Cohort studies of health effects among people exposed to estuarine waters: North Carolina, Virginia, and Maryland.

A variety of human symptoms have been associated with exposure to the dinoflagellate Pfiesteria and have been grouped together into a syndrome termed "possible estuary-associated syndrome." Prospective cohort studies of health effects associated with exposure to estuarine waters that may contain Pfiesteria spp. and related organisms are in progress in North Carolina, Virginia, and Maryland. The three studies recruited cohorts of 118-238 subjects who work or engaged in recreation in estuary waters. Baseline health and neuropsychological evaluations are conducted, and study subjects are followed prospectively for 2-5 years with periodic assessments of health and performance on a battery of neuropsychological tests. Health symptoms and estuary water exposure are recorded by telephone interviews or diaries every 1-2 weeks. Water quality information, including measurements of Pfiesteria spp., is collected in the areas where the subjects are working. Because it is not possible to measure individual exposure to Pfiesteria or a toxin produced by this organism, these studies examine surrogate exposure measures (e.g., time spent in estuary waters, in a fish kill area, or in waters where Pfiesteria DNA was detected by molecular amplification). Preliminary analyses of the first 2 years (1998-2000) of data indicate that none of the three ongoing cohorts have detected adverse health effects. However, there have not been any reported fish kills associated with Pfiesteria since the studies began, so it is possible that none of the study subjects have been exposed to toxin-producing Pfiesteria spp.

Gastrointestinal and respiratory tract symptoms following brief environmental exposure to aerosols during a pfiesteria-related fish kill.

An outbreak of illness with flulike symptoms among state workers responding to a Pfiesteria bloom that resulted in fish death and distress on the Chicamacomico River on Maryland's Eastern Shore was investigated. Using case-control methodology, seven workers present at the Chicamacomico were compared to seven occupationally matched controls not present. Participants completed questionnaires assessing their exposures to water and their symptom histories and were assessed with a standard neuropsychological test battery. Three months later, the same questionnaires and neuropsychological tests were repeated. Three of the seven exposed workers cited minimal direct contact with water and four cited none. During the event, four developed burning eyes or nares and six developed a headache or sore throat. Six developed crampy abdominal pain, nausea, or diarrhea within 4 h of their exposure. In contrast, the only aforementioned symptom reported by controls was headache in two individuals. Acute and follow-up neuropsychological tests showed no consistent pattern of deficiency among the exposed. In conclusion, a flulike clinical illness was observed following exposure to a Pfiesteria-related fish kill, possibly as a result of inhalation of toxic aerosols.

Language functions in patients with multiple sclerosis.

Few studies have demonstrated language impairment in patients with multiple sclerosis (MS) compared to healthy controls. The purpose of this investigation was to examine language functions, specifically naming, comprehension, and verbal fluency, in patients with MS and healthy controls to (1) determine if patients with MS demonstrate language impairment, and (2) provide clarification of MS-related language disturbance, particularly in patients with MS of differing courses. Results showed that both chronic-progressive and relapsing-remitting patients with MS performed significantly more poorly than controls on naming, aural comprehension, letter fluency, and category fluency, as well as other language-based cognitive measures. Chronic-progressive patients obtained significantly lower scores than relapsing-remitting patients on the latter three tests. The language disturbance in this MS sample may be partly explained by impairment in other verbal cognitive functions. These findings highlight the importance of assessing language abilities in patients with MS.

Learning and memory difficulties after environmental exposure to waterways containing toxin-producing Pfiesteria or Pfiesteria-like dinoflagellates.

