Multimodality evoked potentials (auditory, somatosensory and motor) in coma

Neurophysiol Clin (1993) 23, 237-258 © Elsevier, Paris

237 Memoir

Multimodality evoked potentials (auditory, somatosensory and motor) in coma E Facco, M Munari, F Baratto, AU Behr, GP Giron Laboratory of Neurophysiology, Department o f Anesthesiology and Intensive Care, University o f Padua, Via C Battisti 26Z 35121 Padua, Italy (Received 25 February 1992; accepted 12 December 1992)

S u m m a r y - Auditory brainstem responses (ABRs) have proved to be significantly related to outcome, both in severe head injury and brain hemorrhage. Nevertheless, the usefulness o f A B R is limited by the anatomic extent of tile investigated pathways. The combined use of ABRs and somatosensory evoked potentials (SEPs) improves the outcome prediction in comparison to tile use o f only one modality. It mainly decreases the rate of false negatives, since patients with severe hemispheric damage sparing the brain stem m a y have a poor outcome despite normal ABRs. The use o f motor evoked potentials (MEPs) from magnetic transcranial stimulation is also significantly related to outcome: it appears to be far superior to tile clinical evaluation o f motor responses, while the combined use o f MEPs and SEPs gives a new opportunity o f checking sensorimotor dysfunction. ABRs and SEPs may also be useful tools in the confirmation of brain death, the kernel of which is the assessment o f brainstem death: they allow to check lemniscal pathways, which cannot be propedy evaluated by clinical examination, and provide an objective confirmation o f absence of brain stem activity. evoked potentials / c o m a R~sum~ - Potentiels ~voqu~s m u l t i m o d a u x (auditifs, somatosensorieis et moteurs) darts ie coma. Pendant les 10 dernikres annFes, les potentiels gvoquFs se sont rFvF1Fs un instrument utile darts l'~valuation de patients comateux. Les rFponses auditives du tronc cFrFbral (ABRs) sont un FlFment pronostique tant des comas traumatiques que des comas liFs ~ une hFmorragie cFrFbrale, dans la mesure o3 le pronostic dFpend souvent de l'existence d'une lFsion primaire ou secondaire du tronc cFrFbral. NFanmoins, l'utilitF des ABRs est limitFe par l'extension anatomique des structures explorFes. L'Fvaluation pronostique peut ~tre perfectionnFe par I'Ftude des potentiels FvoquFs multimodaux : les patients avec une IFsion hFmisphFrique grave qui gpargne le tronc cFrFbral peuvent avoir un pronostie dFfavorable malgrF des ABRs normales. L'usage combinF des ABRs et SEPs amFliore la visibilitF du rFsultat par rapport h l'usage d'une seule modal#F, en diminuant principalement le hombre de faux nFgatifs. L'usage des potentiels FvoquFs moteurs (MEPs) par la stimulation magnFtique transcr~nienne est Fgalement un dlgment pronostique: il semble ~tre supFrieur gt l'Fvaluation clinique des rFponses motrices, tandis que l'usage combinF de MEPs et SEPs permet d'explorer les troubles sensorimoteurs. ABRs et SEPs peuvent aussi ~tre des instruments utiles pour la confirmation de la mort cFrFbrale, en Fvaluant l' atteinte du tronc cFrFbral : ils permettent de contrOler les voies lemniscales qui ne peuvent ~tre FvaluFes par l'examen clinique, et ils donnent une confirmation objective de la mort du tronc cFrFbral. potentiels ~voqu~s ] coma

