Venomous snake bites, scorpions, and spiders.

Neurologic dysfunction due to natural neurotoxins is an important, but neglected, public health hazard in many parts of the world, particularly in the tropics. These toxins are produced by or found among a variety of live forms that include venomous snakes, arthropods such as scorpions, spiders, centipedes, stinging insects (Hymenoptera), ticks, certain poisonous fish, shellfish, crabs, cone shells, skin secretions of dart-poison frogs, and bacterial poisons such as botulinum toxin. These toxins commonly act on neuromuscular transmission at the neuromuscular junction where acetylcholine is the neurotransmitter, but in certain situations the toxins interfere with neurotransmitters such as GABA, noradrenaline, adrenaline, dopamine, and γ-aminobutyrate. Of the toxins, α-toxins and κ-toxins (e.g., Chinese krait, Bungarus multicinctus) act on the postsynaptic membrane, blocking the receptors, whilst ß-toxin (e.g., common krait, B. caeruleus) acts on the presynaptic membrane, causing impairment of acetylcholine release. Conversely, dendrotoxins of the African mamba enhance acetylcholine release. The toxins of scorpions and spiders commonly interfere with voltage-gated ion channels. Clinically, the cardinal manifestation is muscle paralysis. In severe cases respiratory paralysis could be fatal. Effective antivenoms are the mainstay of treatment of envenoming, but their lack of availability is the major concern in the regions of the globe where they are desperately needed. Interestingly, some toxins have proved to be valuable pharmaceutical agents, while some others are widely exploited to study neuromuscular physiology and pathology.

Electrophysiological correlates of respiratory failure in acute organophosphate poisoning: evidence for differential roles of muscarinic and nicotinic stimulation.

BACKGROUND: Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at these different phases may have important clinical implications. Objective. To compare the electrophysiological findings in patients with early and late respiratory failure following acute OP poisoning. METHODS: A prospective observational case series of consenting symptomatic patients with acute OP poisoning were assessed with daily physical examinations and repetitive nerve stimulation (RNS) studies. RNS was done on right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. Outcomes such as need for ventilation and development of intermediate syndrome (IMS) were noted. Early respiratory failure was defined as occurring within 24 hours of ingestion. RESULTS: Seventy-eight patients were recruited for the clinical and electrophysiological study and of those 59 (75.6%) patients had ingested chlorpyrifos. Seven patients developed respiratory failure within 24 hours of ingestion with overt muscarinic signs. They had no electrophysiological abnormalities at median and ulnar nerves before intubation. Three of them later developed "forme fruste" IMS. Five other patients developed late respiratory failure after 24 hours of ingestion, and all of them showed progressive RNS changes indicating severe IMS prior to intubation. CONCLUSION: The normal RNS in all patients developing early respiratory failure suggests that it is due to a central nervous system (CNS) and muscarinic effect. This emphasizes the need for early rapid atropinisation as a priority, combating the nicotinic effects being less urgent. This is in contrast with the late respiratory failure, which has been shown to be associated with neuromuscular dysfunction. Further studies are needed to quantify CNS and muscarinic dysfunction to assist in the development of better treatments for the severe and early OP poisoning.

Deep coma and hypokalaemia of unknown aetiology following Bungarus caeruleus bites: Exploration of pathophysiological mechanisms with two case studies.

Bungarotoxin present in Bungarus caeruleus (BC) causes life threatening respiratory muscle paralysis. Deep coma and hypokalaemia have been observed in a significant proportion of patients, but the cause is unknown. We postulate the likely mechanism behind these two phenomena. We studied clinical details of two patients admitted with deep coma and performed electroencephalograms (EEG) and brain stem auditory and visual evoked potentials (BAEP and VEP). Daily serum potassium was measured along with urinary potassium excretion as a marker of total extracellular body potassium. Both patients had no brain stem reflexes on admission and the EEG revealed absent alpha and delta activity and presence of dominant theta activity. Alpha rhythm returned on the 3(rd) day in one patient, while in the other it did not, and the latter patient died on the 13(th) day due to disseminated intravascular coagulation. BAEP were delayed and VEP were absent in the deceased patient. Both had low serum potassium and low urinary potassium excretion. Replacement of potassium (up to 1.5mmol/kg/day) did not improve serum potassium and urinary potassium excretion. Absent alpha and delta activity in EEG and delayed BAEP and absent VEP are suggestive of a central action of the venom on both the cortical and brain stem neurones. Persistently low serum potassium and reduced urinary potassium excretion are suggestive of intracellular shift as the causative mechanism of hypokalaemia.

