J Neurol (2002) 249 : 11501159 DOI 10.

1007/s00415-002-0869-z

ENS TEACHING REVIEW

Klaus Kunze

Metabolic encephalopathies

Received: 29 April 2002 Accepted: 23 May 2002

Prof. Dr. med. Klaus Kunze ( ) Neurologische Universittsklinik Hamburg Eppendorf Martinistr. 52 20246 Hamburg, Germany Tel.: +49-40/4 28 03-57 77 Fax: +49-40/4 28 03-81 77 E-Mail: kunze@uke.uni-hamburg.de With support of the E & M Karberg Foundation for Medical Research Hamburg/Germany

s Summary Metabolic encephalopathies, usually multifactorial in origin, may be important complications of many diseases of patients treated in a critical care unit. In many cases these complications arise from more than one cause. Neurological signs of metabolic encephalopathies, ancillary tests and differential diagnosis, etiology and pathophysiology are discussed. In this context major single causes for metabolic encephalopathies are referred to. Metabolic encephalopathies as diseases per se (e. g. Wernickes encephalopathy) and encephalopathies as consequences of deteriorating known diseases (e. g. renal or hepatic diseases) and encephalopathies as complications in patients treated with other diseases in the ICU have

to be differentiated. Encephalopathies are known to be the most common complication of a large group of diseases treated in the ICU; on the other hand, manifestation of metabolic encephalopathy can be taken as a warning of deterioration or beginning organ dysfunction. So it would be misleading so far to reduce the clinical concept of metabolic encephalopathies in ICH to septic encephalopathy only. s Key words beginning hypoxic encephalopathy beginning sepsis encephalopathy brain trauma and encephalopathy ICH and hypokalemia (2 cases) hypercalcemic coma brain tumor and confusional state

Introduction
As a consequence of the numerous advances in early diagnosis and treatment of diseases, critical care has developed as a subspeciality in all clinical disciplines engaged in life-threatening diseases. In neurology this has led to an institutional increase of neurological critical care units dealing with a broad spectrum of vascular infectious immunological and metabolic diseases and malignancies not only as primary diseases of the central and peripheral nervous systems and muscle but also as secondary affections caused by other organ or systemic diseases. In this regard metabolic disturbances play an important role not only as diseases per se but

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also for monitoring the severity of decompensating organ functions during deteriorating primary diseases. Metabolic encephalopathies as complicating disorders need better definitions because in cases requiring intensive care they may indicate the need for further additional measures to be taken. This was already known to the old clinicians (Bright, Osler, Frerichs, Kussmaul and Maier, and von Mering) describing symptoms and signs of encephalopathies in special cases of liver and renal diseases as early as about the end of the nineteenth century. The term metabolic encephalopathies encompasses in principle a large variety of different conditions of the brain in critical conditions.

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The clinical concept of metabolic encephalopathies

s Etiology

must be considered in patients in the neurocritical care unit with multiple trauma, infections and intoxications.

s Pathophysiology
Wilson was the first to use the term encephalopathy for the disease he described in 1912. This term has been used differently through the years, e. g. in many textbooks or papers one can read that encephalopathy is a special condition of the brain not caused by inflammation, in other words, it is not an encephalitis. Therefore some definition is necessary. Encephalopathies represent diffuse multifocal cerebral states which may be caused by many organ dysfunctions and factors. In general they represent functional disturbances of the brain and these are at least in the beginning not combined with morphological correlates. Primary encephalopathies are caused by different mostly genetically defined disturbances of aminoacid, carbohydrate and lipid metabolism whereas secondary or metabolic encephalopathies are caused by hypoxic-ischemic states, many organ dysfunctions including the liver, kidney, and lung, and systemic diseases and many toxic agents. Alcohol is the single most frequent exogenous toxic agent (Table 1). Although different single and distinct factors may cause encephalopathy, a combination
Table 1 Important causes of metabolic encephalopathies Hypoxia Anemia Pulmonary disease Alveolar hypoventilation Ischemia Cardivascular disease (including cardiac arrest) Stokes-Adams syndrome, cardiac arrythmias Hypersensitive carotid sinus Microvascular diseases Hyperviscosity syndrome Hypotension Hypertension Systemic diseases Hepatic disease Renal disease Pancreatic disease (gastrointestinal) Malnutrition (vitamin deficiency) Endocrine dysfunction (hypoglycemia or hyperglycemia and hyperosmolar state) Acid base, electrolyte, and fluid imbalances Vasculitis Infections and sepsis Malignancy (paraneoplastic syndromes) Toxic agents Alcohol, sedatives (barbiturates, narcotics, tranquilizers) Psychiatric medications (tricyclic antidepressants, anticholinergic, drugs, phenothiazine, MAO-inhibitors) Heavy metals Organic phosphates, solvents Other drugs (corticosteroids, penicillin, anticonvulsants)

