Neurotoxicity, Types, Clinical Manifestations, Diagnosis and Treatment

Abstract

Neurotoxicity is a term that refers to the condition in which the nervous system is exposed to dangerous substances (neurotoxicants) either naturally occurring or created, impairing the nervous system’s normal function. Few of these neurotoxins act directly on neural cells, whereas others impair metabolic processes heavily reliant on the neurological system. Neurotoxicity can occur as a side effect of chemotherapy, radiation therapy, drug therapies, organ transplantation, and vulnerability to heavy metals such as mercury and lead, certain foods, pesticides, industrial products, and solvents used in cleaning cosmetics, and pharmaceutical products. Additionally, there are a few naturally occurring compounds. Symptoms of intoxication may begin to develop immediately upon exposure or may take time to manifest. These symptoms may include encephalopathy, limb weakness or numbness, cognitive and behavioral impairments. Following the elimination or decrease of exposure to hazardous chemicals, symptomatic and supportive therapy is provided. The prognosis is highly variable and depends on the duration and depth of vulnerability and the degree of the neurological impairment. Neurotoxicant vulnerability can be lethal in rare instances. Patients may survive in some cases despite their failure to heal completely. In other cases, many individuals recover completely following treatment.

1. Introduction

Understanding brain and nerve poisons have been a long-standing tradition dating back to ancient times. By the turn of the twentieth century, contemporary physiological and biochemical investigations had elucidated a few of these poisons’ mechanisms of action. Neurotoxicity is defined as any unfavorable effect on the central or peripheral nervous systems’ chemistry, structure, or function induced by chemical or physical agents either at maturity or during development. Any impairment of normal function or adaptability to the surrounding environment is regarded as a side effect. Thus, even if functional and structural changes are minimal or reversible, the most prevalent morphological abnormalities, such as neurons, axonopathy, or myelinopathy, may be unfavorable [1].

Additionally, neurochemical alterations should be regarded as harmful even if they are reversible and transient and cause dysfunction. Neurotoxicity can also arise due to indirect effects, such as harm to the cardiovascular or hepatic systems or changes in the endocrine system. Numerous compounds function in various ways and can directly or indirectly affect the neurological system [2].

The nervous tissue present in the brain, spinal cord, and periphery includes an extraordinarily complex biological system that generally describes many of the original traits of individuals. However, as with any profoundly complex system, even minor disturbances to its environment can result in significant functional disturbances. Factors leading to the vulnerability of nervous tissue include a large surface area of neurons, a high lipid content that retains lipophilic toxins, high blood flow to the brain inducing increased effective toxin exposure, and persistence of neurons through an individual’s lifetime, leading to the compounding of damages.

As the nervous system is more vulnerable to toxins, several mechanisms are designed to protect it from internal and external hazards, including the blood–brain barrier. The blood–brain barrier (BBB) and choroid plexus that provide a layer of protection against toxin absorption in the brain. The choroid plexuses are vascularized layers of tissue found in the brain’s third, fourth, and lateral ventricles, which through the function of their ependymal cells, are responsible for the synthesis of cerebrospinal fluid (CSF). Importantly, through the selective passage of ions and nutrients and trapping heavy metals such as lead [1, 2, 3].

2. Mechanism of action in neurotoxicity

Many neurotoxicants function by inhibiting the GABA_A receptor, resulting in prolonged closure of the chloride channel and excess nerve excitation (Figure 1). Cyclodiene, the organochlorine insecticide lindane, and some pyrethroid insecticides prove acute neurotoxicity, at least partly through this mechanism. Symptoms of GABA inhibition include dizziness, headache, nausea, vomiting, tremors, convulsions, and death. Other some acts via Na channel inhibitors (tetrodotoxin), K channel inhibitors (tetraethylammonium), Cl channel inhibitors (chlorotoxin), Ca channel inhibitors (conotoxin), inhibitors of synaptic vesicle release (botulinum toxin, tetanus toxin), receptor inhibitors (bungarotoxin), blood–brain barrier inhibitors (aluminum mercury), Ca-mediated cytotoxicity (lead), and toxins with multiple effects (ethanol). In some cases, the hemostasis of energy can be affected [2].

Figure 1.

The neurotoxins block the receptors, thus preventing the maintenance of proper physiological function.

