Open access peer-reviewed chapter
Abstract
Toxic leukoencephalopathy (TLE) refers to a series of diseases with central nervous system damage caused by poisoning of various toxic substances, including medications, gases, drugs, and ethanol as the main clinical manifestation. TLE mainly causes the damage to white matter fibers and subcortical gray matter nuclei, including basal ganglia nuclei, thalamus and brainstem nuclei (substantia nigra red nucleus), as well as cerebellar dentate nucleus, which manifests as altered mental status, epilepsy, paresthesia, hemiparesis, tetraparesis, or even death. Magnetic resonance spectroscopy (MRS) has contributed to understanding the etiology and stage of TLE. Moreover, the change of brain metabolites, which can be evaluated by MRS, provides additional information for confirming diagnosis, monitoring disease progression, and informing treatment response. In order to describe the MRS characteristics of TLE caused by different etiologies, we will review the spectroscopy change of TLE which is associated with psychoactive substances, immunosuppressant, chemotherapy, and environment (PICE). Therefore, we reviewed the MRS characteristics of heroin-induced TLE, methadone-induced TLE, oxycodone-induced TLE, Wernicke encephalopathy, Marchiafava-Bignami disease, methotrexate-related TLE, metronidazole-induced TLE, carbon monoxide-related encephalopathy, and toluene TLE in this chapter.
Keywords
- magnetic resonance spectroscopy
- psychoactive substances
- immunosuppressant and chemotherapy
- environment
- leukoencephalopathy
1. Introduction
Toxic substances refer to the substances that enter the human body in small doses and can cause health damage through chemical or physical effects [1]. Poisoning refers to a kind of disease in which toxic substances enter the human body and cause biological function or structure change after reaching the toxic amount, resulting in temporary or permanent systemic damage [2]. When toxic substances damage the central nervous system, mainly causing white matter lesions, and some nerve nuclei and gray matter can also be affected, the occurrence of corresponding clinical manifestations is called toxic leukoencephalopathy (TLE) [3].
The neurotoxicology of toxic leukoencephalopathy has the following characteristics: (1) the degree of poisoning is positively correlated with the dose, duration, and concentration of toxin; (2) the cerebral lesions are generally symmetrical; (3) the initial symptoms of the disease are strongly related to the degree of poisoning; (4) the prognosis of patients with central nervous system involvement is unfavorable; and (5) toxic leukoencephalopathy can also have no obvious clinical symptoms.
MRI is the gold standard imaging modality to diagnose the diseases involving the white matter [4]. Magnetic resonance spectroscopy (MRS) is used to detect the change of brain metabolites in a specified region, which can provide additional information to establish diagnosis, differential diagnosis, monitor disease progression, and evaluate treatment response. MRS seems to be a new tool for understanding and diagnosing TLE.
2. Psychoactive substances-related TLE
Psychoactive substances refer to a series of chemical substances that can affect human mood, emotion, and behavior, change the state of consciousness, and have a dependency effect, also known as substances or addictive substances, including heroin, methadone, oxycodone, and alcohol, etc. Toxic leukoencephalopathy can be caused by abuse of psychoactive substances.
2.1 Heroin-induced TLE
Heroin has a strong dependence and toxic effects. Long-term abuse of heroin can cause systemic toxicity damage involving multiple systems and organs, such as brain, liver, heart, kidney and muscle damage, immune system, hematologic system, and reproductive system damage, among which brain damage is the most common. The damage to the central nervous system (CNS) caused by heroin inhalation or intravenous injection is commonly referred to as heroin-induced TLE. The reported CNS damage caused by heroin includes ischemic or hemorrhagic infarction, vasculitis, thrombosis, aneurysm, brain atrophy, and white matter cavernous degeneration. The main clinical symptoms are headache, memory loss, epilepsy, ataxia, paralysis, and other mental disorders [5, 6, 7, 8].
Previous studies have described three clinical stages of heroin vapor-related leukoencephalopathy. The first stage is described as mostly cerebellar symptoms. And the second stage includes both cerebellar and extrapyramidal symptoms. Then the third stage progresses to spasms and akinetic mutism or hypotonic mutism [6]. These clinically recognized stages are related to the degree of white matter involvement on MRI.