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Introduction

According to Frowein (1976), coma can be defined as an unrousable, unresponsive state, regardless of its duration, with eyes continuously closed. However, the term "unresponsiveness" may be misleading, as a variety of responses (eg motor, vegetative) can occur following painful stimulation: it should be regarded only as an absence of response to commands. The eyes closed distinguish coma from other states of reduced responsiveness such as akinetic mutism, aphasia, locked-in syndrome and persistent vegetative state. Coma may be caused by supratentorial and/or brainstem damage. The former usually comprises: a) diffuse grey or white matter lesions of both hemispheres; and b) mass lesions involving the diencephalon (directly or following tentorial herniation). The latter essentially consists of primary or secondary lesions of the braio~stem reticular formation. During the clinical course of coma, secondary neurological complications may occur, such as a rostrocandal evolution due to intracranial hypertension: these can dramatically increase morbidity and mortality when not timely detected and properly treated. Moreover, they can occur rather rapidly, even within minutes. Careful monitoring, able to recognize an impending deterioration before the point-of-no-return is reached, is therefore required. The aims of neurological monitoring in intensive care are essentially two-fold: a knowledge of site, extent and severity of brain damage; b) prognosis. These aspects are closely related, but prognosis strictly depends more on the capability of detecting the point-of-no-return. An early prognosis allows: a) to recognize "critical" patients requiring particular therapeutic regimens; and b) to speak more adequately with relatives, a sensitive domain, particularly in the case of young patients. Although the neurological examination remains the essential basis in the assessment of comatose patients, a variety of investigative techniques (such as CT scan, intracranial pressure, regional cerebral blood flow, EEG and evoked potentials) can improve the knowledge of neurological conditions. Among these, short latency evoked potentials appear to have many ideal features; in fact, they are non-invasive, manageable, easily recordable at the bedside and suitable for serial monitoring. Furthermore, being rarely affected by sedatives and anesthetics at therapeutic doses, they allow to check the functional status of the brain even when the clinical examination and EEG are no longer able to provide reliable information.

Technical r e m a r k s

A detailed description of methods of recordings, wave generators and physiological aspects of evoked potentials is beyond the scope of this paper: only a few remarks are essential here because of their implications in the evaluation of comatose patients.

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Auditory brainstem responses (ABRs) Intubated comatose patients may show changes in amplitude and absolute latency of wave I, due to pressure imbalance and/or fluid in the middle ear and conductive hearing loss (Stockard et al, 1978a), but the interpeak latencies (IPL) are not affected. Some lesions, such as hemotympanum and temporal bone fractures are not unfrequent in head injured patients, and may alter or cancel out the ABRs. When the waveforms are not clear, click polarity may be helpful to improve their quality: rarefaction allows a better definition of wave I, while condensation may improve wave V recording (Comacchia et al, 1980; Chiappa, 1990). Furthermore, when wave I is not clearly recognizable, the placement of a needle electrode in the anterior wall of the external auditory canal can enhance its amplitude (Chiappa, 1990). Among other non-pathological factors affecting the ABRs, worth mentioning are the following: a) hypothermia, which rises the IPL V-I at a rate of approximately 0.16 ms/°C (Stockard et al, 1978; Maugui~re et al, 1988); b) gender: in females the IPL V-I is about 0.2 ms shorter than in males (Comacchia et al, 1984): c) drugs: the ABRs are not significantly affected by sedatives and anesthetics at therapeutical doses (Stockard et al, 1978a; Bobbin et al, 1979; Rowe, 1981; Maugui~re, 1983; Bertoldi et al, 1983) and not even by barbiturate coma (Newlon et al, 1983). Nevertheless, the latter may yield a minor increase of latencies, at least partly due to body temperature decrease (Maugui~re, 1983). The most outstanding changes can occur following lidocaine-thiopental infusions (Garcia-Larrea et al, 1988; Maugui~re et al, 1988) or phenytoine administration at a dose of 20 mg/kg body weight (Maugui~re et al, 1984, 1988) and require much caution in the interpretation of ABRs.