Brain metabolism depends almost completely on the metabolism of systemically derived substrates. About 75 % of hepatic glucose production is used in the brain and about 90 % of cerebral glucose metabolism takes place by the Krebs cycle and the gamma-minobutyric acid shunt. In addition, amino acid and ammonia are taken from the blood during high metabolic rates varying in different regions of the brain. Morphological changes in brain tissue do not always occur in patients with encephalopathies as mentioned above. However, in vascular and special types of hepatic encephalopathies tissue hypoxia and tissue edema and possibly tissue necrosis may be found. On the cellular level morphological changes of astrocytes which resemble Alzheimer Type II cells may be seen. There is evidence from clinical and especially from experimental research that vascular factors, infections, endotoxins and disturbances of the blood brain barrier with changes in the aminoacid and neurotransmitter profile may play a distinctive role in the pathophysiology of encephalopathies. Up to now it is not clear what are the definite causes of encephalopathy. The most conceivable pacemaker seems to be a disturbance of the brain barrier-function but possibly this is among other factors only a basic requirement.

s Clinical features
Clinical signs in metabolic encephalopathies may be divided into global cerebral signs and focal cerebral signs. Global signs predominate and they may be accompanied by mostly less expressed focal signs depending upon the severity of encephalopathy. Both groups are variable in quality and quantity. In the group of global signs (Table 2) especially in early stages confusion and slight cognitive disturbances preponderate but can include altered consciousness, confusional states and psychomotor hyperactivity and autonomic dysfunctions. In more severe cases global brainstem signs with oral and facial automatisms, pathological reflexes as palmomental and grasp reflexes and snouting, changes in spontaneous movements and tremor and multifocal myoclonus and abnormalities of muscle tone (paratonia, decorticate and decerebrate posturing) are found. The expression of these signs is variable even in the clinical course of the same patient. As it is listed in Table 2 they include changes in mental state with altered consciousness, confusional states and psychomotor hyperactivity. Delirium and agitation are commonly seen with

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Table 2 Global cerebral signs Disturbances of consciousness Somnolence Stupor Coma Seizures Vegetative signs Respiration (Cheyne-Stokes) Cardiac arrythmias, cardiac arrest Vertigo, nausea, vomiting Vasomotor and sudomotor disturbances Neuropsychological changes Agitation Hallucination Delusions Delirium Brain-stem signs Oral and facial automatisms Palmomental and grasp reflexes, snouting Reflexes Paratonia Decorticate and decerebrate posturing Tremor Asterixis Myoclonus (multifocal)

or without altered level of consciousness. Seizures are not a rare sign initially or in the clinical course. Single seizures are especially seen in the critical care unit in metabolic abnormalities and drug withdrawal and drug toxicity, in severe cases a status epilepticus can develop. Focal cerebral signs (Table 3) are the different neurological signs from the hemispheres or/and the brainstem. As a rule they are not in the foreground but combined with global cerebral signs and even in cases of distinct expression it seems often not possible to make a clear topographic assignment. The clinical course of encephalopathies is different, from the acute stage directly to coma or even starting with coma, or fluctuating between slight/moderate and worse phases. This fluctuating individual course is a characteristic feature in the clinical assessment of all different types of encephalopathies.
Table 3 Focal cerebral signs Hemispheric signs Visual disturbances Aphasia apraxia Hemispastic, hemiatactic, hemisensory syndromes Reflex and muscle-tone changes Brain-stem signs Cranial nerve disturbances (oculovestibular, pupillomotor) Nystagmus, gaze deviations Brain-stem reflex disturbances Dysarthria, dysphagia, respiratory disturbances Atactic, paretic, sensory syndromes (hemi-, quadri-, alternating) Quadrispastic syndromes, reflex changes Myoclonus