3. Types of toxins and intoxications

Chemicals that disrupt the mammalian nervous system can occur naturally (neurotoxins) or be produced (neurotoxicants). While the term “neurotoxins” refers to substances with neurotoxic potential, this is not an inherent quality of the chemicals but rather a description of the effect that may occur when the tissue concentration surpasses a certain threshold. Neurotoxic biological substances usually demonstrate a high level of target selectivity and toxicity. Microorganisms, reptiles, and vertebrates exhibit direct or indirect neurotoxic effects that are well-understood mechanistically (Table 1) [3, 4].

Life form	Substances with neurotoxic potential
Bacterium	Diphtheria, a toxin
Fungus	3-Nitropropionic acid
Plant	L-BOAA
Insect	Apamin
Reptile	Dendrotoxin
Bird	Batrachotoxin

Table 1.

Natural mammalian neurotoxic potential substances [3, 4].

Other naturally occurring compounds with less strong qualities have been shown to cause neurotoxicity when administered in high concentrations for a sustained length of time. Metals (arsenic, lead, and mercury) and other elements and compounds, such as selenium and vitamin B6, come into this category. While these chemicals are neurotoxic in high concentrations, they are required in trace levels to maintain proper physiological function, particularly in the nervous system. Natural enzymes (thiaminase) that metabolize necessary chemicals (thiamine) are also associated with neurological disorders in both animals and humans. Synthetic chemicals with neurotoxic potential are most frequently obtained through a prescription (vincristine, ethambutol, isoniazid) and over-the-counter (bismuth preparations) pharmaceutical aisles; (pyridethione) products used in antidandruff shampoos; (2,6-dinitro-3-methoxy-4-tet-butyltoluene) fragrance raw materials; and (acrylamide) pyrolysis products used in broiled, baked. Others are associated with particular applications, such as chemical warfare in military and civilian settings (sarin). Directly neurotoxic substances are supplemented by medications that change neurological function due to their effects on another organ system on which the brain relies for proper operation. This class of medications includes those that target the lung, kidney, and liver particularly, as well as drugs that disrupt the nervous system’s constant supply of oxygen (cyanide, azide) and glucose (glucose) (6-chloro-6-deoxyglucose). Chronic liver failure and manganese toxicity are associated with increased signal abnormalities in the basal ganglia on T1-weighted magnetic resonance images, implying that the metal accumulates due to the liver’s general inability to eliminate it (Table 2) [3, 4].

Substance	Primary neurotoxic effects
Organophosphorus compounds (pesticides and warfare agents)	Cholinergic syndrome (certain compounds), peripheral neuropathy (certain compounds only), acetylcholinesterase İnhibition
Lead, inorganic	Peripheral neuropathy acute encephalopathy
Arsenic	Acute encephalopathy peripheral neuropathy
Mercury, inorganic	Cerebellar syndrome and psychological reactions (anxiety, personality changes, memory loss)
Methanol	Optic neuropathy extrapyramidal syndrome, retinopathy
Carbon monoxide	Encephalopathy/ parkinsonism(delayed), neuronal and tissue necrosis secondary to hypoxia
Phenytoin	Fetal phenytoin syndrome, cerebellar syndrome, chronic encephalopathy (cognitive dysfunction), extrapyramidal syndrome (chorea, dyskinesia), peripheral neuropathy
Arsenic	Acute severe encephalopathy, peripheral neuropathy
Tricyclic antidepressants	Seizure disorder (myoclonus), psychobiological reaction (serotonin syndrome, anticholinergic syndrome), tremor, extrapyramidal syndrome (dyskinesia)

Table 2.

Potentially neurotoxic heavy metals and synthetic substances [3, 4].

4. Clinical manifestations of neurotoxicity

These manifestations include signs and symptoms in multiple parts of the central nervous system, including the central, peripheral, and autonomic nervous systems and skeletal muscle. They are typically accompanied by discomfort, altered sensations, such as taste and smell, decreased visual acuity, and hearing loss [5, 6].