MRI showed diffuse symmetric hypointense lesions involving the bilateral periventricular white matter, basal ganglia, brain stem, and superior cerebellum on T1-weighted images (T1WI) and fluid attenuated inversion recovery images (FLAIR), with hyperintensity on T2-weighted images (T2WI), without gadolinium enhancement, and sparing of the subcortical regions, and diffusion restriction on diffusion-weighted images (DWI) in the acute and subacute stages, nonrestricted diffusion appearances in chronic stage [6, 7]. However, some studies showed normal water diffusion on DWI and apparent diffusion coefficient (ADC) mapping in the acute stage. MRS showed increased lactate (Lac) and myo-inositol (mI), decreased N-acetyl aspartate (NAA) and creatine (Cr), normal to slightly decreased choline (Cho), and normal lipid peak in the affected white matter in acute stage. Repeated MRS in chronic stage showed persistent decrease of subcortical NAA/Cr ratio and mI, but partly improve, and significantly reduce of Cho/Cr ratio [6].
MRS revealed the Cho/Cr ratio was low in cortex but was normal in the cerebellum. The Lac/ Cr ratio in cerebellum was significantly increased in patients with the worst clinical condition. The Lac/Cr ratio in Cortex was only increased in the clinically worst patients and dramatically decreased in chronic stage with the corresponding clinical improvement [9]. A metabolic effect from a heroin-related toxin causing mitochondrial dysfunction was postulated.
2.2 Methadone-induced TLE
Methadone is a synthetic μ-opioid receptor agonist, with pharmacologic and analgesic properties similar to those of morphine, is usually used as a substitute therapy for drug abuse or dependence, and is also used to control intractable pain. Overdose of methadone, generally related to pain management, may lead to shallow breathing, unresponsive, pulseless, gait abnormalities, cognitive impairment, even respiratory depression resulting in anoxia, and followed by coma or death. Brain MRI was normal, or showed bilateral white matter hyperintense lesions on T2WI, and revealed extensive bilateral restricted-diffusion lesions throughout white matter on DWI, and hypointense on ADC in the acute stage [10].
In the subacute stage, MRI showed extensive and symmetric hyperintensity abnormalities in the deep white matter of both cerebral hemispheres on FLAIR and T2WI, with sparing of the subcortical U-fibers. And the affected areas had hyperintensity on diffusion-weighted trace images, but without corresponding diffusion restriction on ADC. MRS found a marked decrease of the NAA peak with a relative increase of the Cho peak and a Lac peak [11]. In the chronic stage, MRS showed reduced NAA and increased Cho levels in white matter, and relatively normal gray matter NAA/Cr ratios, with partial normalization of metabolites over time [10].
2.3 Oxycodone-induced TLE
Oxycodone-induced TLE presents as altered mental status and decreased respiratory effort, akathisia can also present with a biphasic clinical presentation of encephalopathy after oxycodone ingestion, and it occasionally leads to acute obstructive hydrocephalus [12]. The bilateral globi pallidi and cerebellar gray matter were preferentially affected, but cerebellar white matter and deep nuclei were spared. Oxycodone acts predominantly on μ-opioid receptors, which are located in the cerebellum and neostriatum, this localization is consistent with the areas of injury of patients on neuroimaging and argues that the opioids themselves are the toxic agent [12]. Opioid toxicity and genetic predisposition were proposed as possible pathogenesis.
Findings of brain MRI in the delayed leukoencephalopathy episode revealed hyperintense lesions in the bilateral globi pallidi, superficial cerebellar hemispheres, corpus callosum, bilateral cerebral peduncles, posterior limbs of the internal capsule, and right frontal subcortical white matter and multifocal punctate areas of multiple white matter tracts on T2WI and FLAIR, with associated contrast enhancement on T1WI, and with corresponding hyperintensity on T1WI, with punctate areas of diffusion restriction in white matter tracts on DWI, and hyperintensity in the bilateral cerebral hemispheres on T2WI and FLAIR with sparing of the cerebellar white matter and deep cerebellar nuclei, are consistent with a subacute toxic encephalopathy related to oxycodone intoxication. MRS in delayed toxic leukoencephalopathy has demonstrated decreased NAA and Cho peaks with an elevated lactate peak in affected white matter in the acute stage. MRS showed qualitatively decreased NAA, Cho, and Cr peaks in the globi pallidi, with normal metabolite ratios, without significant lactate peak in the subacute stage, which supports the diagnosis of a subacute opioid toxic encephalopathy given the decreased metabolite peaks without a Lac peak [12].
2.4 Wernicke encephalopathy
Wernicke encephalopathy is a metabolic disease of the CNS caused by vitamin B1 deficiency, which partly develops in patients with alcohol abuse [13]. Only 1/3 of the patients showed the classic triad of manifestations, namely, ophthalmoplegia, ataxia, and altered mental status. Most of the patients were complicated in the late stage of various related diseases, and the symptoms of different diseases were intertwined and coexisted.