The history must be taken carefully and clinical examination must be regularly repeated. This is especially necessary as the diagnosis encephalopathy is usually a diagnosis of exclusion of other conditions producing the same picture. In this connection not only the different types of encephalopathy have to be taken into account but also vascular diseases of the brain including intracranial hemorrhages, sinus venous thromboses, infectious or immunological diseases of the brain, brain tumors and other causes of raised intracranial pressure. Also in mind should be e. g. malignant hyperthermia, malignant neuroleptic syndrome, acute adrenal failure and thyroid storm. Indeed it is necessary to consider a comprehensive differential diagnosis. To summarize, a careful clinical examination of consciousness, respiration and especially pupillary reactions and ocular movements, and spontaneous movements, muscle tone and posture using the battery of additional medical and laboratory examinations will differentiate symptoms and signs from focal hemispherical or infratentorial neurological diseases on the one hand and from psychiatric diseases on the other (Table 4). Especially is it necessary to include mental status examinations (Table 5) as its findings represent some of the leading signs in encephalopathy. In addition
Table 4 Initial Clinical Examinations and Decisions Assure vital functions (cardiovascular, respiratory, renal, water and electrolyte balance, body temperature) Patients history in great detail Consciousness mental status, neurobehavioural discrepancies Pupils size and reactions, oculomotor system and gaze disturbances Brainstem reflexes Motor functions esp. muscle tone and posture Sensory functions Medical and laboratory examinations focal hemispherical or infratentorial signs signs of psychiatric disorder

Table 5 Neuropsychological Signs Disturbed function Disturbance of consciousness Resulting problems Quantitatively: diminished arousal (vigilance), somnolence, sopor (stupor), coma Qualitatively: awareness (different states) Time, place, situation, and self Short- and long-term memory Perseveration, incoherence, concept formation, problem solving Illusions and hallucinations Mood, emotion, anxiety, ect. Increased or decreased motor drive, restlessness, apathy

Orientation Alertness and memory Thinking (form and contents) Perception Drive and affect Psychomotor activity

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to descriptions of findings, bedside tests can be used (e. g. MMSE, Trail Making Test (A & B),WAIS Digit Symbol). In case of unconscious patients beside recording of the clinical status and abnormal postures special scales should be applied (Glasgow Coma Scale, Innsbruck Coma Scale, Reaction Level Scale, Comprehensive Level of Consciousness Scale). One should bear in mind that these encephalopathies may arise also from basic diseases with which these patients may be referred to the neurocritical care unit, but more frequently metabolic encephalopathies result from complications of other diseases in patients already being treated in the critical care unit. These occur e. g. in organ failure or sepsis or in the course of many other diseases as e. g. cerebral circulation disturbances, intracranial hemorrhages or CNS infections. Therefore such metabolic encephalopathies are often not listed as diagnoses in the critical care unit. But the elucidation of the underlying cause e. g. a beginning sepsis is decisive for treatment and represents the main challenge in this field.

Metabolic encephalopathies by specific causes

s Hypoxia/anoxia and ischemia
Brain function depends on sufficient oxygen and metabolite supply via blood supply. There are many possibilities for severe disturbances in this field e. g. by primary vascular factors, blood factors and cardiac irregularities and especially by cardiac arrest. Outcome from cardiac arrest is generally poor in the majority of cases. Even when they are rescusciated successfully they have to overcome the following complications of anoxic/hypoxic encephalopathy during the next days or the next week. Estimated survival rates from the data of many authors in large series after 6 month are in the range of 11 % to 22 % of the patients who have recovered [1]. In a study of 310 patients with coma not caused by trauma or drugs 16 % of the patients achieved an independent existence within a month [2]. In another study comprising 210 patients with hypoxic-ischemic coma [3, 4] 13 % of patients regained independent function at some point during the first year after illness onset. The prognosis ranges from virtual no chance of regaining function to good. Patients with virtually no chance of regaining independence were identified to have on admission and on day 1 no pupillary light reflexes and motor responses no better than flexor and no spontaneous eye movements whereas the group with the best chance of regaining independence showed actually and on day 1 such motor responses as withdrawal or better and spontaneous eye opening and pupillary light reflexes. Main consequence of cardiac arrest is coma in the context of developing anoxic ischemic encephalopathy. Patients

