Detection of minimal hepatic encephalopathy
Quantitative EEG analysis shows an increase of the relative power of the θ band and a decrease of the mean dominant frequency in the posterior derivations in 15–30% of patients with cirrhosis who do not have clinical evidence of HE (16, 24–27).
In the absence of other causes, the EEG alterations that are observed in this patient population are assumed to reflect the presence of minimal HE. In fact, these alterations (i) roughly correlate with the indices of hepatic dysfunction, (ii) predict the development of overt HE and liver-related death, at least in patients with advanced liver disease (16) and (iii) appear or increase when an amino acid oral challenge causing hyperammonemia is given to patients at risk for HE (28).
The P300 wave, elicited by an active oddball paradigm, was found to be altered in 20–80% of cirrhotic patients with no clinical evidence of HE or with Grade I HE (29). In follow-up studies, changes in P300 latency predicted the occurrence of overt HE (29). However, the changes in the EEG were found to have a higher value than P300 to predict the development of overt HE (30). In fact, P300 reflects a cognitive process, but the initial stage of HE causing changes in the electrogenesis might even precede cognitive dysfunction and more closely represent toxic brain dysfunction (31). At any rate, in the model of minimal HE induced by TIPPS, the delay of P300 latency was found to be more sensitive than those of the late cortical components of SSEPs (32).
Other kinds of CEPs can produce detailed information on the elementary mechanisms underlying cognitive processes in experimental settings (33, 34).
Objective quantification of overt hepatic encephalopathy
In the late 1970s, Conn et al.(35) considered the main background frequency of the EEG as one of the dimensions for HE assessment, as well as the mental state, asterixis and ammonia plasma levels. The use of the main background frequency can be biased in case the mixture of more rhythms that is common is overt HE (e.g. δ and θ band), or in case of instability of the tracing. In addition, it is not clear how to evaluate the presence of transients such as intermittent rhythmicδactivity or triphasic waves and how to consider the reduction in EEG amplitude occurring in severe coma. Despite these problems and only the rough correspondence of the EEG pattern with the behavioural features of HE on a population basis, the EEG has a unique role in producing objective data on brain functioning, especially in non-cooperative patients. In the follow-up of single patients the correspondence between the EEG pattern and the clinical findings might be stricter than that on a population basis.
In summary, the different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are CEPs (P300 paradigm), EEG, VEPs (latency>100 ms) and SSEPs (latency between 25 and 100 ms), which reflect cortical function. Short-latency EPs (BAEPs, SSEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and MEPs can disclose myelopathies. B
Recommendation. The optimal choice of clinical neurophysiological testing, for both research and clinical purposes, could be influenced by the anticipated degree of HE and the dysfunction, which is being sought. The most sensitive techniques (CEPs and quantitative EEG) are the best choices for the mildest degrees of HE, but CEPs rapidly saturate (in terms of change) for increasing degrees of severity. In the case of severe HE, less sensitive techniques can be used (IGCF). In extremely severe HE, the first cortical components of SSEPs are still detectable. The absence of these primary responses should lead to an in-depth assessment of other irreversible causes of brain damage. 2
Management of acute liver failure
With regard to ALF (i.e. the rapid deterioration of liver function in a subject without previous liver disease, accompanied by encephalopathy), there can be a three-fold potential purpose:
- a.Detecting brain dysfunction in patients with rapidly developing hepatic failure and, therefore, contributing to the diagnosis of ALF and the selection for liver transplantation;
- b.Gauging the efficacy of ongoing therapy aimed at delaying or reducing brain oedema, or preventing and treating non-convulsive seizures, thereby gaining time if a cadaver graft is not available or if the patient is not a candidate for liver transplantation; and
- c.Excluding from transplantation those patients who have already developed brain lesions as severe as to compromise any hope of functional recovery and in whom even a graft would not prevent death or unacceptable neurological sequels.
These three goals will be dealt with initially. We then offer some practical recommendations
a. Selecting those patients who need transplant, because of the severity of hepatic encephalopathy
The criteria that are used to select the patients with ALF who need transplantation are clinical. At present, neither EEG nor the EP grading of HE has been used for the selection for transplantation in ALF.
One small non-blinded retrospective study reported the use of SEPs as a tool for OLTs selection (36), showing that the disappearance of middle- to long-latency components (N70) in non-sedated patients (which were still detectable in 24% patients with Grade 4 HE) was superior to the King's College criteria for selection for transplantation (correct classification: 0.96 vs. 0.72 respectively). Such results, however, have been not repeated in a blinded or a larger series of patients. Moreover, it is hard to establish whether the use of sedative drugs would have reduced the diagnostic value of the disappearance of long-latency components of the SSEP.
The choice of a neurophysiological technique should be guided by the severity of HE under investigation. Because of their extreme sensitivity to any cognitive disturbance, CEPs are unlikely to be a valuable tool in the evaluation of ALF. Rather, we recommend using EEG and, if there are significant EEG abnormalities (predominant δ pattern or suppressed low-voltage pattern), to consider the IGCF, which would be analysed according to the presence, abnormality or absence of individual responses and interpeak latencies, or according to Guérit's classification (4).
b. Gauging the efficacy of ongoing therapy aimed at delaying or reducing brain oedema or preventing epilepsy, thereby gaining time in case of cadaver grafts are unavailable or the patient is not suitable for transplantation
The increase in intracranial pressure (ICP) is one of the main problems in patients with ALF. The possibility of substituting (or reducing the use of) invasive ICP monitoring with non-invasive electrophysiological monitoring would be an interesting clinical goal, given the risk of invasive ICP procedures in subjects with ALF. Of note, subclinical epileptic activity can increase ICP (37). The EEG is the only method for the diagnosis of non-convulsive seizures and the only tool available for monitoring its treatment (38–43).