4.1 Encephalopathy

Acute encephalopathies are a common occurrence. The majority are insignificant and dissipate within a few days. Headache, weariness, disorientation, loss of attention and short-term memory, lack of motor coordination, and the resulting gait irregularity, nausea, and dizziness are the most common indications and symptoms. Schaumburg identified several compounds (about 100) as possible causative factors, including aluminum, cannabis, cocaine, domoic acid, lead, organic solvents, and trimethyltin. While acute symptoms commonly resolve rapidly, chronic issues can significantly debilitating influence on job performance and productivity. There is a significant need for long-term follow-up and mental and psychological disorders assessment. Acute (moderate) encephalopathy rarely progresses to chronic (severe) encephalopathy with progressive cognitive and psychomotor impairment [5, 6, 7].

4.2 Movement disturbance

Cerebellar dysfunction, manifested by ataxia, intention tremor, and lack of coordination, is well documented due to chronic mercury exposure; however, overdose with various potentially lethal medications and substances, including 5-fluorouracil, lithium, and acrylamide, has also been reported. Cerebellar dysfunction is notoriously challenging to diagnose. Extrapyramidal syndromes such as parkinsonism, dystonias, dyskinesias, and tics are relatively well-defined toxic syndromes. While the destructive processes are unknown, they are frequently reversible, although symptoms can return years after the condition begins. Parkinsonism is arguably the most well-known form of Parkinson’s disease, owing to an epidemic involving people exposed to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a contaminant found in certain illicit substances. Most syndromes are induced by excessive medication use, particularly phenothiazines, rather than by exposure to non-therapeutic drugs [6, 7, 8, 9].

4.3 Particular sensibilities

Loss of taste and smell and changes in smell and taste are common complaints that are difficult to quantify accurately, and quantitative procedures are not always practical. Despite the frequent involvement of organic solvents, this illness lacks a well-defined pathophysiological basis. Among the problems inherent in quantifying taste is that olfaction plays a significant role in detecting food’s “flavor” and “perfume,” even though many of us would categorize these as tastes. Changes in taste perception are frequently connected with administering a variety of therapeutic medicines. However, they are typically reversible. Although hearing loss has been associated with using organic solvents, particularly toluene, it is more usually associated with well-known ototoxic drugs such as aminoglycosides [6, 7].

4.4 Visual symptoms

Typically, vision loss occurs as a direct result of a toxic or corrosive material striking the cornea and conjunctiva or because the lens loses its transparency due to cataract formation. Direct attacks on the neuronal components of the visual system are less common than indirect attacks. Mydriasis and miosis are two distinct symptoms caused by exposure to or use of parasympathomimetic medications, anticholinesterase inhibitors, and parasympatholytics such as atropine. Nystagmus can develop as a side effect of certain medications, including phenytoin and antibiotics (aminoglycoside). Neurotoxic exposure is rarely associated with direct retinal injury despite a possible association with specific therapeutic medications. Both toluene (which induces demyelination) and hexachlorophene can cause optic nerve injury (leading to deformation of myelin). Alcohol addiction (methanol or ethanol) is also associated with widespread damage of the neuronal components of the visual system. Nonetheless, the etiology is suspected to be compounded by many chronic alcoholics’ nutritional deficiencies [6, 7].