BACKGROUND: At the beginning of autumn, 1996, fish with "punched-out" skin lesions and erratic behaviour associated with exposure to toxins produced by Pfiesteria piscicida or Pfiesteria-like dinoflagellate species were seen in the Pocomoke River and adjacent waterways on the eastern shore of the Chesapeake Bay in Maryland, USA. In August, 1997, fish kills associated with Pfiesteria occurred in these same areas. People who had had contact with affected waterways reported symptoms, including memory difficulties, which raises questions about the human-health impact of environmental exposure to Pfiesteria toxins. METHODS: We assessed 24 people who had been exposed. We collected data on exposure history and symptoms, did a complete medical and laboratory assessment (13 people), and carried out a neuropsychological screening battery. Performance on neuropsychological measures was compared with a matched control group. RESULTS: People with high exposure were significantly more likely than occupationally matched controls to complain of neuropsychological symptoms (including new or increased forgetfulness); headache; and skin lesions or a burning sensation of skin on contact with water. No consistent physical or laboratory abnormalities were found. However, exposed people had significantly reduced scores on the Rey Auditory Verbal Learning and Stroop Color-Word tests (indicative of difficulties with learning and higher cognitive function), and the Grooved Pegboard task. There was a dose-response effect with the lowest scores among people with the highest exposure. By 3-6 months after cessation of exposure, all those assessed had test scores that had returned to within normal ranges. INTERPRETATION: People with environmental exposure to waterways in which Pfiesteria toxins are present are at risk of developing a reversible clinical syndrome characterised by difficulties with learning and higher cognitive functions. Risk of illness is directly related to degree of exposure, with the most prominent symptoms and signs occurring among people with chronic daily exposure to affected waterways.

Nonepileptic posttraumatic seizures.

PURPOSE: Epileptic posttraumatic seizures (PTSs) are a well-recognized consequence of head injury (HI), but HI and nonepileptic seizures (NESs) have not been related. We describe a significant subset of patients with NESs who had their seizures attributed to HI. METHODS: We reviewed the records of all patients diagnosed with NES at the University of Maryland Medical Center over a 6-year period (1989-1995) and selected patients with seizures attributed to a head injury occurring < or =3 years before the onset of their seizures. RESULTS: Of 157 patients with video-EEG confirmed NES, 37 (24%) had the onset of their seizures attributed to an HI. Their average age was 34 years (range, 15-56 years); 68% were women. Nonepileptic PTS usually developed within the first year after HI (89%). Convulsive symptoms were present in 54%. Whereas epileptic PTSs characteristically follow severe HI, the majority (78%) of our patients with nonepileptic PTSs sustained only mild HI. Before their HI, 76% of our patients were employed, working in the home, or students, but only 11% could continue those activities after developing nonepileptic PTSs. CONCLUSIONS: Nonepileptic PTSs are frequently mistaken for epileptic PTSs and result in serious disability. The misdiagnosis of nonepileptic PTSs leads to ineffective and inappropriate treatment. Patients with intractable seizures after HIs, particularly mild HIs, should be carefully evaluated for NESs.

Neurologic symptoms following Pfiesteria exposure: case report and literature review.

Although the recently identified dinoflagellate, Pfiesteria piscicida, may have neurotoxic effects on humans, the precise nature of the neurologic symptoms associated with varying levels of exposure is unknown. Toward this end, we review the neurologic symptoms of three Pfiesteria-exposed laboratory workers reported to data and compare them to the evaluation of an exposed waterman from Maryland. The occupational exposure of a Maryland waterman appears to produce a mild, reversible encephalopathy which predominantly affects functions associated with the frontal and temporal lobes. A comprehensive neurologic examination is recommended for all Pfiesteria piscicida and morphologically related organism-exposed, symptomatic persons.

Neurobehavioral complaints of symptomatic persons exposed to Pfiesteria piscicida or morphologically related organisms.

Over the next year, additional persons in Maryland may be at risk for exposure of toxic Pfiesteria or morphologically related organisms. These persons may present with a variety of memory and other behavioral complaints. This paper examines the kinds of complaints that persons with a documented Pfiesteria-related syndrome have compared to a nonexposed control group. The exposed group was more likely to report difficulties with concentration, forgetfulness, prospective memory, and information overload as well as feelings of confusion, bewilderment, and uncertainty as direct effects of toxin exposure. The exposed group was also more likely to report feeling uneasy, on edge, nervous, and shaky, which is probably a reaction to their newly acquired cognitive deficits and uncertainty about their recovery. In contrast, retrograde memory loss, disturbances of language or social behavior, depression, anger, hostility, or diminished activity levels are not symptoms that exposed persons are likely to report.

Psychologic adjustment of watermen with exposure of Pfiesteria piscicida.