Electrophysiological correlates of intermediate syndrome following acute organophosphate poisoning.

INTRODUCTION: Organophosphate (OP) poisoning is a major global health problem. The late onset of respiratory failure associated with intermediate syndrome (IMS) is a major contributor to the high morbidity, mortality, and cost of OP poisoning. This is particularly important as most poisoning occurs in the under-resourced developing world. Repetitive nerve stimulation studies. An understanding of the abnormalities observed in repetitive nerve stimulation studies during the progression and development of IMS spectrum disorder may help clinicians to utilize electrodiagnostic testing in the better management of their patients with acute OP poisoning. In addition, it will allow researchers to interpret future research that utilizes repetitive nerve stimulation as an outcome measure. A review of the clinical and experimental electrophysiological studies in the IMS shows that subclinical electrophysiological abnormalities are common, progressive, and precede the onset of the clinical IMS. Serial repetitive nerve stimulation studies have been most commonly used and are the most accessible for clinicians. Clinical and experimental studies demonstrate a progression through early initial decrement-increment patterns at high rates of stimulations, which correlate with moderate muscle weakness, to decrement-increment patterns at intermediate- and low-frequency stimulations. Progression to a combination of decrement-increment and repetitive fade patterns correlates with clinical deterioration; severe decrement pattern is usually observed immediately before the onset of respiratory failure. Although electrophysiological features closely parallel clinical severity during progression of IMS, the same is not true during recovery. Electrophysiological changes sometimes improve long before the patient recovers normal strength and respiratory function. Intermediate syndrome. Thus, IMS can be regarded as a spectrum disorder affecting the neuromuscular junction (NMJ) with two main forms: a forme fruste variety associated with mild weakness and the classical IMS with weakness of 3/5 or less than 3/5 on the Medical Research Council (MRC) grading; patients in the latter category are at risk of developing late onset respiratory failure. While IMS remains a clinically important entity, the early occurrence of abnormalities on repetitive nerve stimulation studies suggest that this is part of the continuum of nicotinic receptor stimulation. CONCLUSIONS: Reviewing the anatomical and the functional structure of the NMJ and neuromuscular transmission helps to provide an understanding of the pathophysiological nature of the neuromuscular transmission failure observed in IMS. This includes potential mechanisms of presynaptic feedback which may reduce acetylcholine release and postsynaptic receptor desensitization and provides some explanation for the time course of IMS. It also suggests other potential strategies to reduce OP-induced NMJ toxicity in which repetitive nerve stimulation is likely to be an important tool in judging efficacy.

The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka.

BACKGROUND: Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research. METHODS AND FINDINGS: Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements. CONCLUSIONS: Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.

Abnormal parameters of magnetically evoked motor-evoked potentials in patients with cervical spondylotic myelopathy.

