Neurological symptoms in metabolic encephalopathies
Metabolic encephalopathies represent potentially reversible functional disorders of the brain. Early leading symptom of the disease are neuropsychological disorders and Personality changes. Focal focal signs occur late in the course of the disease or in acute organ failure.
The Pathomechanisms of the cerebral dysfunctions are usually only partially understood.
Diagnosis is based on neurological symptoms. Laboratory parameters provide information only about the severity of the underlying disease, but not about the cerebral situation. The Imaging is only helpful to a limited extent and is mostly used to exclude other intracranial pathologies. Overlapping of individual disease patterns is possible.
Organ diseases, electrolyte disturbances, malnutrition, but also drugs can secondarily lead to severe neurological disease patterns. The neurological symptoms are broad and reflect the temporal dynamics, duration and severity of organ dysfunction and the extent of malnutrition respectively. Hepatic encephalopathy, uremic encephalopathy, osmotic myelinolysis, and Wernicke's encephalopathy are described below.
Hepatic encephalopathy (HE) occurs in acute liver failure and chronic liver disease. The pathogenesis of cerebral dysfunction is complex and only partially known. The accumulation of ammonia in the brain seems to play a central role in this process. Ammonia induces glutamine production in astrocytes and leads to astrocyte swelling and astrocyte dysfunction via an osmotic gradient, additional disruption in tryptophan metabolism and other neurotransmitters is hypothesized, and stimulation of the N-methyl-D-aspartate receptor (NMDA receptor) leads to nitrite oxide release, secondary vasodilation, hyperemia, and consecutive brain edema.
The classification of HE is performed according to etiology and clinical presentation. A distinction is made between HE in acute liver failure, HE in portosystemic bypass without liver disease, and HE in liver cirrhosis. Clinical classification assesses level of consciousness, neuropsychological disturbances, and neurological symptoms. The most common are the West-Haven-Criteria (WHC) with 5 severity levels of the disease (Tab.). Clinical deterioration may develop acutely within hours to days, but may also develop chronically over months. Brief temporary worsening (episodic HE) with intervening months of asymptomatic phases is possible and usually triggered by dietary errors with high protein load, gastrointestinal bleeding, infections, alcohol excess, dehydration, and by the use of hepatotoxic drugs.
HE stages: Stage I HE is a liver dysfunction without clinical-neurological and intellectual abnormalities. If, however, neuropsychological disturbances are shown in extended psychometric tests, one speaks of a latent or a winging tremor. minimal hepatic encephalopathy (MHE). As the disease progresses, there is progressive qualitative and quantitative impairment of consciousness. The development of coma is also possible. Thus represents the most severe form of HE (WHC IV). Disturbances of the sleep-wake rhythm, slowing down of the thought process and slurred speech are early companions of the disease. Tremor in fine motor performance is already detectable in stage I and asterixis ("flapping tremor", "wing beating tremor") from stage II onwards. However, asterixis is not pathognomonic of HE and may also occur in other metabolic diseases and intoxications. A rigid-akinetic syndrome is also frequently observed. Focal focal signs are not typical of HE, as HE is a global cerebral process. The appearance of focal focal signs always requires a structural workup to exclude a secondary pathology (z. B. intracranial hemorrhage due to coagulation disorders). Increasing socioeconomic importance of minimal hepatic encephalopathy. The prevalence of MHE in patients with liver cirrhosis is reported to be 30-70%. The Mini-Mental State Examination (MMSE) can only be seen as a crude screening test to detect MHE and, if negative, must be extended by other, more specific testing procedures (z. B. Number connection test A and B, line tracing test, mosaic test, digit symbol test). In these specific tests, patients with MHE show an early impairment of attention, spatial orientation, short-term memory and a disturbance of frontal-executive performance. Studies have shown that MHE is associated with a reduced quality of life, a higher number of driving errors when driving a motor vehicle, and early onset may be an independent predictor of the further course of cirrhosis. History of chronic or acute liver failure. The clinical neurological picture. The usual parameters such as electrolytes, blood count, liver and kidney function parameters, and coagulation are used to classify the severity of liver disease and to detect complications in a timely manner. Serum ammonia levels correlate with the severity of neurologic symptoms only in episodic HE. In MHE and persistent hepatic encephalopathy, the severity of neurological disease cannot be inferred from the ammonia level. In the early phase of the disease, the EEG recording shows diffuse slowing and, in the advanced stage, additional triphasic waves (
Fig. 1). However, triphasic waves can also occur in other metabolic diseases and are therefore not specific to HE. While somatosensory and visual evoked potentials have no diagnostic significance in HE, auditory P-300 waves are used in the assessment of neurofunctional impairment in liver cirrhosis. Furthermore, first data on electrophysiological assessment of MHE by means of special visual stimulation ("critical flicker frequency") seem to be promising. Magnetic resonance imaging (MRI) in severe HE may show symmetric, hyperintense lesions in T1 weighting predominantly in the globus pallidus, internal capsule, putamen, caudate nucleus, and mesencephalon.