Somatosensory evoked potentials (SEPs ) The most important aspect of the method is reference: in fact, only the non-cephalic reference allows to record both far-field and near-field potentials, unlike the frontal one. This aspect is of paramount importance in comatose patients, where the assessment of the level of dysfunction is essential in the evaluation of rostrocaudal evolution. The main limits of frontal reference are: a) impossibility of recording 1x) through N18 far-field components; b) the N13 recorded from the neck is, in fact, the algebraic sum of the "cervical" N13 and the far-field, scalp-recorded P13-14 (Desmedt, 1984; Iragui, 1984), precluding the evaluation of N13/P13-14 dissociation in brain death (Facco et al, 1990); and c) the frontal reference also distorts N20 and P23-27 waveforms, since they become the algebraic sum of parietal N20 and P23-27 with prerolandic P22 and frontal N30 (Maugui~re et al, 1987; Facco et al, 1990a). Despite its limits, the frontal reference has been used in most papers dealing with coma. In conclusion, when SEPs are to be recorded in comatose patients, the non-cephalic

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reference should be used; the earlobe contralateral to the stimulated site can also be used, when the cancellation of N18 is desirable, such as in SEPs mapping (see Facco et al, 1990a for further details). Like the ABRs, the SEPs may be affected by some non-neurological factors: a) Gender: shorter latencies of N13 and N20 are present in females, but the N13-N20 interval is not significantly affected (Chu, 1986); b) body temperature: the temperature of the arm may affect the absolute latencies of the waves, changing the conduction velocity of peripheral nerves, but the central conduction time (CCT) is less affected. A decrease of N13-N20 interval equal to 0.18 ms/°C of body temperature has been observed during hyperthermia (Matthews et al, 1979), while the reverse occurs during hypothermia; thus, body temperature should be taken into account when predictions are made for patients with marked hyper- or hypothermia; and c) drugs: short latency SEPs are only slightly affected by sedatives and anesthetics (McPherson et al, 1985). Barbiturate coma does not significantly affect the central conduction time in the cat (Sutton et al, 1982); conversely, in man the infusion of thiopental at a rate of 1.25 mg/kg/min significantly increases the N13-N20 interval: after 1 h of infusion the mean N13-N20 interval appears to be some 2 ms higher than the basal value (Drummond et al, 1985). Motor evoked potentials (MEPs) MEPs may be obtained following both electric and magnetic stimulation and it is well known that the two methods do not give exactly the same results. There is now evidence that the former yields a direct discharge, while the latter results in an indirect discharge (Hess et al, 1987; Amassian et al, 1989), unless an appropriate orientation of the coil is used (Amassian et al, 1989). Thus, both the stimulated structures and the latencies of waves are not the same: as a consequence, studies on electrical MEPs are not directly comparable with those on magnetic MEPs and results might be quite different. When coma is concerned, a critical aspect is ho~v to obtain facilitation: patients are "unresponsive" and cannot obey commands; nevertheless it is probably an important manoeuvre for the following reasons: a) facilitation makes the delivered stimulus more effective, and this may be of importance when cortical excitability is decreased: in some cases the stimulus may not be strong enough to excite the motor cortex even when maximal stimulator output is used and the MEPs may be obtained only with facilitation; b) comatose patients may have different degrees of spontaneous muscular tone (from flaccidity to hypertonus): this might yield a sort of ,spontaneous" facilitation, which can change intensity from patient to patient and can even vary in intensity in the same patient during the clinical course. There is some evidence that maximal facilitation in awake subjects occurs with less than 5% of maximal voluntary contraction (see Chiappa, 1990) and starts prior to voluntary movement (Starr et al, 1988), therefore, MEPs in comatose patients might be to some extent facilitated even with no apparent contraction of the target muscle. If