with absence of pupillary or corneal reflexes in the early days of coma only rarely recovered consciousness. In a prospective randomized controlled study of 155 successfully resuscitated consecutive patients out of 677 resuscitation attempts during 2.5 years 68 patients were followed up and examined by a neuropsychologist. 41 patients (60 %) were found to have moderate to severe cognitive deficits three months after cardiac arrest. One year later about one half of the survivors had still moderate to severe neuropsychological sequelae that were thought to be permanent. Symptoms of depression were found in 22 patients (45 %) and severe depression in 12 patients (24 %). Nimodipine failed to show any effects on cognitive functions tested. Focal hypoperfusion often persisting even in recovered patients was not associated with a specific neuropsychological pattern. So frontal hypoperfusion did not correlate with the results of MMSE [5]. Pathological examinations of the brains indicate widespread necroses in these cases. Experiments with 148 male Wistar rats showed that hypoxia alone does not explan brain necrosis. For this additional ischemia is necessary [6]. In their systematic review Zandbergen et al. referred to 33 qualified studies and found as main prognostic variables out of 14 for poor outcome the absence of pupillary light reflexes and the absence of motor responses to pain on day 3 and bilateral absence of early cortical SSEP within the first week [7]. In this context it should be mentioned that beside these clinical and electrophysiological predictors for poor outcome of anoxic ischemic coma there are biochemical markers such as serum neuron-specific enolase [8] and S100 protein [9] as early predictors for outcome. Intention or action myoclonus as a sequel to periods of hypoxia was originally described together with neurophysiological analysis by Lance and Adams 1963 [10]. In the meantime it was found that a myoclonic status is a strong indicator for a poor outcome [11]. Additional support in the assessment of hypoxic/ anoxic coma can be gained to a certain extent from electroencephalography with graded classification [12, 13, 14]. Important criteria are the burst-suppression pattern and the development of alpha-coma in the deeply comatose patients. A recent prospective study on early prognosis in coma after cardiac arrest of 60 patients claims that the combination of Glasgow Coma Score at 48 hours, SSEP, and if these are non-conclusive, EEG features, permit a quite reliable outcome prediction. Concentrations of serum neuron-specific enolase and ionised calcium were of no additional prognostic help [15]. It seems that brain imaging with PET could prove to be a reliable method for prognostic assessment in future [16]. In this group of encephalopathies the hemorrhagic

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shock syndrome with encephalopathy occurring in previously well babies and infants which carries a poor prognosis should be mentioned [17, 18].

