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How to recognize and treat metabolic encephalopathy in Neurology intensive care unit
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.198192
Metabolic encephalopathy (ME) represents a syndrome of temporary or permanent disturbance of brain functions that occurs in different diseases and varies in clinical presentation. It can be manifested in a range from very mild mental disorders to deep coma and death. Clinically, it is characterized by a variety of psychiatric and neurological symptoms and signs. The most common causes of ME are: hypoxia, ischemia, systemic diseases and toxic agents. ME is the most frequent in elderly people who have previously been exhausted by chronic illnesses and prolonged stay in bed. ME is a very common complication in patients treated in intensive care units. Treatment and prognosis of the disease are varied and depend on aetiology, as well as on the type and severity of clinical presentation. Mortality of patients with septic encephalopathy ranges from 16-65%, while the one-year survival of patients with encephalopathy and liver cirrhosis is less than 50%. Keywords: Encephalopathy, intensive care, metabolic disorders
The word encephalopathy originates from the Greek word ενκεφάλη (inside the head) and πάθος (suffering). The ancient Greeks used this word when they wanted to indicate a disease or suffering inside the head.[1] In clinical practice, the word metabolic encephalopathy was used for the first time in 1912 when Kinner Wilson tried to explain the state of global cerebral dysfunction caused by systemic stress, which can vary in the clinical picture from a very mild disorder to deep coma with decerebrate rigidity.[2] Metabolic encephalopathy has usually been defined as a diffuse cerebral dysfunction, typically manifesting as changes in cortical functions and as disorders of consciousness, ranging from confusion to coma.[3] Others have suggested that metabolic encephalopathy is a temporary or permanent illness, more a symptom than a disease, that includes various forms of pathological conditions that are predominantly manifested by disorders of mental functioning.[4] However, metabolic encephalopathy may also be defined as a systemic disorder with diffuse brain damage affecting the hemispheres, brain stem, and reticular activating system.[4]
Demographic and epidemiological data suggest that encephalopathy correlates with age. The number of patients with encephalopathy increases after the age of 65 years. People older than 75 years, who reside in nursing homes have a 60% chance of developing encephalopathy, whereas in a population younger than 55 years, this proportion is 1.1%.[5],[6] Encephalopathy occurs in 10–40% of hospitalized patients older than 65 years, whereas 8–70% of patients develop septic encephalopathy. According to data from the United States, encephalopathy has being registered in 100–200,000 patients with anoxia and 12–16% of patients with thiamine deficiency, every year,[1],[7] In patients with cirrhosis, the hepatic encephalopathy develops in 45–80% of cases, depending on the severity of liver damage.[1],[7],[8] Etiology The causes of metabolic encephalopathy are different. The most frequent ones are hypoxia, ischemia, systemic disease, and toxic agents.[9],[10] Hypoxia occurs in chronic conditions such as anemia, pulmonary diseases (chronic obstructive pulmonary disease), and alveolar hypoventilation. Ischemia occurs mostly due to cardiovascular diseases including acute congestive heart failure, cardiac arrhythmia, microvascular disease, and hypo- or hypertension. In the context of systemic diseases, metabolic encephalopathy has often been seen with hepatic and renal insufficiency, pancreatitis, malnutrition, electrolyte imbalances (such as hyper- and hypoglycemia, hyper- and hypocalcemia, and hyper- and hyponatremia), particularly in sepsis, infection, vasculitis, and malignancy (paraneoplastic syndromes). Metabolic encephalopathy may also occur as a result of various toxic agents such as alcohol, sedatives (barbiturates, narcotics), psychiatric agents (tricyclic antidepressants, anticholinergics, phenothiazines), heavy metal poisoning, organic phosphates, and other drugs (anticonvulsants, corticosteroids, penicillin, etc.).[9],[10],[11],[12] Kaplan and Rossetti distinguished four types of encephalopathy based on clinical symptoms and conditions that lead to the development of encephalopathy. These groups include patients treated in emergency departments, intensive care units, general hospitals, and psychiatric wards [Table 1].[12],[13]