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this is true, a routine use of facilitation should be recommended to obtain only the shortest latencies, thus decreasing their variability. The last factor of variability is the position of the coil during cervical stimulation, which can affect the exact point of spinal root stimulation, but this seems to imply changes of central motor conduction time less than 0°5 ms (Facco et al, 1991). As voluntary contraction is obviously impracticable in comatose patients, alternative methods must be used, such as tonic vibration at a frequency of 30-80 Hz or double stimulation with proper interstimulus interval (Rossini et al, 1987); however, vibration may partly inhibit the response decreasing the MEPs amplitude. A simpler, although rougher, and more "clinical" method of facilitation has been recently tried in a study on MEPs following magnetic stimulation in coma (Facco et al, 1991): it consists of delivering a painful stimulus (the same used for clinical evaluation of motor responses) just before each magnetic stimulus; the latter must be delivered during the motor response (fig 1). This method is far from ideal, but is very simple. always available and to our experience appears to be effective (Facco et al, 1991). Its main limits and pitfalls may depend upon: a) possible habituation of motor response to painful stimuli (although empirically it does not appear to be so relevant); b) possible latency changes due to variations of the level of facilitation achieved in each motor response, the latter not being standardizable; and c) the virtual incapability of obtaining facilitation in deep coma with absent motor response; however, it concerns mainly preterminal and terminal patients with a Glasgow Coma Score equal to 3, while in all other patients, included decerebrated ones, a motor response to painful stimuli is generally present. The relationship between MEPs and sedatives, anesthetics, toxic or metabolic factors able to decrease cortical excitability is not yet well understood; furthermore, we sometimes found a reversible conduction block of pyramidal tracts following brainstem ischemia (Facco et al, 1989) or appearance of MEPs only with facilitation, despite the use of maximal stimulator output (Facco et al, 1991). Thus, absent MEPs in a comatose patient should not be considered as an unerring sign of poor outcome and great caution should be used in their interpretation.

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Evoked potentials in post-traumatic coma One important advantage of short latency evoked potentials in the operating room and the intensive care unit is the possibility of checking the functional status of the explored pathways even when the clinical examination is not reliable. Among coma states of different aetiologies, severe head injury has been the most extensively studied (for review, see Chiappa et al, 1990; Facco et al, 1990). In 1978, Uziel and Benezech reported a close relationship between ABRs and anatomic or functional level of coma, where ABRs abnormalities correlated with abnormalities o f brain stem reflexes and prognosis, but not with posture; we obtained similar results in cases of severe head injury (Martini et al, 1984). Likewise, we never found any relation between ABRs, SEPs and the Glasgow Coma Scale, the latter being a far less accurate predictor of the outcome (Martini et al, 1984; Facco et al, 1990a, 1991a). Also, MEPs appear to be more reliable indicators of both motor impairment and prognosis than the clinical data (Facco et al, 1991). As far as prognosis is concerned, the most widely used ABR parameters used for early outcome prediction are the IPL V-I, the amplitude ratio (AR) of wave V/I and the~absence of waves, butsometlmes even absolute amplitudes and latencies have been used. Unfortunately, ABRs gradings reported in the litterature are not homogeneous (Greenberg et al, 1977; Seales et al, 1979; Kamaze e t a l , 1982; MjCen et al, 1983; Anderson et al, 1984; Ottaviani et al, 1986; Cant et al, 1986; Fischer et al, 1988) and the different criteria make difficult, or even impossible, any comparison between series. Furthermore, some authors indicate abnormality as deviation from the mean value of their control sample without providing an exact number (MjOen et al, 1983; Anderson et al, 1984; Ottaviani et al, 1986; Cant et al, 1986; Fischer et al, 1988); however, in this case one can imagine that the threshold of abnormality for the IPL V - I would be around 4.50 ms, corresponding approximately to the mean plus 2.5-3 standard deviations of controls. This value is similar to the one reported by other authors (Karnaze et al, 1982; Martini et al, 1984; Facco et al, 1985, 1988). Further dyshomogeneities are present in methods, sucla as intensity and frequency of the stimulus, presence/absence of contralateral masking and the side taken into account (the "better" or "worse" side) forprognostic prediction. In general, the reliability of a method depends on its resolution power and grading of its abnormalities: when early prognosis is the aim, an arbitrary classification, performed a priori on a supposed hierarchical scale of degrees of abnormalities, may be misleading if it does not discriminate a reversible dysfunction from irreversible damage and might lead to underestimating the effectiveness of the method. Thus the contradictory results reported in the literature on ABR prognostic power might partly depend on different ABR gradings. We tried to work out an ABRs grading a posteriori, rather than a priori, checking the distribution curve of both IPL V-I and AR V/I in survivals and deaths and empirically looking for the critical value able to divide these two subpopulations (Martini et al, 1984; Facco et al, 1985, 1988, 1989, 1990b). We performed these studies on