The typical MRI findings of Wernicke encephalopathy patients are bilateral and symmetrical hyperintense lesions in the mammillary bodies, thalami, tectal plate, and periaqueductal area on T2WI and FLAIR [14]. A previous MRS study found that the NAA/Cr ratio decreased in the thalami and cerebellum and a lactate peak in the cerebellum in the acute stage, and the NAA/Cr ratio increased in the thalami after thiamine supplement, but NAA/Cr ratio did not improve in the cerebellum in the chronic stage. Another research revealed a decreased NAA/Cr ratio without detectable lactate in the thalami in the subacute stage, and NAA/Cr ratio increased after thiamine administration. However, the other research reported that a remarkable increased lactate level in the thalami, but without NAA/Cr ratio changes in the acute stage [14, 15, 16].
2.5 Marchiafava-Bignami disease
Marchiafava-Bignami disease (MBD) is a rare disease associated with alcoholism, the prevalence of which is less than 0.002% in alcoholics [17]. The pathological characteristics are symmetrical demyelination, necrosis, and atrophy of the corpus callosum, extra-callosal white matter can be simultaneously affected, even the cortex [18]. The clinical manifestations of MBD lack specificity, which manifested as unconsciousness, confusion, delirium, mutism, seizures, and brain disconnection syndrome [19]. In the era where the diagnosis depended on the pathological manifestations at autopsy, MBD was considered a fatal disease [20]. The accuracy and number of antemortem diagnoses were greatly improved after the extensive application of neuroimaging techniques [19]. However, only a few patients achieved favorable recovery after treatment, and most had poor outcomes.
MRI plays an important role in the diagnosis of MBD. In the acute stage, symmetrical lesions in the corpus callosum with hypointensity or isointensity on T1WI and hyperintensity on T2WI and FLAIR, without obvious mass effect, and the lesions can extend to the adjacent white matter [21, 22, 23]. DWI showed hyperintensity in the lesions, with hypointensity on ADC [24]. Some patients with gadolinium-enhanced in lesions in the corpus callosum [25]. With the progression of the disease to the subacute and chronic stage, necrosis and cystic degeneration can appear in the corpus callosum, with hypointensity on T1WI and hypointensity on T2WI and FLAIR in the center part of the lesions, and hyperintensity in the peripheral part of the lesions, especially in the genu and splenium of corpus callosum [26]. DWI showed restricted diffusion in the center part of the lesions of the corpus callosum, and with restricted diffusion in the peripheral part [25]. Moreover, no abnormal contrast enhancement was observed, and the corpus callosum atrophied and thinned, and was particularly clear and intuitive on sagittal scans [25].
In previous studies, MRS was usually performed in the acute phase of MBD, the corpus callosum was the most commonly selected region of interest, followed by periventricular white matter and right parietal region, occasionally in anterior central gyrus [27, 28, 29, 30, 31, 32, 33, 34]. In the acute phase, MRS showed that decreased NAA peak and NAA/Cr ratio, a slightly increased Cho peak and Cho/Cr ratio, and a Lac peak could be observed [27, 28, 29, 31, 32, 34]. In the subacute phase, there is a decrease in NAA/Cr ratio, a partial and gradual decrease in Cho/Cr ratio, and a Lac peak in some patients were observed [30, 31, 33]. In the chronic phase, the NAA/Cr ratio partially recovered and the Cho/Cr ratio gradually decreased. The temporary dysfunction of axons can explain the partial recovery of NAA/Cr ratio, and the decrease of Cho/Cr ratio is synchronized with the chronic phase of demyelinating. Lac was initially replaced by lipid peak in chronic phase, which was consistent with axonal injury [30, 35]. Lac or lipid peaks were not obvious after nearly 1 year of symptoms. MRS findings suggested that metabolites change over time and supported the pathogenic theory that inflammatory response may be accompanied by MBD demyelination and micronecrosis. The resonance signals of taurine and scyllo inositol increased significantly when observing the brain of MBD patients who abstained from alcohol by MRS [30].
3. Immunosuppressant-related TLE
3.1 Methotrexate-related TLE
Methotrexate is an anticancer and immunomodulatory drug. Methotrexate-related TLE is a rare complication in methotrexate therapy. The severity of methotrexate-related TLE ranges from mild reversible leukoencephalopathy to irreversible and even fatal disseminated necrotizing leukoencephalopathy. Methotrexate-related TLE can occur even with low-dose administration and can especially develop with intrathecal or intravenous administration. The most frequently reported symptom was seizures, followed by nonspecific symptoms such as cognitive dysfunction, disorientation, headaches, and visual disturbances [36].
