sleep.

Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

Time-dependent sensitization of plasma beta-endorphin in community elderly with self-reported environmental chemical odor intolerance.

This study examined plasma beta-endorphin as a marker of the physiological stress response in community elderly who were either high (n = 15) or low (n = 15) in self-rated frequency of illness from environmental chemical odors. Individuals who report nonatopic multiple sensitivities to or intolerances for low levels of environmental chemicals also claim high rates of comorbid food sensitivities or intolerances. Subjects gave 9 AM blood samples for plasma beta-endorphin 90 min after ingesting either 1% fat cow's milk or a soy-based nondairy drink, on six different mornings in the laboratory after all-night sleep recordings. The six sessions-were divided into three sets of two successive days each, with each set [involving baseline (ad lib milk), nondairy (soy-based), and dairy diets] separated from the next by 3 weeks. In the chemically tolerant subjects, stably lower beta-endorphin levels suggested that milk may have been a physiologically less stressful beverage than was the soy drink. In contrast, the chemical odor intolerant group exhibited a) increased levels of plasma beta-endorphin averaged over the 6 days (p = .02); and b) marked fluctuations in endorphin from one laboratory day to the next (Group x Diet x Day interaction, p = .005). The findings were consistent with time-dependent, context-dependent sensitization of beta-endorphin in the chemical odor intolerant individuals.

A polysomnographic study of sleep disturbance in community elderly with self-reported environmental chemical odor intolerance.

Subjective sleep complaints and food intolerances, especially to milk products, are frequent symptoms of individuals who also report intolerance for low-level odors of various environmental chemicals. The purpose of the present study was to evaluate the objective nature of nocturnal sleep patterns during different diets, using polysomnography in community older adults with self-reported illness from chemical odors. Those high in chemical odor intolerance (n = 15) exhibited significantly lower sleep efficiency (p = .005) and lower rapid-eye-movement (REM) sleep percent (p = .04), with a trend toward longer latency to REM sleep (p = .07), than did those low in chemical intolerance (n = 15), especially on dairy-containing as compared with nondairy (soy) diets. The arousal pattern of the chemical odor intolerant group differed from the polysomnographic features of major depression, classical organophosphate toxicity, and subjective insomnia without objective findings. The findings suggest that community elderly with moderate chemical odor intolerance and minimal sleep complaints exhibit objectively poorer sleep than do their normal peers. Individual differences in underlying brain function may help generate these observations. The data support the need for similar studies in clinical populations with chemical odor intolerance, such as multiple chemical sensitivity patients and perhaps certain veterans with "Persian Gulf Syndrome."

Use of clonazepam in mania and schizoaffective disorders.

The authors report three cases in which clonazepam controlled the acute symptoms in one manic and two schizoaffective patients. Clonazepam treatment led to a decrease in agitation and logorrhea, without the side effects associated with neuroleptics.

Elevated antidepressant plasma levels after addition of fluoxetine.

Four patients treated with tricyclic antidepressants and one patient treated with trazodone all demonstrated marked increases in plasma levels of these drugs after the addition of fluoxetine. Such increases could increase adverse effects.

Illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia.

This article summarizes (1) epidemiologic and clinical data on the symptoms of maladies in association with low-level chemicals in the environment, i.e., environmental chemical intolerance (CI), as it may relate to chronic fatigue syndrome (CFS) and fibromyalgia; and (2) the olfactory-limbic neural sensitization model for CI, a neurobehavioral synthesis of basic and clinical research. Severe CI is a characteristic of 20-47% of individuals with apparent CFS and/or fibromyalgia, all patients with multiple chemical sensitivity (MCS), and approximately 4-6% of the general population. In the general population, 15-30% report at least minor problems with CI. The levels of chemicals reported to trigger CI would normally be considered nontoxic or subtoxic. However, host factors--e.g., individual differences in susceptibility to neurohormonal sensitization (amplification) of endogenous responses--may contribute to generating a disabling intensity to the resultant multisystem dysfunctions in CI. One site for this amplification may be the limbic system of the brain, which receives input from the olfactory pathways and sends efferents to the hypothalamus and the mesolimbic dopaminergic [reward] pathway. Chemical, biologic, and psychological stimuli can initiate and elicit sensitization. In turn, subsequent activation of the sensitized limbic and mesolimbic pathways can then facilitate dysregulation of behavioral, autonomic, endocrine, and immune system functions. Research to date has demonstrated the initiation of neurobehavioral sensitization by volatile organic compounds and pesticides in animals, as well as sensitizability of cardiovascular parameters, beta-endorphin levels, resting EEG alpha-wave activity, and divided-attention task performance in persons with CI. The ability of multiple types of widely divergent stimuli to initiate and elicit sensitization offers a new perspective on the search for mechanisms of illness in CFS and fibromyalgia with CI.

Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals.

Sensitization in the neuroscience and pharmacology literatures is defined as progressive increase in the size of a response over repeated presentations of a stimulus. Types of sensitization include stimulant drug-induced time-dependent sensitization (TDS), an animal model related to substance abuse, and limbic kindling, an animal model for temporal lobe epilepsy. Neural sensitization (primarily nonconvulsive or subconvulsive) to the adverse properties of substances has been hypothesized to underlie the initiation and subsequent elicitation of heightened sensitivity to low levels of environmental chemicals. A corollary of the sensitization model is that individuals with illness from low-level chemicals are among the more sensitizable members of the population. The Working Group on Sensitization and Kindling identified two primary goals for a research approach to this problem: to perform controlled experiments to determine whether or not sensitization to low-level chemical exposures occurs in multiple chemical sensitivity (MCS) patients; and to use animal preparations for kindling and TDS as nonhomologous models for the initiation and elicitation of MCS.

Medical histories and psychological profiles of middle-aged women with and without self-reported illness from environmental chemicals.

BACKGROUND: Cacosmia, which is a predictor of cognitive deficits in industrial samples, is a core symptom of several controversial syndromes. Previous studies of cacosmic populations have considered only psychiatric but not medical or family histories of identified patients. METHOD: This questionnaire survey study examined subjective characteristics of illness from chemical odors, sensitivity to chemicals, psychological and stress profiles, and medical, psychiatric, and family health histories of 28 middle-aged women with cacosmia in self-reported poor health attributed to chemicals (MCS), 17 controls with cacosmia in good health, and 20 normal controls without cacosmia in good health. RESULTS: Those with MCS rated themselves in significantly poorer overall health with higher Pennebaker symptom scores, a larger number of chemical triggers, and greater frequency of illness from chemicals than the other two groups, even after controlling for variables on which the groups differed (i.e., education, Symptom Checklist-90 [revised] somatization, obsessive-compulsiveness, depression, anxiety, phobic anxiety, psychoticism, Barsky Somatic Symptom Amplification, and Cheek-Buss shyness). Despite increased levels of affective distress, those with MCS reported the greatest intolerance for alcohol and the lowest alcohol consumption. CONCLUSION: The data suggest that women with MCS report increased disability, multiple medical diagnoses including inflammatory and gynecologic dysfunctions, and psychological distress. The data are consistent descriptively with the phenomenology of somatization disorder. However, the persisting significance of group health rating differences after controlling for psychological variables, the lack of differences in life stress ratings between those with MCS and healthy cacosmics, the later age at onset (60% after age 30 years), and the lack of excess family psychiatric histories in this sample of women with MCS suggest a potential role for an organic factor in the evolution of poor health in certain cacosmics.

B complex vitamin patterns in geriatric and young adult inpatients with major depression.

This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non-alcoholic inpatients with major depression. Twenty-eight percent of all subjects were deficient in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non-psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini-Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression, but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study.

Sensitization studies in chemically intolerant individuals: implications for individual difference research.

Chemical intolerance (CI) is an individual difference trait in which persons report feeling ill in multiple physiological systems from low levels of a wide range of chemically unrelated environmental substances. This paper discusses the neural sensitization model for progressive host amplification of polysymptomatic responses elicited by chemical exposures following an initiating event. The sensitization model accommodates hypotheses for initiating and eliciting CI in human populations that involve both environmental chemicals and physical or psychological stressors. Recent studies in this laboratory have demonstrated sensitization in individuals with CI over repeated sessions for dependent variables such as electroencephalographic (EEG) activity and diastolic blood pressure. Psychological distress variables alone do not explain these findings. Individuals with CI and/or vulnerability to sensitization share specific characteristics, for example, female gender, certain genetic background (offspring of alcohol-preferring parents), and personal preference for high sugar/ carbohydrate intake. Overall, the data suggest that the 15-30% of the general population who report heightened CI are highly sensitizable. Sensitizability may serve an adaptive, sentinel function in threatening environments with poor signal-to-noise ratios. However, as sensitization gradually shifts operating set points of physiological systems out of the normal range in response to allostatic load, this process may contribute to the development of chronic, polysymptomatic health conditions such as multiple chemical sensitivity and/or fibromyalgia. Individual response specificity and stereotypy rather than toxicant properties may determine which types of central, autonomic, and/or peripheral nervous system dysfunctions manifest at subclinical and clinical levels.