s Hepatic encephalopathy
It is wellknown that hepatic encephalopathy is a consequence of liver function disturbance and it is graded from I (slight) to IV (coma , unresponsive). Table 4 comprises the clinical design parameters of this encephalopathy. The pathophysiology of this extensively investigated encephalopathy refers to neurotoxins (ammonia metabolism, short and medium chain fatty acids, mercaptans, phenols), and altered neurotransmission including false neurotransmitters and benzodiazepine-like substances [19, 20]. The onset of the disease is sometimes difficult to recognize and the very early stages without knowing the later clinical course may be confounded with psychiatric disturbances or alcohol effects. Therefore the recognition of subclinical hepatic encephalopathy is still a matter of clinical research [21]. However, the topic of this section is the severe hepatic encephalopathy to be treated in the critical care units. Especially this refers to the fulminant hepatic failure (FHF) and the acutely decompensating chronic hepatic encephalopathies in the stage III/IV. In about 80 % viral hepatitis and acetaminophen poisoning with variable frequency account for FHF. The rapid clinical course usually requires earlier and more often critical care treatment than the encephalopathy in decompensating chronic liver diseases. In such severe hepatic encephalopathies in about 1030 % seizures occur possibly mainly caused by hypoglycemia which is found in about 40 % of the cases. But in FHF the main complication is cerebral edema sometimes dramatically evolving which is found in about 80 % of the cases and which is one of the major causes of mortality (about
Table 6 Stages of hepatic encephalopathy I Inverted sleep pattern and hypo-/hypersomnia. Short attention span, low perception, impaired calculation. Mood changes, anxiety/apathy. Coordination and handwriting disturbances, tremor. II Slow response, poor memory, disorientation for time, inappropiate behavior, asterixis, ataxia, dysarthria. III Confusion, delirium, paranoia, disorientation, amnesia, perseveration, hperventilation, nystagmus, hyperreflexia, Babinski sign, rigidity, muscle twitching, incontinence, possibly epileptic seizures. IV Coma*, abnormal flexion or extension responses, brisk oculocephalic responses, dilated pupils and sluggish responses to light. In the early stages of coma reaction to painful stimuli, later unresponsive. * Coma is defined as unresponsiveness to any external stimuli with preserved vital functions in the lying subject with eyes closed. In early stages there may some unidirectional movements to painful stimuli.

8090 % of patients with FHF die). Other severe complications are epileptic seizures, bleeding from the upper gastrointestinal tract and combinations with renal dysfunction (hepatorenal syndrome) and the concomitant respiratory alkalosis and hypotension among other disturbances. Up to now it is not decided definitely whether there are in FHF the same pathophysiological conditions as in the other types of hepatic encephalopathy or additional factors accounting for the rapid clinical course and the poor prognosis. The poor chances for patients with FHF by supportive care make them to candidates for liver transplantation though research concerning guidelines for transplantation and results for long-term follow up is still under way [22, 23, 24]. With respect to deteriorating chronic hepatic encephalopathies there are case reports indicating that patients treated with the benzodiazepine-receptor-antagonist flumazenil improved (single doses of 0.20.3 given every 13 min for a total dose of 2 mg, or infusion of 2 mg in 15 min). This could be proven even by electroencephalogram recordings. Improvement took place in about two thirds of the patients treated and lasted at least for minutes or hours. The effect could be confirmed in studies only for a selected group of patients [25], and it could not be considered to be for a pathophysiological entity. For diagnostic procedures in supposed hepatic encephalopathy it should be pointed out that the electroencephalogram recordings show a slowing in frequency as in other encephalopathies, depending of the severity, but besides that in severe cases a bilaterally synchronous delta activity especially over the frontal and ocipital regions is seen. This finding should not be confused with a petit mal status. Possibly FAEP changes could give early hints of developing encephalopathy. Brain imaging may give further diagnostic information but with the exception of brain edema it is especially valuable for differential diagnosis. Progressive hepatic encephalopathy is in the first place a monitor for the severity of hepatic disease. Therefore treatment of encephalopathy means treatment of the liver disease [22, 26, 27, 28, 29].

s Renal encephalopathies
Diseases of the kidney such as glomerulonephritis, pyelonephritis, interstitial nephropathies and arteriosclerotic diseases with their broad pathogenetic spectrum lead to uremia with accumulation of toxic substances causing encephalopathy. Therefore failure of renal function causes encephalopathy with only not the special pathogenesis of uremia. Clinical signs are quite clear cut especially in acute renal failure which is mostly seen in shock, by nephrotoxic agents, and other e. g.