Preliminary study of the psychologic adjustment of watermen with exposure to Pfiesteria piscicida was conducted on watermen with the most severe exposures and their occupationally matched controls. Participants in the exposed group were seven symptomatic recreational and commercial fishermen who had direct exposure to the Pocomoke River or other estuarial waters on Maryland's Eastern Shore before, during, and/or after periods of documented fish kills and Pfiesteria activity. The control group included eight commercial fishermen who worked on the ocean side of the Eastern Shore and had no reported exposure to estuaries with documented Pfiesteria activity. Both exposed symptomatic and nonexposed watermen completed the Profile of Mood States to assess depression, anxiety, and other relevant mood states as part of their participation in the larger investigation of the human health effects of Pfiesteria piscicida. Preliminary results suggest that both exposed symptomatic and nonexposed watermen are psychologically healthy and exhibit what psychologists refer to as the classic Iceberg Mood Profile. The Iceberg Profile is characterized by endorsement of symptoms suggestive of high energy, enthusiasm and positive mood (e.g., lively, active, energetic, cheerful, vigorous, etc.) and relative minimization of symptoms suggestive of negative or depressed mood (e.g., tense, anxious, restless, grouchy, forgetful). Therefore, the Pfiesteria-related symptom complex documented in the exposed watermen cannot be explained by functional or psychiatric factors and is probably due to exposure.

A critical review of the Pfiesteria hysteria hypothesis.

Mass hysteria or mass psychogenic illness is the spread of the belief of an illness (symptoms and the origins of the symptoms) through a population. The characteristics of mass psychogenic illness were reviewed and compared to the recent outbreak of human illness in the Pocomoke region in Maryland in the summer of 1997. The findings suggest that the nature of the symptoms complex--the onset and recovery course; the absence of secondary gain or job-related stress for most of the symptomatic persons; the predominance of males in the symptomatic group; and the baseline emotional stability of all persons examined--are inconsistent with the reported features of psychogenic illness in response to unknown environmental or chemical toxins. Although there may be individuals who exhibited hypochondriacal, hysterical, or other functionally based reactions, the recent outbreak of Pfiesteria-related illness probably does not represent an episode of mass psychogenic illness.

Pfiesteria in Maryland: preliminary epidemiologic findings.

In the fall of 1996, fish kills in Maryland rivers were attributed to the dinoflagellate, Pfiesteria piscicida. After a group of researchers established a potential link between exposure to Pfiesteria and an illness causing memory problems, state health authorities closed a portion of the Pocomoke River. To determine the extent of illness, the range of symptoms, potential risk factors for disease, and to provide information to concerned citizens, a toll-free hotline was created. All symptomatic persons who called the toll-free number were administered a standardized questionnaire. Persons who had been exposed to Pfiesteria or Pfiesteria-laden waters were more likely to have respiratory, neurologic, dermatologic, and gastrointestinal problems than those persons without exposure. Among the persons calling the hotline, many had extensive neuropsychologic testing. Of the neuropsychologic test battery, low scores on the Rey Auditory Verbal Learning Test (RAVLT), a standardized measure of learning and memory, best characterized illness related to Pfiesteria exposure. Patients with low RAVLT scores were more likely to have neurologic symptoms and skin lesions than control subjects. Low RAVLT scores were associated with fishing (OR, 9.00, 95% CI, 106, 409.87), catching fish with lesions (OR, 6.17, 95% CI 1.27, 32.10), and handling fish with lesions (OR, 5.34, 95% CI, 1.05, 29.92), but not with consumption of seafood. While preliminary, these results do suggest that some risk factors for Pfiesteria-related illness may be easy to modify and used to prevent unnecessary human exposure.

Use of the North American Adult Reading Test to estimate premorbid intellectual function in patients with multiple sclerosis.