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selected patients with no ear lesions and normal canal otomicroscopy in order to avoid the most important factors which make up unreliability of ABR; only clicks of alternate polarity were used to avoid method-related changes of wave amplitude. Other non-neurological factors were not taken into account since they yielded minor changes of the IPL V - I ; for example, hyperthermia might cause an IPL V - I decrease below 0.2 ms in most cases, since it was vigorously treated in our routine management protocol, while no severe hypothermia occurred in our patients, apart f r o m brain dead ones where rewarming was performed in order to diagnose brain death properly. Furthermore, our patients were neither under barbiturate c o m a nor showed severe organ failure which could significantly affect the evoked potentials at the time of testing. In our e x p e r i e n c e , the distribution c u r v e for I P L V - I in s u r v i v i n g patients appeared to be o f gaussian type: the chances of coming out f r o m post-traumatic coma drastically decrease when the IPL V - I exceeded 4.5 ms, a value corresponding to the mean plus 2 standard deviations of survivals (Facco et al, 1985). Likewise, the outcome worsened when AR V/I fell below 0.5 (fig 2), both in head injury and subarachnoidal hemorrhage, while the combined use of both parameters appeared to improve the early prognosis in comparison to the use of only one (Facco et al, 1989, 1990b). Furthermore, both ABRs grading and effectiveness were similar in children and adults (Munari et al, 1990). These results agree with those of K a m a z e et al (1982, 1985) w h o reported a decreased rate o f good o u t c o m e in patients with 4.5 < IPL V - I < 4.9 and/or decreased AR V/I and a poor prognosis in patients with more severe abnormalities of ABRs. Perhaps A B R effectiveness might be further improved taking into account temperature and gender, thus decreasing the main non-neurological factors of variability;

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however, we did not consider them in order to get a simpler grading and a simpler statistical analysis based on a binary division o f both ABR data (normal vs IPL V-I > 4.5 ms or AR V/I < 0.5) and outcome (survival vs death and persistent vegetative state), which were more suitable for small samples. Furthermore, the aim of our studies was the assessment of early prognosis in terms of risk, rather than absolute certainty, and our protocol appeared to be the best arrangement between simplicity and accuracy, although implying some unavoidable errors. In other words, the values of IPL V-I = 4.5 and AR V/I = 0.5 suggested are to be considered as the limits b e y o n d which the risk of poor o u t c o m e significantly increases, leading one to recognize critical patients requiring stronger therapeutic efforts: by definition, this grading purposefully implies the existence of a few 'false positives', whose falseness also depends upon the capability of successful treatment. Since in some cases it is very difficult, if not impossible, to obtain with absolute certainty the prognosis during the early stage, it looks more reasonable to speak in terms of risk, in order to avoid a negative therapeutic approach; this is the opposite of the unerring prediction of poor outcome, w h i c h would imply the withdrawal of treatment. In other quoted studies the ABRs prognostic accuracy was lower, mainly due to a higher rate of false negatives (ie patients with normal ABRs and poor outcome) (Greenberg et al, 1977a; Anderson et al, 1984; Cant et al, 1986; Fischer et al, 1988). These different results may depend on sample fluctuations, grading differences and test timing from the injury. Some patients may suffer neurological deterioration following ABR recording, increasing false negativity of very early predictions: the rate of false negatives seems to be lower when predictions are made between the 4th and 7th day post-injury (Seales et al, 1979; Facco et al, 1988). In fact, during this period secondary brain damage (eg development of brain edema, intracranial hypertension and brainstem dysfunction) usually reaches its peak and the highest rate of ABR positivity can be found. Later on, brain edema may decrease as a result of therapy and ABRs may progressively improve, although some patients remain vegetative despite ABRs normalization: this may depend on severe, irreversible supratentorial damage yielding a secondary, still reversible dysfunction of the brainstem (due to mass effect) 4 - 7 days post-injury. Two major ways of ABRs deterioration due to secondary brain damage can occur during the clinical course: a) simultaneous worsening of all waveforms; b) progressive deterioration from wave V to I (Maugui~re et al, 1988). The former depends upon brain ischemia, while the latter depends upon rostrocaudal evolution. However, there seems to be no close correlation between intracranial pressure and ABRs (Garcia-Larrea et al, 1988; Maugui~re et al, 1988). The limits of ABRs can at least be partly overcome by SEPs from upper limb stimulation. The capability of exploring a large part of the central nervous system makes SEPs more sensitive than ABRs to severe brain lesions not involving the ponline or mesencephalic level: for example, patients with severe hemispheric damage sparing the brainstem may have a poor outcome, despite completely normal ABRs.