The typical MRI findings are symmetrical hyperintense lesions in white matter, brainstem, basal ganglia, thalamus, cerebellum, and even spinal cord on T2WI and FLAIR, with restricted diffusion on DWI and on ADC, with or without gadolinium enhancement. The limited published data from MRS studies showed a reduced NAA and Cr and an elevated Cho with or without a lactate peak, which may be associated with an acute demyelinating mechanism [36].
3.2 Metronidazole-related TLE
Metronidazole is widely used in a variety of infectious conditions and with good tolerance and has been used to help diminish or control the signs and symptoms of inflammatory bowel disease, its adverse reactions rarely occur in peripheral neuritis and brain damage, which are mostly transient and reversible, but few persistent nerve damage [37]. MRI findings of an adolescent patient with Down syndrome and Crohn’s disease treated with metronidazole revealed hyperintense lesions in the corpus callosum, basal ganglia, brainstem, substantia nigra pars compacta, red nucleus, globus pallidus, putamen, caudate, and cerebellum on T2WI and FLAIR, with slightly contrast enhancement of the lesions in the red nucleus and cerebral peduncles. MRS examination demonstrated a persistent Lac elevation during metronidazole treatment in the splenium and basal ganglia. Repeat MRI and spectroscopy studies showed new lesions in the medial thalami and a persistent lactate resonance in addition to the previously described abnormalities. Repeat MRI at 3 months follow-up showed near-complete resolution of the previous abnormalities, MRS shows resolution of elevated lactate peak, lower spectral signal-to-noise ratio reflects reduced volume sampled within the splenium [37]. The findings on MRS suggest the possibility of a reversible mitochondrial dysfunction as a cause of the abnormalities.
4. Chemotherapy-related TLE
4.1 Methotrexate-induced leukoencephalopathy
Methotrexate is a commonly used antimetabolic drug, which is widely used in the treatment of leukemia, lymphoma, and osteosarcoma. Methotrexate interferes with DNA synthesis by inhibiting dihydrofolate reductase, an enzyme that plays a crucial role in reducing folate, which plays an important role in DNA synthesis. The incidence of MTX-induced leukoencephalopathy ranges from 3–10%. Studies reported the restricted diffusion on DWI, which is an early sign to accurately diagnose acute MTX-induced leukoencephalopathy [38]. The brain MRI showed widespread periventricular hyperintensity on FLAIR, and with a specific pattern of restricted diffusion on DWI, MRS showed a slight elevation of the Cho peak with a normal NAA/Cho ratio, indicating multifocal supratentorial neuronal losses suggested a demyelinating process, which was more consistent with leukoencephalopathy [38].
5. Environment-related TLE
5.1 Carbon monoxide-related encephalopathy
Delayed encephalopathy due to carbon monoxide intoxication refers to the patients with acute carbon monoxide (CO) poisoning at first, then suddenly developed series of nervous system manifestations, mainly including dementia, altered mental state, pyramidal and extrapyramidal symptoms, and even coma after complete clinical recovery, the duration is usually ranging from 2 to 40 days.
Diagnosis was based on present history of exposure to CO, blood carboxyhemoglobin concentration in arterial blood immediately after admission and presence of acute neurological symptoms on admission, and series of nervous system manifestations after a lucid interval. Acute low-dose CO intoxication seems to cause reversible neuropsychological impairment whereas patients’ exposure to high-dose CO may show a complex clinical pattern, that is, delayed encephalopathy and neuropsychiatric sequelae may occur after a lucid interval of 3 days to 4 weeks after the initial recovery from the acute stage. Although neuropsychiatric disorders are common, delayed encephalopathy is a rare and unclear complication.
MRI is routinely used to illustrate abnormalities in the CO-intoxicated brain. Cerebral MRI showed symmetrical and diffuse hypointensity on lesions in the centrum semiovale and periventricular white matter on T1WI, with hyperintensity on T2WI and DWI, and mild hypointensity or isointensity on ADC in the ultra-acute or acute phase. All of these hyperintense lesions on T2WI and DWI with low ADC in the CWM persisted in the subacute and chronic phases. In severe cases, the lesions could also appear in the subcortical white matter, corpus callosum, and internal and external capsules. Additionally, the pathognomonic sign of CO intoxication is the lesions in the globus pallidus [39].