In principle, an increase in ICP can give rise to both cortical (EEG, IGCF) and IBSC alterations. Despite the fact that the EEG changes reflect the severity of ALF in experimental animal models (44) and that a good relationship between EEG changes and ICP/cerebral perfusion pressure was also proven in humans (45), there is no proof that EEG monitoring is superior to clinical evaluation for non-sedated patients. With regard to EPs, the latencies of the late components of flicker vision EPs (fVEPs) (latency range>100 ms) were found to reflect changes of ICP, but the time course of their changes was slower than that of ICP in an open non-blinded study (45). The P1 component of fVEP proved to be an index of HE in an open, non-blinded study comparing 10 patients with ALF and 10 patients with acute hepatitis who did not develop ALF, despite the absence of formal comparisons with other classifications (46). In the same setting, BAEPs were found to detect mainly prolongation of the III–V interpeak and, to a lesser extent, of the I–V interpeak that did not correlate with HE or with its outcome. Of note, an imperfect correlation between ICP and clinical neurophysiological parameters should not automatically be interpreted as a failure of clinical neurophysiology, because it may also reflect the fact that some increase in ICP may be neurologically irrelevant.
It may be difficult to differentiate those EEG and IGCF alterations that are due to metabolic disturbances from those that are due to increased ICP. Additional problems occur by the concurrent use of sedative drugs in these patients, or by hypothermia (47), which also influence brain electric activity (48).
By contrast, because the relationships between body temperature and subcortical conduction times are known, any IBSC change, in conjunction with ICP monitoring, can provide some help to detect the brainstem consequences of increased ICP. This is the basis of systems designed for continuous monitoring of EEG spectrum, BAEPs and SSEPs (49) or for continuous monitoring of EEG and SSEP (50).
In summary, the use of EEG monitoring in patients with ALF admitted in ICU is worth investigating, as EEG is the only tool to monitor seizure activity. EEG, BAEPs and SEPs can theoretically complement ICP monitoring by establishing the neurological relevance of an increase in ICP. The issue of whether the installation of an invasive ICP monitoring system might be avoided or reduced based on EEG, IGCF or IBSC findings, thereby avoiding an increased risk of intracerebral bleeding, deserves further clarification. B
c. Excluding from transplantation those patients who have developed brain lesions as severe as to compromise any hope of functional recovery and in whom even a graft cannot prevent death or unacceptable neurological sequel
The EEG may not provide useful information to exclude patients from transplantation, because full EEG recovery has been described in patients with ALF even without transplant and flat EEG (51). In fact, the absence of EEG activity does not prove the existence of severe brain oedema and brainstem deficits (4, 6). Moreover, at least in experimental settings, EEG activity was proved to be absent in ALF even when fVEP still showed the existence of cortical activity (44).
The issue of whether absent cortical EP components (IGCF Grade 4) or BAEP changes consistent with major pontine involvement constitutes a sufficient criterion to exclude an individual patient from transplantation deserves further discussion.
Few uncontrolled studies have evaluated the applicability of SSEPs in the detection of patients with ALF who have excessively severe brain damage. Madl et al.(36) found that all the three patients out of 25 with ALF in which N20 disappeared died in a few hours. Similar results were obtained by Yang et al.(52, 53), who observed that all patients in whom N20 and P25 disappeared had died within 24 h after SSEP recording. By contrast, data on children with ALF due to Reye's syndrome also indicated possible recovery in subjects with absence of scalp SSEPs components (54). However, this study was performed in children and its applicability in adults is uncertain. Moreover, major signs of pontine involvement can also reflect a pre-existing, pontine damage (multiple sclerosis, posterior fossa tumour, etc.) which is prognostically irrelevant.
In the absence of any pre-existing pathology, a bilateral absence of N20 or BAEPs indicating structural pontine involvement provides firm evidence that the current neurological status of the patient is not just due to HE but that some secondary complication occurred (brainstem haemorrhage or brainstem lesions due to an increase in ICP). Although absent cortical SEPs indicate a particularly severe neuronal dysfunction, usually of an ominous prognosis, there is still some theoretical possibility that this situation may be reversible. Indeed, while there is now universal agreement that, in post-anoxic coma, a bilateral loss of N20 heralds death or vegetative state (54, 55), in head trauma a bilateral N20 loss after midbrain dysfunction has been associated with recovery in up to 15% of patients (56). An increase in ICP may cause bilateral loss of the N20 because of midbrain compression, thus interfering with subcortical conduction. Thus, even if unlikely, the possible reversibility should be investigated with imaging (computerized tomography scan or, if negative, magnetic resonance imaging or single photon emission computed tomography to recognize whether blood flow is still detectable). Noteworthy, such extreme alterations have never been described as a mere consequence of sedative drugs.
That is to say that the actual prognosis in this situation depends on its aetiology and pathophysiology, which must be sought before taking any positive or negative decision regarding transplantation.
Neurophysiological tools cannot be used in isolation to exclude consideration for liver transplantation. Even the bilateral absence of the N20 component of SSEPs is, in itself, not sufficient to exclude transplantation. However, it would be ethically unacceptable to offer transplantation to such a patient without further examination aimed at determining the irreversibility of the central nervous system compromise. B