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combined use of both modalities improves the outcome prediction in comparison to the use of only one modality (abnormal ABRs: IPL V-I > 4.5 ms, AR V/I < 0.5 or absent wave V; abnormal SEPs: N13-N20 > 8.0 ms or absent N20; GR, good recovery; MD, mild disability; SD, severe disability; PVS, persistent vegetative state; D, death). I

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In other words, SEPs may improve outcome prediction in comparison to the use of ABRs only being able to decrease false negatives. Many authors claimed that SEPs are far more reliable than ABRs (Greenberg et al, 1977a; Anderson et al, 1984; Cant et al, 1986); nevertheless, SEPs also imply a non-negligible rate of false negatives (Fischer et al, 1988; Facco et al, 1990a). The combined classification of ABRs and SEPs seems to decrease the rate of false predictions in comparison to the use of only one modality (Facco et al, 1990b; fig 3). SEPs mapping promises to improve further on the sensitivity and prognostic accuracy of SEPs, allowing to check prerolandic and frontal components: in fact, some patients may have a severe frontal damage sparing the somatosensory areas. In such cases, the conventional SEPs may be normal with normal CCT, whereas the N30 may be bilaterally lost: these patients are likely to remain severely disabled or vegetative, behaving as false negatives in conventional SEPs recordings and true positive in SEPs mapping (Facco et al, 1991a). Like the ABRs, the dyshomogeneity of SEPs gradings in the literature make any

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comparison between series difficult, although all of them generally consider ncreased CCT and absence of N20 as prognostic parameters' (see Facco et al, 1990 for review): in particular, it is not possible to define from published data whether a critical delay of C C T exists, which may discriminate between good and poor prognosis. We tried to check this point empirically, analysing the distribution of N 1 3 - N 2 0 interval in our patients in the same way we did for IPL V-I: a breakpoint between good and poor outcome appeared to lie at values of N13-N20 around 8 ms (Facco et al, 1990a; fig 4). It should be pointed out that this value is higher than the upper limit of normal estimated as mean plus 3 standard deviations, and may be checked only a posteriori looking at what concretely happens to the patients. A milder delay of CCT may of course be a good index of dysfunction, but it is a "reversible" one, and we must find the limit between reversible and irreversible brain damage if early prognosis is our aim. However, the data reported in the literature substantially agree on the reliability of SEPs, despite the different methods (most studies use a frontal reference) and gradings. The u s e of non-cephalic reference gives a clearer idea of