The therapy of HE is avoidance and prevention of neurotoxicity. therapy of all factors that cause worsening of the hepatic situation (z. B. Alcohol abstinence, avoidance of hepatotoxic drugs, therapy of gastrointestinal bleeding, treatment of infections). Administration of lactulose, probiotics, L-ornithine-L-aspartate and rifaximin in cycles of 3-6 months reduces the production and adsorption of ammonia in the intestine. In MHE, the administration of lactulose causes. Rifaximin to significantly improve results in psychometric tests. Non-convulsive epileptic seizures occur in 10-20% of patients with HE III/IV and are treated with benzodiazepines and levetiracetam. In advanced HE (West Haven criteria III/IV). In acute liver failure, intracranial prere elevation occurs in up to 95% of cases. However, continuous intracranial prere monitoring is indicated only in individual cases. Intracranial prere crises are treated with analgesia, mannitol, and hypertonic saline. The creation of a portosystemic shunt (TIPS) can lead to improvement in HE and delay organ transplantation. Liver transplantation represents the maximal therapy for HE. However, immunosuppressive therapy, rejection reactions, and opportunistic infections after organ transplantation may become new neurological-diagnostic and therapeutic challenges (see below).
Similar to HE, uremic encephalopathy (UE) also presents with a wide spectrum of neurologic symptoms. The pathogenesis of HE is also not understood in detail, complex and multifactorial. In renal failure, a wide variety of organic substances accumulate, which interact as neurotoxins with the release of excitatory and inhibitory neurotransmitters. Uremia leads to impaired cerebral metabolism, reduced oxygen extraction and disruption of the ATPase-dependent calcium pump at the brain cell. Calcium levels in the cerebral cortex of patients with renal failure are twice as high as in healthy individuals, with renal secondary hyperparathyroidism likely playing an additional pathogenetic role.
Clinic: While in acute renal failure the clinical symptoms correlate with the level of serum urea, chronic renal failure often shows only discrete symptoms despite high serum urea. Fatigue, apathy, impaired concentration, fine-beat action tremor, and a reduction in attention span are early symptoms of renal failure. As the disease progresses, emotional lability, decreased drive, short-term memory impairment, lack of abstract and divergent thinking, grasping templates, positive palmomental and muzzle reflexes, and sleep disturbances occur. Severe disease course is characterized by delirium, visual hallucinations, epileptic seizures, and fluctuating level of consciousness. Coma is possible. Rigid muscle tone elevation and hyperreflexia are present long into the course of the disease and are still detectable at the onset of coma. Fluctuating hemiparesis with alternating side occurs in up to 45% ("alternating hemiparesis"). Myoclonia and an asterixis come late in the course of the disease. Meningismus is palpable in up to 30% of patients. The dialysis option leads to a significant reduction of severe UE. But also during dialysis treatment many patients complain about impulsive and memory disorders. Mild cognitive impairment is seen in up to 30% of patients; severe cognitive deficits are palpable in 10% of patients. Elderly dialysis patients show a significantly higher incidence of dementia syndrome than the comparison age group. This is attributed to the higher vascular risk profile of kidney disease patients. The development of multi-infarct dementia is attributed. In addition, dialysis patients suffering from sleep disorders (z. B. obstructive and central sleep apnea syndrome). Prolonged sleep deprivation and increased daytime sleepiness worsen cognitive function.