Patients treated in emergency departments and intensive care units usually develop encephalopathy as a result of use or misuse of a large number of medications in the treatment of chronic conditions. These are usually neuroleptics, antidepressants, hypnotics, analgesics, opioids, anti-Parkinsonian drugs, anti-convulsants, antibiotics, depressors of the central nervous system (CNS), immunosuppressive agents, etc. Moreover, patients treated in these units may suffer from psychogenic and posttraumatic conditions, as well as ictal and postictal conditions. Furthermore, encephalopathy can occur in the presence of alcohol and toxin abuse. It is frequent in chronic organ diseases (kidney, lung, liver, heart) associated with electrolyte imbalances (glucose, Na, Ca, Mg, PO4, urea, creatinine, pancreatic enzymes, cardiac enzymes, etc.) and osmotic disorders. These patients usually have frequent infections such as urinary and/or respiratory tract infections. Encephalopathy may also develop in primary infections of CNS, as well as due to the prolonged effect of anesthetics and sedatives.[13] Pathophysiological mechanisms Pathophysiological mechanisms of encephalopathy are not fully understood. It is considered that vascular effects and the effects of toxins and infections, have the most important role in its development.[9],[14],[15] Damage to the brain–blood barrier causing disruption of the amino acid and neurotransmitter systems is considered to be an important factor. Due to the inadequate functioning of the neurotransmitter systems within the brain, various consequences can occur such as focal or global edema, accumulation of toxic metabolites, capillary vasogenic edema, as well as depleted energy processes.[15] The complete pathophysiology of encephalopathy is unknown; however, in encephalopathy associated with sepsis, several mechanisms have been proposed.[16] Inflammation triggers endothelial activation in the brain, which leads to malfunction of the blood–brain barrier. Consequently, this leads to the release of inflammatory mediators such as cytokines and chemokines, which enter the brain parenchyma, causing damage to the cellular metabolism. Furthermore, cellular dysfunction initiates oxidative stress and mitochondrial dysfunction, which cause the disruption of neurotransmission and leads to apoptosis. The cholinergic, gamma-amino butyric acid (GABA), beta-adrenergic, and serotonergic systems are altered and neurotransmission functioning is damaged, especially in the neocortex and hippocampus.[17] Additional factors in this neuroinflammatory process are the release of excitatory amino acids, hyperglycemia, neurotoxic pharmacological agents, hemodynamic changes, coagulopathy, and hypoxemia.[18] Different mechanisms operate in encephalopathy caused by medications or toxins. Increase in the glutamine and glutamate complex peak in magnetic resonance (MR) spectroscopy illustrates the neuronal and astrocytic excitotoxic injury during the administration of acute intravenous immunoglobulin therapy.[19] The use of valproic acid, 5-fluorouracil, carbamazepine, and acetazolamide may cause the inhibition of urea cycle enzymes with consequent hyperammonaemia and encephalopathy.[20],[21],[22],[23] Interaction through GABA receptors occurs during intrinsic valoproate toxic effects or due to direct topiramate toxicity.[24] The combined antiepileptic valproate and topiramate therapy causes reduction of topiramate metabolism through cytochromeP 450 pathway. Cephalosporins may also induce encephalopathy through GABA A receptor inhibition.[25] It has been proposed that acute confusion may occur through two major mechanisms, namely a decrease in the central cholonergic activation (characterizes delirium) and an increase in the proinflammatory cytokine concentrations (interleukin 8, tumour necrosis factor alpha, interleukin 10).[26]
Metabolic encephalopathy correlates with the severity of the metabolic disorder that caused it. Clinical presentation varies from subtle behaviour changes (obliviousness, absent-mindedness) to severe consciousness disturbances such as stupor or coma, or personality disorders with psychomotor hyperactivity, agitation, hallucinations, and illusions.[2],[9],[27] Orientation and mood disorders, thought and memory disorders, intellectual deterioration, dementia, and depression may also occur. However, the most common symptom in metabolic encephalopathy is delirium.[2],[9],[26],[28],[29] Neurological symptoms and signs may be focal or global, and may be associated with other less frequent symptoms. In the initial stage of the disease, global symptoms may be observed in the form of disorders of consciousness, confusion, disorientation, and delirium [Glasgow Coma Scale (GCS) usually between 11and 14]. Moreover, various autonomic nervous symptoms may be present such as insomnia, nausea, heart rhythm disorders, and breathing problems.[2],[9] As the disease progresses, the clinical picture may be evident by epileptic seizures, oral and facial automatisms, pathological reflexes, myoclonism, tremor, and coma (GCS: 8–10). In the most severe stages of the disease, decerebrate/decorticate rigidity may occur, as well as the development of a deeper level of coma (GCS: less than 8), followed by death.[2],[9] Focal neurological symptoms and signs can originate either from the hemispheres or the brain stem. The hemispheric symptoms consist of vision disorders, apraxia, aphasia, hemispasticity, hemiataxia and hemisensory syndromes, as well as pathological reflexes.[2],[9] Signs of brain stem lesions may be manifested by cranial nerves signs (changes in pupil size, oculomotor disturbances and nystagmus), pathological brain stem reflexes, dysarthria, dysphagia, ataxia, hemi- or quadriparesis, as well as by various sensitive end-respiratory disorders.[2],[9] The clinical presentation may sometimes include extrapyramidal signs (in cases of hyperbilirubinemia or kernicterus) as well as cerebellar ataxia (in cases of hypothyroidism, celiac disease or hyperthermia). However, these symptoms are rarely seen.[9]