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thrombotic thrombocytic purpura or myoglobinuria. Increasing importance has gained underlying immunosuppressive treatment. Uremic encephalopathy presents like other encephalopathies with changing expression of global cerebral symptoms such as fluctuating disturbance of consciousness and agitation but in this case with additional hyperpnea (Kussmaul or Cheyne-Stokes type), hyperreflexia, multifocal myoclonus, tremor, asterixis and brain stem signs with different types of nystagmus and muscle tone abnormalities.With progress of the underlying disease especially in not treated cases epileptic seizures, delirium and coma may develop. In the EEG a delta activity predominates depending upon the severity. In principle there are no basic differences between acute and chronic renal failure. Laboratory examinations show an increased serum creatinine up to about 100 mol/l per day, under special circumstances up to 400 mol/l. Besides that signs of hyperkalemia, hyperphosphatemia, hypocalcemia and metabolic acidosis are found. The electroencephalogram shows as in other acute encephalopathic stages a generalized slowing with an excess of delta and theta waves within 48 hours after onset of renal failure. The grade of slowing increases with increased serum creatinine. In about 14 % of the patients with chronic renal failure bilateral spike and wave complexes in the absence of clinical seizure activity occur. Brain imaging for encephalopathy in uremia is only helpful to exclude other causes for the global cerebral syndrome. The pathophysiology of uremic encephalopathy up to now is uncertain. Extensive animals experiments have shown biochemical changes in the brain especially in acute renal failure. Beside that in acute as in chronic renal failure parathyroid hormone level is elevated with a concomitant elevated calcium content in the cerebral cortex. I In dogs EEG changes and brain calcium abnormalities can be prevented by parathyroidectomy, so these changes appear to be PTH dependent [31]. Besides encephalopathy, polyneuropathy (firstly described by Kussmaul and Maier in 1866) occurs in up to 70 % of patients under treatment for chronic renal failure. This is a symmetrical sensory and motor neuropathy accentuated distally in the extremities. Isolated mononeuropathies have been found too. The severity of peripheral nervous system affections may monitor the severity of renal failure. If it proceeds under dialysis it can completely improve after kidney transplantation. Complications of dialysis refer to dialysis disequilibrium syndrome and dialysis encephalopathy. Dialysis disequilibrium syndrome described by Fraser and Arieff 1962 is characterized by headache, nausea, emesis, blurred vision, muscle twitching, hypertension, tremor, asterixis, multifocal myoclonus and disorientation. In severe cases psychosis, stupor, and coma are seen. In EEG early slowing and bursts of medium to high voltage slow waves below 3/sec may be found.

Progressive dialysis encephalopathy (dialysis dementia) is a severe frequently fatal neurological disease firstly described in 1970 [33] characterized by initial speech disturbances, involuntary motor phenomena, gait disturbance, seizures, and especially features of Alzheimers disease. In children this disease may be more acute. The etiology remains undefined. There is strong evidence for neurotoxicity from aluminium [30, 31, 32, 33, 34, 35]. As in all manifestations of metabolic encephalopathies other diseases have to be excluded and it should be pointed out here that symptoms and signs of complications of dialysis can be confounded with intracranial hemorrhage especially subdural hematoma, consequences of electrolyte disturbances, drug intoxications especially benzodiazepines, major depressions, and Alzheimers disease and others. A further complication of dialysis may be Wernickes encephalopathy (Wernicke-Korsakow-Syndrome) with the classic triad of symptoms : mental symptoms, eye symptoms and gait disturbances [36, 37, 38, 39]. There are many other causes for thiamine depletion in acute ill patients other than alcohol leading to Wernickes encephalopathy. It should be kept in mind that initially only one of the symptom groups may be present. That means that patients with a disturbance of consciousness suffering from a beginning Wernickes encephalopathy not known before may be referred to the critical care unit. Some critical care units are accustomed to treat all not clearly defined disturbances of consciousness initially parenterally with thiamine in order to avoid mistakes.

s Septic encephalopathy
This encephalopathy gained most interest in recent years though it was in principle already known at the end of nineteenth century as mentioned in the introduction. But it reflects in a special way the advance of management in severely diseased patients. By these advances later stages of illness come into the scope of management in the critical care unit. Neurology of critical care means the detection of signs indicating that progressive basic disease has spread to the nervous system. Multiorgan failure with and without sepsis are the leading causes of mortality in critical care accounting for 1050 % of the deaths. Already in 1978 a disturbance of protein metabolism with muscle protein breakdown and deranged plasma amino acid pattern was found in liver failure and three years later it could be proven by animal experiments that, in sepsis, plasma and brain amino acids were deranged with a decrease of branched chain amino acids and an increase in most neutral amino acids in brain similar to the findings in portasystemic encephalopathy [40, 41, 42, 43]. Later this could be