BACKGROUND CONTEXT: Magnetic stimulation (MS), which is used to evaluate motor pathways, is helpful in evaluating cervical spinal cord compression (cervical myelopathy [CM]). Previous studies have shown that the central motor conduction time (CMCT), which is the time taken for the nerve impulses to reach the cervical spinal roots after the stimulation of the motor cortex, is prolonged in CM. However, the duration of motor-evoked potentials (MEPs) in CM has not been studied in detail. PURPOSE: To compare the duration, CMCT and amplitude of MEPs by MS between patients with clinical and magnetic resonance imaging (MRI) features of CM and a control group. STUDY DESIGN/SETTING: A cross-sectional study done at Teaching Hospital, Peradeniya, Sri Lanka. PATIENT SAMPLE: Consecutive patients with clinical features of cervical spondylotic myelopathy, without coexisting neurological abnormality. METHODS: Transcranial and cervical spinal magnetic stimulation were performed on 21 patients with clinical and MRI features of spondylotic CM (mean age, 43.5years; range, 36-63 years; 9 men) and 17 healthy volunteers (mean age, 39.05 years; range, 23-54yrs; 6 males) using a circular coil with a Magstim 200 stimulator. MEPs were recorded over abductor digiti minimi muscle on both hands. RESULTS: Seventeen patients had upper motor neuron (UMN) features in all four limbs; in the others, both lower limbs and one upper limb were affected. The upper limbs with UMN features had shorter duration MEPs compared with the control group. The CMCT and the total motor conduction time were also delayed in the CM group. All three differences were very highly significant (t=5.75, -3.76, 5.27; p<.001). The amplitudes showed no significant difference between the two groups (t=1.27, p=.208). CONCLUSION: This study shows that in addition to the CMCT, the duration of MEPs is also useful in evaluating patients with CM using MS.

Parallel infusion of hydrocortisone +/- chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites.

OBJECTIVE: To investigate the efficacy of continuous infusion of hydrocortisone with or without chlorpheniramine bolus against early adverse reactions to polyspecific antivenom. DESIGN AND SETTING: Prospective, double-blind, randomised, placebo-controlled trial at General Hospital, Anuradhapura, Sri Lanka. SUBJECTS: 52 patients with snake envenoming were randomised to receive infusion of hydrocortisone (Group A), hydrocortisone with chlorpheniramine bolus (Group B) or placebo (Group C) during the administration of antivenom. INTERVENTION: Hydrocortisone 1000 mg in 300 mL of normal saline infusion was started 5 min before and continued for 30 min after antivenom. Chlorpheniramine 10 mg intravenous bolus dose was given 5 min after commencement of antivenom. MAIN OUTCOME MEASURES: Occurrence and severity of adverse reactions to antivenom. RESULTS: Adverse reactions were observed in 80% (12/15) of Group A, 52% (11/21) of Group B, and 81% (13/16) of Group C. Reactions were mild or moderate except in two patients. A significant reduction in the number of adverse reactions was seen in Group B compared with the placebo group (difference, 29 percentage points; 95% CI, 0.2 to 58 percentage points). There was no significant difference between Group A and the placebo group. CONCLUSION: Prophylaxis with a parallel hydrocortisone infusion alone is ineffective in reducing the occurrence of acute adverse reaction to antivenom serum, but combining it with chlorpheniramine seems efficacious.

Pesticide poisoning in the developing world--a minimum pesticides list.

In parts of the developing world, pesticide poisoning causes more deaths than infectious diseases. Use of pesticides is poorly regulated and often dangerous; their easy availability also makes them a popular method of self-harm. In 1985, the UN Food and Agriculture Organisation (FAO) produced a voluntary code of conduct for the pesticide industry in an attempt to limit the harmful effects of pesticides. Unfortunately, a lack of adequate government resources in the developing world makes this code ineffective, and thousands of deaths continue today. WHO has recommended that access to highly toxic pesticides be restricted--where this has been done, suicide rates have fallen. Since an Essential Drugs List was established in 1977, use of a few essential drugs has rationalised drug use in many regions. An analogous Minimum Pesticides List would identify a restricted number of less dangerous pesticides to do specific tasks within an integrated pest management system. Use of safer pesticides should result in fewer deaths, just as the change from barbiturates to benzodiazepines has reduced the number of deaths from pharmaceutical self-poisoning.