Diagnosis of UE is made on the basis of the patient's history, increased renal function parameters, and decreased diuresis. Cerebral imaging is used to exclude other structural intracranial pathology, but diffuse cerebral atrophy with dilated ventricles is frequently visualized. Individual case series describe a signal change in T2-weighted MRI images in the basal ganglia, periventricular white matter, and internal capsule. These changes are more pronounced under dialysis. Reversible after organ transplantation. Uremic patients with meningismus may have mild pleocytosis and protein elevation (cell count< 25/mm3, protein< 100 mg/dl) have. However, an inflammatory process must then always be excluded microbiologically and serologically. EEG changes are nonspecific and more pronounced in acute uremia. Diffuse slowing in the delta/theta frequency range with frontal accentuation is seen. Late in the course of the disease, bilateral spike-wave complexes without clinical seizure activity can be seen in up to 20%.
Dialysis complications: Dysaquilibrium syndrome is now a rare complication of dialysis treatment and is mainly observed in patients with prolonged severe uremia and severe hypertension. Caused by an osmotic gradient between brain cells. Extracellular space due to excessively rapid dialysis. Since urea can diffuse out of the brain cell only slowly, too rapid a decrease in serum urea leads to water influx into the brain cell and the development of brain edema. The syndrome is characterized by acute onset migrainiform headache, nausea, vomiting, muscle cramps, delirium, myoclonia, and epileptic seizures and occurs at the end of dialysis. A temporarily short dialysis interval and a low dialysis exchange volume usually lead to rapid stabilization of symptoms. The use of aluminum-containing dialysates and aluminum-based phosphate binders used to cause dialysis encephalopathy and dialysis dementia. The clinical picture was characterized by a subacute course of dysarthria, dysphasia, apraxia, severe personality change, psychosis, myoclonus, and epileptic seizures with fatal outcome within a few months. Today, this is only a sporadically observed disease. Attributable to a treatment error due to the use of aluminum substances.
The differential diagnosis of UE are osmotic myelinolysis, hypertensive encephalopathy, reversible posterior leukencephalopathy syndrome, and drug overdose due to delayed renal elimination.
After organ transplantation severe encephalopathy syndromes are described under immunosuppressive therapy with tacrolimus and cyclosporin. Neurotoxicity of these substances is multifactorial and leads to axon swelling and demyelination. Tremor, epileptic seizures, and dysarthria to anarthy are early symptoms of toxic side effects. MRI shows hyperintense changes predominantly in the subcortical, occipital, temporal, and parietal brain regions in the FLAIR and T2-weighted sequences. Dose reduction of the substances brings rapid improvement of the symptoms.
Osmotic myelinolysis (pontine and extrapontine myelinolysis)
Adams and coworkers first described the picture of central symmetric demyelination in the pons ("central pontine myelinolysis," CPM) in 1959. For a long time, the disease was associated with chronic alcohol abuse and pathological similarities to Marchiafava-Bignami syndrome (demyelination of the corpus callosum and other commiral pathways) were seen. However, the main cause of CPM is rapid correction of hyponatremia. The changes may also affect extrapontine brain areas such as the thalamus, striatum, white matter of the cerebellum, and the deep layers of the neocortex with the adjacent white matter ("extrapontine myelinolysis", EPM; Fig. 2). Frequently, CPM. EPM together on. Alcoholism combined with hyponatremia are the most common causes of CPM (Fig. 3).