The diagnosis of encephalopathy is based on clinical features and arterial blood gas analysis, laboratory analysis of blood biochemistry, electroencephalography (EEG), somatosensory evoked potential (SSEP), and imaging methods [multislice spiral computed tomography (MSCT) and magnetic resonance imaging (MRI)]. Arterial blood gas analysis is used to evaluate respiratory, cardiovascular, and metabolic functions. It represents a very important step in the emergency services because it may provide a quick answer regarding the content of oxygen and carbon dioxide in the blood.[30] However, in addition to this basic information, arterial blood gas analysis also provides a quick orientation on the electrolyte status (Na, K, glucose) as well as bicarbonates. Based on this information, clinicians can further focus the search on the detection of the underlying etiology of encephalopathy [Table 2].[30]
After the interpretation of the arterial blood gas analysis, evaluation of the complete blood count (CBC) and biochemistry should be performed. CBC analysis provides information regarding the potential presence of anemia, or of variations in hematological indices such as leukocytosis or leukopenia, and thrombocytopenia or thrombocytosis. A high erythrocytic sedimentation rate usually points to the existence of infection and/or autoimmune disorders. It may be registered in various types of anemia, thyroiditis, nephrotic syndrome, cardiac diseases or malignancies.[31] The spectrum of biochemical analysis of blood levels that is required includes glucose, urea, creatinine, uric acid, bilirubin, as well as electrolyte levels (the latter including sodium (Na), potassium (K), magnesium (Mg) and calcium (Ca) levels), as well as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), creatine phosphokinase (CK), and C-reactive protein (CRP). Each of these biochemical parameters may point to the potential cause of encephalopathy. For instance, elevated levels of urea, creatinine, and uric acid followed by electrolyte dysfunction and anaemia indicate the presence of a kidney disease.[32] Hyponatremia is usually recorded in patients in intensive care units as well as in patients taking some types of chronic therapy (e.g., the prolonged use of diuretics).[33] In the cases having sepsis, fever accompanied by elevated levels of leukocytes, CRP, procalcitonin, and other laboratory abnormalities (anemia, disseminated intravascular coagulation (DIC), increased transaminases, bilirubin, etc.) may be registered. The main markers of septic encephalopathy are neuron-specific enolase (NSE) and calcium-binding protein beta (S100β), which are shown in studies to be the main predictors of the occurrence of septic encephalopathy.[34] In cases in whom the biochemical analysis of blood does not explain the reason for disorders of consciousness, more specific parameters should be investigated such as the ammonium ion, phosphorus, pancreatic enzymes, viruses, toxins and drugs, antibodies, and tumor markers. It is important to perform an EEG and an SSEP as diagnostic procedures in the work up metabolic encephalopathy. In the cases of encephalopathy, EEG can register generalized slowing or suppression of the EEG reactivity, loss of fast rhythm with occurrence of diffuse slow activity (theta and delta), presence of particular EEG patterns (focal or generalized), intermittent activity suppression, or an electrocortical silence.[35],[36] In the patients with hypoglycemia, EEG can register diffuse theta activity with occasional occurrence of specific patterns, e.g., frontal intermittent rhythmic delta activity (FIRDA), or spikes and sharp waves as well as spike-wave discharges in temporal regions.[37] In hyponatremia, EEG detects diffuse slowing in the theta range, followed by paroxysmal delta activity and FIRDA or periodic delta waves, as well as the occurrence of periodic lateralized epileptiform discharges (PLEDS).[37] In hypokalemia, diffuse slow activity can be seen together with paroxysmal delta/theta activity, as well as focal paroxysms of sharp waves and spike-waves during hyperventilation (HV).[38] In patients with cirrhosis, in addition to diffuse slow activity (theta and delta), triphasic waves with bifrontal predominance may be registered. Furthermore, in these cases, other epileptic patterns in the form of spikes or sharp waves can also be detected.[39] However, triphasic waves are not specific only for hepatic encephalopathy. They can also be registered in patients with septic encephalopathy together with diffuse slow theta/delta activity [Figure 1].[40]
Use of SSEPs in the prognosis of coma, especially in the case of ischemic or anoxic etiology, is of particular interest. Some typical changes that are found include an increased amplitude and latency, and changes in the conduction velocity and time-frequency distribution.[41] Neuroimaging procedures Neuroimaging procedures of the head, either CT or MRI are important in the diagnosis of disorders of consciousness because they can exclude organic lesions. CT or MRI findings in patients with encephalopathy are usually normal. However, diffuse or focal edema may be registered. Moreover, changes in the signal intensity in the form of hypo- or hyperintensity in certain regions of the brain can also be detected. The region of basal ganglia, thalamus, cerebral cortex, and hemispheric white matter are usually the target of toxic or acquired metabolic encephalopathy.