Epilepsy in Latin America

A epilepsia é um importante problema de saúde pública da América Latina com uma incidência de 57 para cada 1000 habitantes em determinadas comunidades. Entre os fatores que contribuem para essa alta incidência estäo as doenças parasitárias, especialmente a neurocisticercose, outras infecçöes intracranianas de origem bacteriana e viral, danos cerebrais perinatais, traumas cranianos e fatores hereditários, muitos deles evitáveis ou modificáveis. O tratamento médico da epilepsia está longe do ideal em muitos dos países latino-americanos. Mesmo as investigaçöes básicas como o EEG näo säo facilmente disponíveis e existe um suprimento pequeno de drogas antiepilépticas. Existe uma difundida e algumas vezes indiscriminada prescriçäo de fenobarbital apesar de seus efeitos potenciais adversos. Serviços de controle de dosagem sérica de antiepiléptico näo säo comumente disponíveis. Näo existe uma reabilitaçäo vocacional para reintegraçäo do paciente à sociedade. O problema é formado pelas atitudes da populaçäo pobre e pela ignorância. Mesmo nas regiöes mais desenvolvidas do continente, a epilepsia está associada ao preconceito, ao medo e ao estigma. Nas zonas rurais, säo comuns os meios sobrenaturais de tratamento. A preocupaçäo com a saúde básica partindo das organizaçöes governamentais ou voluntárias seria a melhor estratégia para minimizar algumas das terríveis consequências da epilepsia nessa populaçöes.

Neurological manifestations of malaria

O envolvimento do sistema nervoso central pela malária é revisto neste artigo, Malária cerebral, a encefalopatia que complica exclusivamente a infecçäo pelo Plasmodium falciparum, atinge essencialmente crianças e adolescentes em áreas hiperendêmicas. Uma das hipóteses para a sua patogênese consiste no desvio da circulaçäo capilar por obstruçäo de capilares e vênulas cerebrais por eritrócitos parasitados. Outra, a teoria humoral, propöe que a resposta inflamatória, imunomediada e inespecífica, liberta substâncias vasoativas capazes de produzir alteraçöes endoteliais e de permeabilidade. Malária cerebral tem taxa de mortalidade até 50% e também considerável morbidade a longo prazo, particularmente em crianças. A sintomatologia cerebral pode ser complicada por hipoglicemia, principalmente em doentes tratados com quinino. Outras manifestaçöes incluem intracraniana, oclusäo arterial cerebral e sintomatologia transitória extrapiramidal e neuropsiquiátrica. Em Sri Lanka, alguns doentes em recuperaçäo têm mostrado ataxia cerebelar, autolimitada, provavelmente devida a mecanismos imunes. Malária é causa frequente de convulsöes febris nos trópicos e contribui para o desenvolvimento posterior de epilepsia. Envolvimento medular e dos nervos periféricos também têm sido descritos. Durante episódios febris, alguns doentes têm apresentado paralisia transitória semelhante à paralisia periódica. A patogênese das manifestaçöes neurológicas na malária continua por ser esclarecida e oferece excelentes perspectivas de investigaçäo tanto clínica como experimental

Malaria and the nervous system

El paludismo cerebral se define como encefalopatía aguda que complica exclusivamente a la infección por pasmodium falcíparum y que afecta principalmente a niños y adolescentes en áreas hiperendémicas. La fisiopatología de esta entidad se explica por el taponamiento de los capilares y vénulas cerebrales por paquetes de glóbulos rojos parasitados o por una respuesta inflamatoria no específica, mediada inmunologicamente, con liberación de sustancias vasoactivas capaces de producir daño endotelial y alteración en la permeabilidad capilar. El paludismo cerebral tiene una mortalidad del 50 por ciento, así como una morbilidad elevada, especialmente en niños. Por otra parte, el desarrollo de hipoglicemia, especialmente en pacientes tratados con quinina, puede complicar la sintomatología cerebral. Otras manifestaciones neurológicas del paludismo cerebral incluyen: hemorragia intracraneal, oclusión de arterias intracraneales y manifestaciones transitorias de tipo extrapiramidal o psiquiátrico. En Sro-Lanka se ha reconocido, además, una ataxia cerebelosa aislada y autolimitada, probablemente medida por mecanismos inmunológicos, en pacientes que se están recuperando de una infección por plasmodium falciparum. El paludismo es una causa relativamente común de crisis febriles en regiones tropicales y también contribuye al desarrollo de epilepsia en edades posteriores de la vida. Existen además, varios periféricos en pacientes con paludismo cerebral, así como la parálisis periódica. La fisiopatología de estas manifestaciones neurológicas no se encuentra bien determinada, pero ofrece excelentes oportunidades para investigación, tanto a nivel clínico como experimental.