4.5 Peripheral nervous system neuropathies

These are frequently mistaken with axonopathies. However, the terms do not refer to the same thing. Peripheral neuropathy can develop within the neuron, resulting in the death or dysfunction of cells (in which case we call a neuronopathy). Axon degeneration (axonopathy) or loss of neuronal or axonal function may occur when the myelin sheath is disrupted. Channelopathy may develop from a change in the function of ion channels, or the toxin may target nerve terminals (leading to a neuromuscular transmission syndrome). Neuronopathies are easily recognized since they are much more likely to be sensory in origin and affect areas supplied by the injured neurons. The mechanisms by which they cause harm are not well understood. Methyl mercury is the neurotoxin most frequently connected with this illness. Proprioception may be compromised before or more severely than subsequent pain, whereas nerve conduction velocity and muscular strength are preserved. Healing is unpredictable, as neurons may survive or perish as a result of the toxic insult. Demyelinating neuropathies affect the peripheral nervous system when the Schwann cell or internode’s myelin sheath is damaged. Diphtheria toxin can cause segmental demyelination by damaging the Schwann cell. Hexachlorophene and perhexiline have also been associated with myelin disturbance. Recovery is dependant upon the activation and replication of surviving Schwann cells. Regenerated internodes are slightly shorter than typical in length, myelin sheaths are thinner, and nodes can be somewhat longer than usual. Remyelinated axons conduct at a slower pace in general. Axonopathies are lesions of the peripheral nervous system produced by axon destruction. The presenting signs and symptoms typically manifest gradually and initially impact the long axons and distant locations. Sensory symptoms predominate over motor problems, and ankle reflexes degrade fast. The signs and symptoms then spread proximally for the duration of the axon’s “regeneration.” Healing occurs as a result of damaged axon regrowth. Recovery is often slow due to the 0.5–3.0 mm per day rate of axonal development. Numerous industrial chemicals, such as acrylamide, arsenic, carbon disulfide, n-hexane, lead, organic mercury, and thallium, have been shown to cause axon damage. While recovery is often uncomplicated, chronic ataxia, stiffness, and hyperreflexia can occur following severe poisoning. Axonal channelopathies are caused by aberrant ion channel activity and manifest as faulty axonal conduction. These are typically made up of natural toxins. The motor nerve terminal is a major target for a range of natural neurotoxins (clostridial toxins, cone snail toxins, snake, spider, and scorpion venoms), all of which induce harm to the nerve terminal. What is unknown is the involvement of the nerve terminal in the expression of toxic insult induced by a variety of harmful substances, including organophosphates and acrylamide, both of which have been shown to cause considerable nerve terminal damage. It is unsurprising that most axonopathies that die back originate at the nerve terminal [6, 7, 9].

4.6 Skeletal muscle

Skeletal muscle injury is rather infrequent. The bulk of toxicological problems in skeletal muscle is the result of genuine denervation. Several myotoxic substances, including clofibrate and related compounds such as insecticides and organophosphates, can cause substantial muscle loss by rhabdomyolysis. Diazacholesterols and herbicides containing chlorophenoxyisobutyric acid stimulate myotonic activity, whereas licorice, diuretics, and excessive alcohol use induce hypokalemic paralysis. Skeletal muscle regenerates rapidly following the removal of the causative factor. Rhabdomyolysis’s most important acute clinical consequence is a significant risk of acute renal failure [6, 7, 8, 9].

4.7 Psychiatric and Behavioral disorders

Depression is the most frequently reported symptom of neurotoxic diseases in patients. These individuals frequently express feelings of depression, anxiety, and forgetfulness. While the psychological signs of aluminum toxicity are normally mild, they can progress to severe dementia and parkinsonism/dementia syndrome. Lithium overdose with lysergic acid diethylamide may result in cerebellar ataxia, dementia, and severe psychotic illnesses (LSD). Due to widespread disdain for psychiatric/psychological disorders, there is a dearth of reliable knowledge regarding the diagnosis, management, and prognosis of mental health complaints associated with such intoxication. Additional study on the acute and chronic effects of neurotoxic drugs on cognitive function is necessary [6, 7].

5. Tests to detect neurotoxicity/Neurotoxicology screenings

While substances that lead to neurotoxic effects can be found by routine toxicity screening testings (e.g., chronic, acute, developmental/reproductive toxicity), specific standards exist to further evaluate compounds’ potential neurotoxicity. The requirements established by the USEPA (the United States Environmental Protection Agency) are based on a functional observational battery, motor health assessments, and neuropathological examinations. Similarly, the OECD (Organization for Economic Cooperation and Development) criteria emphasize clinical results, practical test findings (e.g., motor activity, sensory response to stimuli), and neuropathology. These batteries are intended to provide a Tier 1 screening for neurotoxicity, with positive findings necessitating additional testing (Tier 2), which may involve specialized behavioral tests in addition to electrophysiological and neurochemical data. Examples include memory and learning tests, nerve conduction velocity measurements, and biochemical tests linked to neurotransmission or indices of cell integrity or function. Specific recommendations for developmental neurotoxicity (DNT) testing have also been created in the United States of America and Europe. The mother is exposed to the test drugs from prenatal day 6 to postnatal day 10 or 21, ensuring exposure both in utero and via maternal milk. The examinations cover developmental milestones and reflexes, motor activity, hearing testing, learning and memory tests, and neuropathology. DNT has been demonstrated to be exceedingly practical and beneficial in detecting substances and agents that have the potential to cause developmental neurotoxicity during neurotoxicity testing. However, additional effort is needed to improve these tests, either because they are susceptible and generate a significant proportion of false positives or because they are insufficiently sensitive and thorough [8, 9, 10, 11].