Immunological clearance of 75Se-labelled Trypanosoma brucei in goats.

An experiment was conducted to determine, under different conditions, the capacity of young adult East African goats to eliminate intravenously inoculated [75Se]selenomethionine-labelled Trypanosoma brucei from the bloodstream. Over 80% of labelled trypanosomes, preincubated for 1 h in inactivated normal goat serum, were detectable in the circulation 1 h after inoculation into normal goats. By contrast, after incubation in serum from goats which had been immunised against the homologous trypanosome clone, parasites were largely removed from the bloodstream within 5 min after inoculation. When the goats were necropsied 1 h after the inoculation of radiolabelled trypanosomes, 50% of the injected activity was found in the liver and lungs, the contribution of each organ being dependent to some extent on whether the inoculum was via a mesenteric or the jugular vein. The same result was obtained when labelled parasites were incubated in normal goat serum, and then inoculated into immunised goats; thus, rapid blood clearance occurred, and high activity was detected in the lungs and liver. The results confirm those of previous studies in laboratory mice in which the removal of trypanosomes from the circulation of an immune animal was achieved primarily by uptake of opsonised trypanosomes by elements of the mononuclear phagocytic system.

Clinically relevant EEG studies and psychophysiological findings: possible neural mechanisms for multiple chemical sensitivity.

This paper addresses the evidence for the face, construct, and criterion-related validity of the olfactory-limbic/neural sensitization model for multiple chemical sensitivity (MCS). MCS is a poorly-understood, controversial condition in which low levels of environmental chemicals are reported to trigger disabling levels of illness in certain individuals. Neural sensitization processes could generate an endogenous amplification of responsivity to exogenous substances, thereby providing a plausible explanation for the apparent lack of a classical toxicological dose-response relationship in MCS. Convergent data from both survey and psychophysiological studies of MCS patients and of persons from the community without MCS, but who report elevated frequency of illness from chemical odors (cacosmics), support the involvement of the limbic system and the sensitizability of cacosmics, as predicted by the model. Recent studies show that cacosmics do sensitize their heart rate, blood pressure, and plasma beta-endorphin responses to repeated exposures to a novel laboratory procedure involving dietary manipulations over time. Cacosmia may represent a pathological form of neural plasticity. Taken together, the model and the available evidence suggest the need for more intensive investigation of MCS from the standpoint of possible neurobiological mechanisms affecting cognitive, emotional, and somatic functions.

Relationship of normal serum vitamin B12 and folate levels to cognitive test performance in subtypes of geriatric major depression.

This retrospective study evaluated the relationships between normal serum vitamin B12 and folate levels and neuropsychologic measures in a sample of 60 geriatric inpatients with psychotic depression, nonpsychotic depression, bipolar disorder, and dementia--all consecutively referred for cognitive testing. The psychotic depression subgroup demonstrated numerous significant positive correlations between B12 and cognitive subtests not seen in other diagnostic subgroups, especially those of IQ, and verbal and visual memory. Metabolic factors including vitamin B12 may play specific roles in the cognitive dysfunctions of different geropsychiatric disorders.

Trait shyness in the elderly: evidence for an association with Parkinson's disease in family members and biochemical correlates.

The emergence of potential treatments to slow the progression of idiopathic Parkinson's disease (PD) has increased the need for early identification of persons at risk. Although considered controversial, some prior studies indicate that PD patients may have premorbid histories of greater trait introversion or shyness as well as increased rates of disorders associated with shyness (e.g., anxiety, affective disorders, and irritable bowel syndrome). Essential features of trait shyness include (a) inhibited and avoidant behaviors and (b) physiological hyperreactivity to the novel or unfamiliar. In parallel, (a) depression in PD patients is associated with increased harm avoidance (a possible serotonergic function), and (b) PD patients have premorbid and comorbid decreases in novelty-seeking (a possible dopaminergic function). Taken together, previous research suggests the following hypotheses: (1) given evidence for marked heritability of shyness, shy elderly should report higher rates of PD in their family members than would nonshy elderly; and (2) shy elderly without PD should exhibit psychological and biologic characteristics similar to those reported in PD. Two groups, representing the top 27% (n = 37) and bottom 31% (n = 43) of scores on a standardized shyness scale, were drawn from a larger cohort of 138 older adults (ages 50-90) living in an active retirement community. Seventeen percent of the shy versus 2% of the nonshy reported PD in a family member or self (P < .05). Shy elderly were significantly more anxious (P < .01) and depressed (P < .05) than were the nonshy.(ABSTRACT TRUNCATED AT 250 WORDS)