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confirmed in patients with sepsis showing that aromatic amino acid levels correlated with APACHE II scores and mortality. Scores were higher in shock patients with higher levels of ammonia and sulfur- containing amino acids with a higher mortality rate [44]. This encephalopathy became an important factor in surgery dealing with sepsis. In a large controlled study comprising initially 2568 patients between October 1983 and April 1986 Sprung and coworkers [45] evaluated 1333 patients. Of these 23 % had an altered sensorium secondary to sepsis with a higher mortality rate (49 %) than those without mental signs (26 %). Mortality was significantly higher in septic patients with Gram-negative bacteremia than those with Gram-positive bacteremia or negative blood cultures. This was later confirmed in a new prospective case series of 91 consecutive patients with an incidence of septic encephalopathy between 5062 % according to the method used to grade altered mental status [50]. Special investigations of encephalopathy in sepsis by the Ontario/Canada-group started with twelve fatal cases of encephalopathy associated with sepsis in a ten years retrospective pathological study that favored as a cause bacterial invasion of the brain with formation of disseminated microabscesses [46]. In a prospective study performed in a tertiary care hospital comprising 69 patients with fever and positive microbial cultures 32 patients had marked brain dysfunctions with certain type of EEG abnormalities. Furthers EEG studies in patients with septic encephalopathy could prove and confirm that the encephalogram is a sensitive index of brain function in septic encephalopathy and that it would be useful to monitor EEG in encephalopathy-suspected patients as these findings correlated with severity and mortality [47, 48, 49]. In a new prospective study [50] earlier results could be confirmed even by clinical scoring of mental status and Glasgow Coma Score in combination with APACHE II scores. In these studies clinical signs proved to be as diffuse brain dysfunction without focal signs, cranial nerve dysfunctions, decerebrate postures, or paralyses. The principal clinical abnormality constituted by alterations in the conscious level and the EEG. A problem in these cases arises in principle in the method applied for bedside mental testing but the evaluation of the tests resulted in comparable data. An additional gain in differentiation of encephalopathy by examination of evoked potientials could not be obtained [51]. The definite cause for septic encephalopathy as for other metabolic encephalopathies remains uncertain. There are many data pointing to circulation disturbances of the brain [52, 53, 54]. Possibly these data represent epiphenomena. Many biochemical data cited above show similarities between hepatic and septic encephalopathy requiring blood- brain-barrier alteration. There may be a factor in CSF attacking the cytoskeleton

and there may be early oxidative stress as recent preliminary experimental data showed [55, 56]. Septic encephalopathy should not be confounded with encephalopathy in endotoxemia, as animal experiments in this field have shown [57, 58, 59, 60].

s Immune mediated encephalopathies

This represents a large group of diseases and special problems which cannot be discussed in this article dealing with neurology in critical care. Especially vasculitides and connective tissues diseases [61] have to be taken into account as well as critical neurological illness in the immunocompromised patient [62]. In addition the different paraneoplastic syndromes causing encephalopathies have to be mentioned. Experiences with neurological complications after bone marrow transplantation (BMT) are currently discussed. Two pathological and three clinical studies have investigated this topic. About half of the patients had neurological complications, most of them occurring during the first six months after transplant. Most of the complications were encephalopathies. These were caused either by the transplant procedure, cyclosporin, systemic infections, microangiopathic thrombopathy or complications induced by graft- versus host-disease. One prospective study listed neurological complications in 56 % of the patients (out of 115 consecutive patients having BMT for leukemia). 25 % had major neurological complications, sixteen patients had more than one complication (metabolic encephalopathy 30 %, seizures 30 %, psychiatric symptoms 11 %, and other). Complications were evaluated during thirty days after BMT. Probability of survival at day 90 was lower in patients with then without major central nervous system complications [63, 64, 65, 66, 67]. Immunosuppressive therapy (e. g. cyclosporin) may cause a reversible posterior leucoencephalopathy syndrome [68].