Additionally, concerns have been expressed about historical control data, toxicokinetic parameters, toxicity mediated by the mother versus direct effects, test selection, and their analysis and interpretation. Toxicologists have increasingly recognized the need for acceptable and accurate alternatives to conventional animal testing in recent years, highlighting the issues associated with rising costs and time requirements for toxicity assessment tests, the growing number of chemicals being developed, and commercializing the demand in response to recent legislation and efforts to reduce the number of animals used in toxicity testing. This, combined with efforts in the field of developmental neurotoxicity, has resulted in the development of alternative models, either using mammalian cells in vitro or nonmammalian model systems (using zebrafish), that may serve as valuable tools for neurotoxicity and developmental neurotoxicity testing, particularly for screening. These alternative tests should be utilized as Tier 1 testing for drugs and agents with an uncertain DNT potential. Given the complexity of the nervous system and the range of possible neurotoxic outcomes, developing a single test that covers the entire spectrum of neurotoxicity is challenging. Rather than that, a battery of tests should be explored that includes some in vitro experiments with mammalian cells and one or two tests using nonmammalian models. This can be augmented by applying computational approaches and procedures to develop a quantitative structure–activity relationship. Additionally, novel methodologies that are a component of “omics” technology can be applied in these endeavors. Alternative models for DNT must strive to reproduce a large number of events that occur in vivo, and given the complexity of the central nervous system (CNS), the approach for DNT is significantly more extensive than for other toxicity target organs [11, 12, 13, 14, 15].

6. Long-term effects of neurotoxicity/developmental neurotoxicity

Neurotoxic effects linked with developmental exposure during pregnancy, nursing, early childhood, and adolescence are frequently documented following a brief period of exposure. Nonetheless, evidence indicates that the insalubrious effects of toxicants may take months, if not years, to manifest clinically. The “silent” phase refers to the time period during which an individual may display no signs or symptoms of poisoning. Silent toxicity is a term that refers to continuing morphological or biochemical damage that is clinically undetected unless concealed by special techniques. Silent toxicity is comparable to carcinogenesis, in which cellular and molecular damage develop years, if not decades before clinical symptoms show. This area contains numerous instances of silent poisoning. Parkinsonism-dementia, frequently referred to as Guam’s disease, is the most widespread kind, with a latency of several decades between supposed yet-undefined exposures and clinical manifestations. Another case of bovine spongiform encephalopathy (mad cow disease) is a form of Creutzfeld–Jacob disease with a documented latency of decades [8, 15, 16, 17, 18, 19]. The time interval between the onset of clinical symptoms and exposure to a neurotoxic event can be explained by a number of factors. For example, while a specific population of neurons may be injured, the brain’s plasticity may compensate for this loss temporarily. Exogenous stressors (stress, illness, chemical exposure) or the normal aging process, on the other hand, may disclose the silent toxicity. Alternatively, an organism may be capable of compensating for a specific defect. Nevertheless, persistent loss of function may eventually exhaust the brain’s functional reserve and plasticity. The likelihood of such a latent period occurring between exposure and clinical manifestation occurring throughout the development stage is significantly greater. David Barker was a pioneer in establishing the possibility that many adult disorders have fetal origins. The “Barker hypothesis” is the name given to this concept. Toxic substance exposure has the potential to directly destroy or modify developmental programming, resulting in later-life functional impairments [8, 9, 19, 20, 21, 22]. Diethylstilbestrol is the most prominent example, which may contribute to an increase in vaginal adenocarcinoma around puberty as a result of in utero exposure. Perinatal exposure of rats to the Gram (−) bacteriotoxin lipopolysaccharide causes a 30% loss in dopaminergic neurons in the substantia nigra and persistent injury to the dopaminergic system, implying that, in humans, prenatal infections occurring at a specific gestational age may result in the birth of an individual with significantly fewer dopaminergic neurons. This could be an example of developmental neurotoxicity. This may seem minor, given that Parkinson’s disease does not manifest clinically until around 80% of dopaminergic neurons are lost completely. When the aging process culminates in the typical progressive loss of dopaminergic neurons, this early-life lesion may play a substantial role in an individual’s development of Parkinson’s disease. Exposure to some pesticides during development, such as the herbicide paraquat and the fungicide maneb, both of which act on dopaminergic neurons, has also been related to the development of Parkinson’s disease later in life. Similarly, developmental exposure to the now-banned organochlorine insecticide dieldrin has been found to cause significant and long-lasting alterations in the dopaminergic system, as well as a silent dopaminergic dysfunction. Rarely, modest and mild injuries may worsen as an individual develops and ages. In this manner, the neurotoxic effects of embryonic MeHg exposure do not manifest themselves for years. Microencephaly produced by uterine exposure to methyl azoxy methanol resulted in an early loss of cognitive abilities, and the neurotoxic consequences of neonatal exposure to triethyltin, a glial neurotoxicant, were increased with age. This cannot be the case in all other situations. Nonetheless, developmental exposure appears to have irreversible neurotoxic effects, and even if they do not deteriorate with age, they have long-term ramifications, as evidenced by perinatal lead exposure [23, 24, 25, 26, 27, 28].