[42] In patients with hepatic encephalopathy, in T1 sequence, a hyperintense signal in the globus pallidus, the subthalamic regions and the brain stem may be registered, whereas in T2 sequence, diffuse edema in the cortical regions (in the form of hyperintensity of perirolandic and occipital regions) can be detected.[43] Deep white matter changes may be seen, with the appearance of hyperintensity on T2 sequences in the region of internal capsule, corona radiata, and splenium of corpus callosum, suggesting a restriction of diffusion.[42] In patients with posterior reversible encephalopathy syndrome (PRES), CT or MRI findings of the head show changes in the white matter in the form of hyperintensity (MRI) or hypointensity (CT), especially in the occipital and parietal regions, although changes may also be registered in the posterior frontal and temporal regions. On the other hand, pathological findings in cerebellum are rarely seen.[44] Hypoxic ischemic encephalopathy usually show normal findings on CT scan performed in the initial hours. However, after 24 hours, the CT scan can register diffuse cerebral damage characterized by reduced attenuation (diffuse edema) in comparison with brain stem and cerebellum. Usually, this is a sign of a poor prognosis.[45]
The treatment of metabolic encephalopathy implies the management of the underlying disease that emerged from the evaluation of the neurological symptoms and signs. In case of encephalopathy caused by thyrotoxic crisis, in addition to the standard therapy with glucocorticoids, plasmapheresis has also been recommended.[45] Uremic encephalopathy is treated by dialysis. This type of encephalopathy is never isolated, but is always associated with other metabolic disorders. Therefore, the clinical presentation in these situations is always a combination of the manifestions of several metabolic disorders.[46] In case of hyponatremia, therapy consists of fluid restriction with sodium deficit replenishment. However, serum sodium concentration correction has been limited up to 12mEq/L/day because intensive compensation may result to central pontine myelinosis and favors the further development of encephalopathy.[47] On the other hand, in cases of unknown etiology, urgent therapeutic procedures should be conducted, such as ensuring an adequate respiration and circulation, an arterial blood gas analysis, the biochemical analyses of blood, as well as blood and urine tests to detect toxins.[4] In cases who are in coma or those suffering form acute consciousness disorders of unknown cause, correction of hypoglycemia should be undertaken as well as the administration of antagonists of benzodiazepines and/or opiates (naloxone amp. intravenously). For Wernicke encephalopathy prevention, thiamine (100 mg intravenous) is used. If encephalopathy is manifested by epileptic seizures, the first line of choice are benzodiazepines. In case of nonresponsiveness to this therapy, introduction of antiepileptic medications is recommended.[4] In all patients, X-ray of the heart and lung, head CT, lumbar puncture, and EEG should be performed.[4] If the etiology of encephalopathy still remains unknown, investigation should be expanded to specific blood analyses (ammonium ion, tumor markers, virological analysis of blood, CRP, procalcitonin, toxicological analyses, etc.).
Differential diagnosis of metabolic encephalopathy includes various pathological conditions, i.e., alcohol or drugs intoxication, metabolic imbalances (electrolytes, hypo or hyperglycemia, organic kidney damage, and/or liver failure), systemic infections, primary CNS infections, autoimmune diseases, vasculitis, cancer, degenerative diseases (dementia, and Jakob–Creutzfeld disease), traumatic conditions, ictal and post-ictal states, as well as psychiatric disorders (psychoses).[1]
The prognosis of patients with metabolic encephalopathy depends on the cause and type of encephalopathy. According to Eidelman et al., mortality from septic encephalopathy depends on the level of quantitative disorder of consciousness, measured by the Glasgow Coma Scale (GCS) score. Consequently, a GCS score of 15 has a 16% mortality, a GCS score of between 13–14 has a 20% mortality, a GCS score of between 9–12 has a 50% mortality, whereas a GCS score of between 3–8 has a 63% mortality rate.[48] Survival statistics of patients suffering from liver cirrhosis and hepatic encephalopathy is less than 50% annually, or less than 25% over 3 years.[49] In patients with hypoxic anoxic encephalopathy, the prognosis is even worse and depends on the length of anoxia. Even when there is a recovery in the first week after cardiac arrest, most of these patients die due to other hospital associated complications.[50] Thus, according to Young, the recovery from cardiac arrest in the hospital is approximately 44%, whereas only 17% will eventually be able to leave the hospital without a severe deficit; the reported recovery from hypoxic encephalopathy is even worse.[50]
In conclusion, metabolic encephalopathy represents a serious group of symptoms, originating from various diseases that requires a multidisciplinary approach regarding treatment and follow-up. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1]
[Table 1], [Table 2]
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