However, since the disease is also associated with malnutrition, immunosuppressive therapy after organ transplantation (especially liver transplantation), malignancies, burns, and long-term exercise (e.g., sports), it has been associated with a number of other disorders. B. triathletes, marathon runners) occurs, extreme blood glucose and plasma protein fluctuations, but also rapid compensation of hypernatremia are discussed as further factors. Common pathologic end pathway of injury is osmotic dysequilibrium leading to endothelial cell damage, breakdown of the blood-brain barrier, and osmotic myelinolysis in different brain areas. Additional release of myelotoxic substances due to cellular osmotic stress is likely to. CPM presents with nuclear cranial nerve deficits, pseudobulbar paralysis, tetraparesis, and ataxia. Extrapyramidal movement disorders, paresis, and cognitive impairment become prominent in EPM. Most severe courses with a locked-in syndrome in CPM. Cortical deafferentation in EPM is possible.
Diagnosis occurs by means of MRI examination. Diffusion-weighted images show characteristically localized changes early; discrete contrast enhancement is occasionally possible at lesion margins. Evoked potentials support the functional disorder.
Management: Slow serum sodium correction is essential to prevent CPM. Serum sodium levels above 120 mmol/l (SNa) of short duration are rarely associated with the development of CML. Sodium substitution when SNa levels are below 120 mmol/l and duration exceeds 48 hours has a higher risk of CPM/EPM because of compensatory intracellularly accumulated osmolytes (z. B. Pass cell membrane only slowly. Thus, prolonging osmotic dysequilibrium. Sodium substitution is performed with hypertonic saline solution. An increase of SNa by 0.5 mmol per hour must not be exceeded. If SNa values are below 105 mmol/l, a more rapid substitution may be sought initially, until this value is reached. The use of vasopressin receptor antagonists ("vaptans") may be another option in the future to correct SNa in euvolemic hyponatremia. SNa correction must always be accompanied by strict. Close monitoring of laboratory values associated. Modern imaging and laboratory diagnostics have significantly improved the diagnosis, therapy and prognosis of CPM/EPM. However, the initial clinical picture and imaging are not predictive of outcome. A restitutio ad integrum is possible despite the most severe symptomatology. Impressive imaging possible.
Wernicke's encephalopathy (thiamine deficiency encephalopathy)
Thiamine (vitamin B1) is an essential coenzyme in carbohydrate and lipid metabolism and is required for the synthesis of amino acids and neurotransmitters. Thiamine deficiency leads to Wernicke encephalopathy (WE), an acute-onset clinical picture with neurocognitive behavioral abnormalities, eye movement disorders and gait ataxia (Wernicke encephalopathy triad). A WE has long been closely associated with chronic alcoholism. Accompanying malnutrition seen. However, the disease also occurs in unbalanced diets, eating disorders, gastrointestinal diseases and after gastrointestinal and bariatric surgical procedures.
Clinic: Vitamin B1 stores are depleted after 2-3 weeks, but clinical symptoms may take weeks to appear. Lack of temporal and situational orientation, delayed thought ductus, and apathy are the most important symptoms of WE (80%) and are often misinterpreted. Optomotor dysfunction with horizontal gaze direction nystagmus, conjugate gaze paresis, and partial ocular muscle paresis occurs in only 30% of sufferers; trunk and gait ataxia occurs in 20%. Thus, the classic triad of WE is observed in only 10% of those with the disease. WE is a clinical diagnosis. There are no laboratory parameters that acutely confirm the diagnosis. MRI shows typical symmetric changes in the periaqueductal gray and paramedian thalamus in just under 50% (
Fig. 4). Hemorrhagic changes in the lesions are possible.
Management: WE is a neurologic emergency, and suspicion requires prompt intravenous or intramuscular thiamine substitution. There are no studies on optimal dose, frequency, and duration of therapy. Recommendations are between 500-1.500 mg thiamine intravenously per day for 2-3 days followed by a maintenance dose of 100-250 mg thiamine for at least another 3-5 days. Ophthalmoplegia usually improves with thiamine substitution within a few hours, ataxia within days, and improvement in cognitive impairment occurs within weeks. Initial daily doses of 100-250 mg thiamine must be reported as too low. Promote permanent cerebral damage. The mortality rate of WE is still reported to be 20% today. The majority of patients survive in a Korsakow syndrome, a severe amnestic syndrome with lack of ability to learn new things and lack of divergent thinking.