s Electrolytes and endocrine disturbances

Changes in water, acid-base regulation and blood electrolytes may cause metabolic encephalopathies. This is a continuous challenge of being aware that this could be the cause of unexplained mental status in the ICU as known to be so for hypoglycemia. In addition the major importance of hyponatremia should be noted [69]. In rat experiments producing acute and chronic hyponatremia it could be proven that age, gender and the cerebral effects of vasopressin were major determinants of mortality in this type of experimental metabolic encephalopathy [70, 71]. Chronic symptomatic hyponatremia of postmenopausal women can be assosiated with major morbidity and mortality. Treatment with IV

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sodium chloride was assosiated with significantly better outcomes than fluid restriction when given for respiratory insufficiency [72]. Encephalopathies in endocrine disturbances which cannot be discussed in detail here have also to be taken into account. They are found in thyroid, parathyroid and adrenocortical diseases. Diagnosis can be difficult e. g. in acute cases of Hashimoto s encephalopathy.

Metabolic encephalopathies in [neuro-] critical care medicine

Besides different special metabolic encephalopathies, encephalopathic conditions may arise in many other diseases requiring per se critical care treatment for organ dysfunction. In a study of 61 patients (Table 7, 8) additional symptoms pointing to encephalopathy had been vigilance disturbances (22.5 %), psychosyndrome (25.0 %), delirium (17.5 %), hallucinations (12.5 %) and brainstem signs (22.5 %), vegetative dysregulation (12.5 %), seizures (7.5 %) in different combinations. In further studies in patients in the ICU with additionally developing mental state changes such as increased psychomotor activity, agitation and hallucinaTable 7 Main initial diagnoses Metabolic encephalopathies n = 61 Brain injury/Polytrauma Stroke SAH ICH Seizures Alcohol sequelae Multiple organ failure Systemic encephalopathy Other diseases 20.9% 6.0% 6.0% 16.4% 17.9% 12.0% 12.0% 10.0% 9.0%

tion on the one hand and slowing, confusion or sopor on the other there were found cerebral (hemorrhage, increasing ICP or vascular spasms) or extracerebral (elctrolyte changes, esp. hyponatremia, respiration or renal insufficiency, hypoglycemia, and beginning sepsis syndrome) complications. In traumatic brain injury, stroke and intracerebral hemorrhages extracerebral complications were found to be in the foreground, whereas cerebral complications came rather into play in SAH and brain tumors, but combinations of both type complications were seen too. Patients with additional encephalopathy presented with longer medium stay in the ICU: e. g. patients with traumatic brain lesions 11.5 days instead of 9.1 days; patients with stroke 6.3 instead of 4.6; patients with intracerebral hemorrhages 16.5 instead of 8.3; patients with SAH 18.6 instead of 9.5 days. In these cases a deterioration of the basic disease to varying degrees had to be taken into account. In many cases an influence on the further clinical course was to be seen. Metabolic encephalopathies represent a crucial problem in severely diseased patients. They may develop in the clinical course of deteriorating disease as well as complications during treatment in the critical care unit. Signs of metabolic encephalopathy may be an early indication of developing complications. This is a plea for careful control of the clinical neurological status of the patients.

References
s Suggested readings
Hacke W (ed) Neurocritical care Springer, Berlin, Heidelberg, New York 1994 Kunze K (ed) Praxis der Neurologie 2. vollstndig berarbeitete Auflage Georg Thieme, Stuttgart, New York 1999 Plum F, Posner JB The Diagnosis of Stupor and Coma 3rd Edition F. A. Davis , Philadelphia 1982 Wijdicks EFM Neurology of Critical Illness F. A. Davis, Philadelphia 1995

Table 8 Clinical manifestations by Metabolic encephalopathies n = 61 Pulmonary infections Heart/circulation disturbance Brain edema Delirium Pancreatitis Coagulation disturbance with intracerebral bleed. with gastrointest. bleed. Sepsis Thromboemblic. complications 18.0% 14.8% 11.5% 8.2% 8.2% 8.2% 8.2% 4.9%

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References
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