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both cortical and far-field components, improving the location o f brain damage (preor postrolandic or both, hemispheres and/or brain stem). In patients with absent N20, only the non-cephalic reference allows to check the P13-P14-N18 components, discriminating patients with preserved brain stem function from terminal ones; furthermore, it is essential in the confirmation of brain death (Facco et al, 1990). Although an increased CCT in ABRs and/or SEPs, or even bilateral absence o f N20, strongly suggests a severe brain dysfunction, one should be very cautions in predicting a poor outcome on the basis of a single recording performed in the early stage: some patients may undergo a progressive improvement with restoration of both the N20 and CCT and recover, if properly treated (Facco et al, 1990a), especially when the abnormalities of ABRs and/or SEPs depend upon secondary brain damage, such as brain edema and intracranial hypertension (fig 5). In other words, the irreversibility of secondary brain damage depends on both its severity and duration: therefore, single recordings in the early phase of clinical course should not be used to withdraw treatment, but, on the contrary, be used to recognize critical patients requiring stronger therapeutical efforts. As far as MEPs are concerned, only few data are so far available in the literature. MEPs from electrical stimulation do not appear to be related to the outcome (Zentncr and Ebner, 1988, 1988a; Nau et al, 1988). On the contrary, our experience using magnetic stimulation in coma is far more promising (Baratto et al, 1990; Facco et al, 1991): magnetic MEPs appear to be closely related to the outcome and seem to be more sensitive detectors of motor pathways dysfunction than the clinical evaluation. Figure 6 shows an increased motor CCT from thenar muscles in a serious head-injured patient with normal upper limb flexion. The combined use of SEPs and MEPs, allowing to check the sensorimotor function, can improve the outcome prediction in comparison to the use of only one modality. The main limit of magnetic MEPs is a more than negligible rate of both false negatives (likewise ABRs and SEPs) and false posifives; however, the latter will probably decrease with a routine use of facilitation, since it is often able to elicit normal MEPs in patients with good outcome and absent relaxed response (a representative case has been previously reported: see Facco et al, 1991).

Evoked potentials in cerebrovascular disorders ABRs and SEPs appear to improve the assessment of comatose patients following brain vascular disorders. The problems related to methods and grading are essentially the same as those already discussed with regard to head injury. Christianto and Lumenta (1984) reported a good correlation between the absolute amplitude and latencies of waves I, III, and V of ABRs and outcome in cerebral hemorrhage. Afterwards, Shigemori et al (1987), using a grading similar to the one reported by Greenberg et al (1977) in severe head injury, concluded that SEPs were more reliable than ABRs in hypertensive putaminal hemorrhage, mainly due to a lower rate of false negatives. However, the SEPs appear to be scarcely related to the

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clinical data, since Wang et al (1984) reported that the CCT was abnormal only in patients with grade IV according to Hunt and Hess (1968). In patients submitted to surgery, the data are controversial: Wang et al (1984) reported that SEPs were significantly related to the outcome, both in the pre- and postoperative period, while Jarratt et al (1985) did not find any correlation between preoperative CCT and outcome. Our data suggest a high predictive power of both ABRs and SEPs in coma following cerebral hemorrhage (Facco et al, 1989): the distribution curves in survivals and deaths for both IPL V - I and AR V/I are similar to those of head-injured patients, showing that the same grading can be used in both diseases; as far as SEPs abnormalities are concemed, we did not find N13-N20 increases in our sample, unlike head injury, and the only patterns observed were a normal SEPs or absent N20. In vertebrobasilar occlusion, the main ABRs changes are" a) increased latency and/or decreased amplitude of waves IV-V; b) increased IPL III-I; c) presence of only wave I or absent response (Oh et al, 1981; Hammond et al, 1985; Kaji et al, 1985; Towle et al, 1985; Ferbert et al, 1988). These abnormalities seem to reflect lesions ipsilateral to the stimulated ear (Oh et al, 1981; Hammond et al, 1985). A serial monitoring is important especially in patients with absent response, which may depend on a transient cochlear ischemia (Kaji et al, 1985). None of our patients with absent I V - V waves came out of coma (unpublished data), while in locked-in syndrome we found normal ABRs and SEPs with severely abnormal MEPs (Facco et al, 1989a); in the early stage, evoked potentials may allow a clear diagnosis when the CT scan is still silent. Moreover, the combined use of ABRs, SEPs and MEPs may be helpful in the localization of brain stem damage: in fact, the presence of normal ABRs and SEPs with abnormal MEPs shows that the ischemia involves only the ventral brain stem, while the absence of I V - V waves shows mesencephalic lesions. More recently we observed a patient with left hemipares~s and normal CT scan and MRI (unpublished data): ABRs were normal, while MEPs from left thenar muscles were absent and SEPs from left median nerve showed the absence of P14, N18 and N20 components, suggesting a lesion in the caudal brain stem. The MRI was able to detect an ischemic lesion at this level only 2 weeks later'.