7. Treatment and Prognosis

The treatment of neurotoxicity involves terminating, eliminating, or reducing dangerous chemicals and commencing therapy to reduce symptoms and offer necessary support [2, 3].

The difficulty is that if biotoxicity or neurotoxicity is the underlying cause of the pain or sickness and the treatment plan does not include a detoxification regimen, the overall recovery will almost certainly be incomplete and take longer than necessary [2, 3].

Biotoxicity/neurotoxicity treatment protocol can also include acupuncture, herbal remedies & nutritional supplements, nutritional counseling, and prescription of medication. For example, the key factors in the initial management of acute arsenic intoxication are gut decontamination and hemodynamic stabilization in patients with suspected acute arsenic poisoning. Generally, in such neurotoxicity, rapid stabilization with fluid and electrolyte replacement in an intensive care setting is very important. Aggressive intravenous fluid replacement therapy maybe even life-saving in serious poisoning. Gastric lavage may also be useful soon after acute ingestion to prevent any further absorption. The efficacy of activated charcoal is controversial, but its administration together with a cathartic (such as sorbitol) is frequently recommended, but if profound diarrhea is present, cathartics must be withheld. Hemodialysis may be beneficial in a patient with concomitant renal failure. Chelating agents administered within hours of arsenic absorption can successfully prevent the full effects of arsenic toxicity. If patients are treated within several hours after arsenic ingestion, chelation is likely to be beneficial. Therefore, even if arsenic ingestion is only suspected but not confirmed, consultation with a clinical specialist with expertise in the treatment and management of arsenic poisoning is essential [29].

Generally, neurotoxicity has a prognosis and outcome that are determined by the extent and duration of toxic substance exposure and the extent of brain damage. In some cases, individuals die due to neurotoxins exposure, while others live but do not fully recover. The patient may recover entirely following the necessary treatment [2].

8. Innovations in the future

The potential threats to human health posed by hazardous chemicals in the surrounding environment have become a significant public health concern. It is critical to have the necessary abilities, tools, and facilities to study neurotoxicity in an individual. Treatment for patients exposed to environmental neurotoxins is not yet defined, and multidisciplinary teams will be necessary to manage the most severe cases. Diagnostic indicators for neurotoxic diseases based on rapid-response biomarkers should be identified and developed more efficiently to be used by all centers. Two essential variables should be considered—the severe effect on the developing fetus and newborn, the long-term health consequences of chronic exposure to low levels of environmental neurotoxins, and the long-term health consequences of severe acute poisoning in patients.

Additionally, a conclusive study is needed to address the frequent allegation that putative neurotoxins lack a “safe” limit, owing to our inadequate understanding of the lethal synergy that can occur when multiple toxins are exposed concurrently. Additionally, significant progress is anticipated in elucidating the relationship of harmful environmental chemicals and susceptibility risk factors in progressive neurodegenerative diseases such as motor neurons, Parkinson’s disease, and Alzheimer’s disease [2, 3, 4].

9. Conclusion

Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system. Neurotoxins can be found naturally in the environment, and they could be synthetic. Some neurotoxins act directly on neural cells; others interfere with metabolic processes on which the nervous system is primarily dependent— The effects of neurotoxicity can appear and disappear rapidly, evolve slowly over days or weeks, regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure. The treatment is terminating the toxins exposure and providing symptomatic treatment.