The North American Adult Reading Test (NART-R) has proven to be a valid means of estimating premorbid intellectual function in a variety of neurologic patient samples. The NART-R was administered to a group of patients with multiple sclerosis (MS) varying in course and degree of physical disability and healthy controls as part of an extensive neuropsychological battery examining numerous verbal cognitive functions, particularly language. The MS sample demonstrated significantly worse NART-R performance than did controls which could not be explained by differences in estimated premorbid intellectual function. Patients with a chronic-progressive course specifically obtained significantly lower scores than did controls, whereas there were no differences in the scores obtained by patients with chronic-progressive and relapsing-remitting courses or by patients with a relapsing-remitting course and controls. Thus, NART-R performance may not be a valid estimate of baseline IQ for patients with neurologic disorders with suspected language impairment.

Distinctive forms of partial retrograde amnesia after asymmetric temporal lobe lesions: possible role of the occipitotemporal gyri in memory.

We tested the hypothesis that partial forms of retrograde amnesia were associated with highly asymmetric lesions to the inferior and anterior-medial temporal lobe. Postencephalitic subjects EK and DR were both impaired on standardized retrograde memory tests, but showed strikingly different profiles in cognitive tasks of name stem completion, name:face matching, temporal ordering, forced choice recognition, and occupational judgments of famous names and faces from the past 3 decades. EK sustained left inferior and anterior-medial temporal lobe lesion with a small right temporal polar lesion, and showed near-complete loss of retrieval, knowledge, and familiarity associated with famous names but minimal deficiencies with famous faces. DR sustained right inferior and anterior-medial temporal lobe lesion and showed a milder retrograde loss limited to utilizing famous face prompts in name stem completion, name:face matching, occupational judgments, and forced choice recognition. These impairments were also different from the memory retrieval deficit, but intact recognition shown by a case of ruptured anterior communicating artery aneurysm with presumed basal forebrain damage. We hypothesize that EK's extensive loss of famous name knowledge was related to left inferior temporal lobe damage, particularly in the lateral and medial occipitotemporal gyri. This region in the left temporal lobe may serve as a critical processing area for retrograde memory that permits activation of established semantic, temporal, and visual (i.e., facial) associations biographically dependent on the category of proper names. On the basis of connectional anatomy patterns in the nonhuman primate, this region receives extensive hippocampal output and is interconnected with the temporal polar region and cortical association areas, which have been implicated in retrieval and storage aspects of retrograde memory. In the right hemisphere, the occipitotemporal gyri may serve an important role in famous face processing as part of a bilateral neural network.

The Brief Repeatable Battery of Neuropsychological Tests for Multiple Sclerosis: a preliminary serial study.

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for MS consisting of the selective reminding, 10/36 spatial recall, symbol digit modalities, paced auditory serial addition (PASAT) and word list generation tests is a sensitive measure of early cognitive impairment in MS patients. We administered it to 19 chronic stable MS patients every 60 days for 120 days to examine variability. The mean coefficient of variation for the tests ranged from 18% to 22%. A significant practice effect was seen in the PASAT results (P < 0.05) using the Wilcoxon signed rank test. These results suggest that cognitive fluctuations analogous to motor fluctuations may occur in MS patients and that the BRB-N may be useful in clinical trials of agents expected to alter cognitive function in MS patients if test-retest variability and practice effects are taken into account. Further study is warranted.

Complex partial status epilepticus accompanied by serious morbidity and mortality.

Nonconvulsive status epilepticus (NCSE) accounts for approximately 20% of all status epilepticus (SE). Although convulsive SE is recognized as a medical emergency, prompt diagnosis and treatment of patients with NCSE is often not emphasized because its consequences are thought to be benign. We report 10 patients with persistent neurologic deficits or death after well-documented NCSE in the form of complex partial status epilepticus (CPSE). All patients had prolonged CPSE lasting 36 hours or longer, as documented by clinical and EEG findings. Causes for CPSE were preexisting epilepsy with partial and secondarily generalized seizures (3 patients), vascular disease (2 patients), encephalitis (2 patients), and metabolic disease (1 patient); causes were unknown for two patients. Poor outcomes identified included persistent (lasting at least 3 months) or permanent cognitive or memory loss (5 patients), cognitive or memory loss plus motor and sensory dysfunction (3 patients), and death (3 patients). NCSE in the form of CPSE is not a benign entity. Serious morbidity and mortality may occur due to the adverse effects of prolonged seizures and as a result of acute brain disorders that precipitate the seizures.