MRS studies demonstrated increased Cho peak and Cho/Cr ratio and reduced NAA peak and NAA/Cr ratio in the white matter, gray matter, and basal ganglia in the early period, and a Lac peak appeared in subacute stage, with an increased Lac/Cr ratio [39, 40, 41, 42, 43, 44, 45]. The persistent increase of Cho was thought to reflect the course of progressive demyelination. The appearance of lactate and decrease in NAA reflected that the neuron injury became irreversible. Patients with Lac peak persisted after the NAA and Cho peaks had disappeared in the chronic stage were supposed to show poor prognoses, because extensive neuronal tissue is irreversibly damaged. After starting hyperbaric oxygen therapy, the Cho/Cr ratio in the white matter started to decrease and the lactate peak disappeared in chronic stage [45]. The NAA/Cr ratio gradually increased and did not return to the normal range. MRS showed metabolites in the gray matter had reverted to normal in chronic stage, consistent with neuronal recovery [39]. In white matter and centrum semiovale, NAA/Cr had almost returned to normal, Lac was no longer significantly detected, and mI/Cr had further increased, consistent with chronic gliosis [41, 42, 43].
Compared with patients with transit acute symptoms only, the mean Cho/Cr ratios in bilateral centrum semiovale were significantly higher in patients with delayed neuropsychiatric sequelae, and no significant difference in mean NAA/Cr ratio between the above two groups [41]. These findings suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents inflammation accompanied by demyelination in the centrum semiovale, and can predict chronic neurological symptoms [41].
5.2 Toluene TLE
Toluene, which is an organic solvent, inhaling of a large amount of toluene mainly causes inhibition of central nervous system. The myelin sheath structure of the central nervous system is rich in lipids. Toluene can easily enter the lipid-rich brain parenchyma through the blood-brain barrier, and damage the cell membrane, resulting in pathological and physiological changes such as nerve tissue demyelination, gliosis, and iron deposition, thus causing a series of clinical manifestations such as toxic brain disease. Toluene TLE is caused by long-term inhalation of toluene, characterized by cognitive impairment, headache, blurred vision, insomnia, hands tremors, and ataxia. These clinical manifestations lack specificity. MRI showed diffuse and symmetric hyperintense lesions in subcortical white matter, deep white matter, bilateral external capsule, bilateral globus pallidus, bilateral thalamus, and bilateral cerebellar dentate nuclei on T2WI and FLAIR, with hypointensity on T1WI, restricted diffusion in the same regions on DWI, and reduced ADC value. The most characteristic feature is the symmetrical “bracket” shaped hyperintense lesions of the bilateral external capsules on T2WI. ASL showed normal CBF in the bilateral white matter, cortical gray matter, and basal ganglia. MRS revealed that decreased NAA peak and increased Cho peak, decreased NAA/Cr ratio, and increased Cho/Cr ratio in the corona radiata [46].
Compared with the health control, the NAA/Cr ratio in the cerebellum and centrum semiovale of the toluene abusers was significantly lower, but mI/Cr was higher. Furthermore, no significant difference was found in the NAA/Cr, Cho/Cr, and mI/Cr ratios of the thalami. There was no difference Cho/Cr ratios between toluene abusers and control group. The NAA/Cr and mI/Cr ratios in cerebellum and centrum semiovale were significantly associated with the duration of abuse [47].
6. Conclusion
The clinical manifestations of patients with TLE are often lack of specificity. TLE is usually related to psychoactive substances, immunosuppressant, chemotherapy, and environment (PICE), and the diagnosis is based on a history of exposure to toxic substances, clinical symptoms and signs, corresponding toxic substances found in laboratory tests, MRI suggests symmetrical white matter damage, with or without deep brain nuclei and cerebellar lesions. Meanwhile, MRS can reveal the changes of metabolites in the affected lesions at different stages, as a supplementary means of clinical and conventional neuroimaging. Therefore, MRS is helpful for the diagnosis and differential diagnosis of TLE and can provide information on metabolic abnormalities of early lesions.
Acronyms and abbreviations
Toxic leukoencephalopathy | |
Magnetic resonance spectroscopy | |
the central nervous system | |
T1-weighted images | |
fluid attenuated inversion recovery images | |
T2-weighted images | |
diffusion-weighted images | |
apparent diffusion coefficient | |
lactate | |
myo-inositol | |
N-acetyl aspartate | |
creatine | |
choline | |
Marchiafava-Bignami disease | |
carbon monoxide |
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