Impact of frontal lobe lesions on rehabilitation and recovery from acute brain injury.

The frontal lobe has been viewed historically in very different ways, ranging from enigmatic and mystifying to the crucial neural substrate for higher cognition and social behavior. Frontal lobe damage poses a unique and difficult set of challenges to the patient, their family and the neurorehabilitation team. Because of the role of the frontal lobe in adaptation and adjustment, such damage adversely affects a patient's participation in the process and content of rehabilitation. To aid diagnosis and treatment planning, a model of frontal lobe organization is outlined, focusing on the specific cognitive and behavioral symptom clusters associated with superior mesial, inferior mesial, dorsolateral and orbital frontal lesions. A taxonomy of social executive processes is presented for identifying impairments in social behavior and personality, based upon the domains of social self-regulation, social self-awareness, social-sensitivity (empathy), and social-salience. Specific interventions are described that encompass dopamine agonist therapy for blunted affect, mutism and akinesia, cognitive strategies for improving organization and planning deficits, and evolving treatments for social impairments.

Altered serial position learning after frontal lobe lesion.

The serial position function is a powerful and highly reliable feature of human learning, with well-described primacy and recency effects. We tested the hypothesis that frontal lobe lesions in patients would disrupt the serial position function since such patients are known to have disturbed temporal ordering, learning in the presence of interference, encoding and organizational approaches to learning. Performance was compared in patients with focal, acquired lesions of frontal and non-frontal cortices, using a standardized paradigm of verbal list learning. Results indicated a similar pattern of performance on first trial learning for the two groups. However, across learning trials, frontal lesion subjects failed to maintain significant primacy and recency effects. Non-frontal lesion subjects consistently showed the expected U-shaped serial position curve across all trials. Subjective organization in learning was particularly deficient in the dorsolateral frontal lesion subjects. We propose that serial position effects are qualitatively different after frontal lobe lesion, being transitory and prone to alteration by the cumulative effects of disturbed temporal-spatial processing across learning trials.

Frontal lobe and frontal-striatal substrates for different forms of human cognitive flexibility.

Frontal lobe and basal ganglia lesions have been associated with similar cognitive impairments, although their specialized roles in behavior are likely to be different. We examined whether these structures mediate distinctive or overlapping aspects of a complex behavioral process that has been associated with both neural sites, i.e. cognitive flexibility. Patients with focal ischemic lesions to the frontal lobe and basal ganglia were compared on two forms of cognitive flexibility: (1) shifting response set (i.e. reactive flexibility), and (2) producing a diversity of ideas (i.e. spontaneous flexibility). Results indicated that frontal lobe and basal ganglia damage each caused a similar degree of impairment in reactive flexibility, both groups performing at a significantly lower level than posterior cortical lesion and normal comparison groups. However, frontal lobe damage markedly disturbed spontaneous flexibility, while performance after basal ganglia lesion was significantly higher and comparable to posterior cortical lesions. Findings suggest that the frontal lobe and basal ganglia participate differently in the neural substrate of cognitive flexibility. The frontal lobe appears to mediate spontaneous flexibility. The production of diverse ideas may require direct cortical-cortical interactions by the frontal lobe in order to access knowledge systems with novel strategies that transcend the most common semantic linkages. In contrast the corticostriate system appears to mediate reactive flexibility, as the frontal lobe, basal ganglia and their interconnections are required for its operation.

Long-term psychological consequences of childhood frontal lobe lesion in patient DT.

Patient DT was examined 26 years after she acquired focal frontal lobe damage at 7 years of age. This report focused on several aspects of psychological outcome, including the empirical study of social development into early adulthood. Standardized measures of empathy, psychosocial development, and personality were analyzed, along with a moral judgment interview and patterns of adult social behavior. Results indicated that DT has a very limited capacity for empathic understanding, inadequate identity development, difficulties in vocational adjustment, and a concrete level of moral reasoning. Her social behavior and profile of test scores suggest that social development and adaptation have been arrested at early adolescent levels. We conclude that early frontal lobe damage has profound effects on social development, and that the frontal lobes provide a crucial neural substrate for social maturation.