E v o k e d potentials in postanoxic c o m a

qhe reversibility of coma following cardiac arrest can often be checked with the clinical evaluation, since it has been reported that patients who improve, do so in a lew days after the insult (Eamest et al, 1979; Snyder et al, 1980, 198] ). 'Ihe brain stem is notably more resistant to anoxia than the cortex and, therefore~ can be preserved even when severe cortical damage has occurred: from an anatomical point of view, the picture consists of a cortical laminar necrosis (Dougher~T et aL 1981). As a consequence, a good prognostic accuracy of SEPs can be expected, but no! of ABRs. Several data are reported in the literature on postanoxic coma (Goitein et al, 1983; Yagi and Baba, 1983; Brewer and Resnick, 1984; Marcus and Stone, 1984; Brunko

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F i g 7. ABRs and SEPs from median nerve in a child with postanoxic coma: ABRs were normal throughout the clinical course, while the SEPs showed bilateral absence o f N20 on the first hospital day and no i m p r o v e m e n t o n s u b s e q u e n t recordings; the patient remained vegetative.

et al, 1985; Rappaport et al, 1985; Walser et al, 1985; Ganes and Lundar, 1988; Ganji et al, 1988); however, most of them comprehend coma states of different etiologies, often making it hard to extrapolate those regarding postanoxic coma from the others. Rossini et al (1982) reported a case of cardiac arrest which occurred during ABR recording, where a progressive decrease of wave amplitude up to flattening was recorded during the phase of circulatory arrest. After resuscitation the waves quickly reappeared, but with persistent delay of III and V and increased IPL V-I; the patient died a few days later. As expected, ABRs have proved to be unreliable prognostic indicators in children (Rappaport et al, 1985); m o r e o v e r , ABRs are seldom absent due to cochlear ischemia, precluding any evaluation of brainstem damage (Brunko et al, 1985). A representative case of post-anoxic coma in a child is shown in figure 7: the ABRs were normal, while no cortical components were present in SEPs recorded 12 h after the insult; this picture remained unchanged throughout the clinical course and the patient remained vegetative. Walser et aI (1985) reported a significant correlation between SEPs and outcome: the amplitude of cortical components appeared to be a better prognostic determinant than the CCT, the former being more closely related to cortical function. Although SEPs are more accurate prognostic indicators than ABRs, Marcus and Stone (1984) reported that only some 20% of patients with preserved N20 came out of coma. In conclusion, ABRs can only predict a poor outcome when abnormal, but this event is not so frequent, considering the pathophysiology of anoxia. SEPs are far more suitable, but the data in the literature often do not allow to check their effectiveness~ the data of anoxic patients being intermingled with those of other diseases. Although ABRs are hardly effective, the combined ABRs and SEPs data are highly predictive oi persistent vegetative state when the picture retx)rted in figure 7 is observed.

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Evoked potentials in brain death Since the kernel of brain death is the diagnosis of the death o f the brainstem (Jennett and Teasdale, 1981; Pallis, 1982; Facco and Giron, 1988), short latency evoked potentials are good candidates for its confirmation. In fact, they have many useful features: a) they allow a direct and objective functional evaluation of the brain stem; b) they are not roughly affected by drugs, toxic and metabolic factors which make both the EEG and clinical evaluation unreliable; c) they allow t ° explore the brain, stem even in patients with peripheral lesion of the eyes in whom the brainstem reflexes cannot be elicited (such as in craniofacial trauma); and) they are noninvasive and easily recorded at the patient's bedside. A wealth of data allows us to evaluate the role of ABRs and SEPs in the diagnosis of brain death (Trojaborg and Jorgensen, 1973; Starr, 1976; Anziska and Cracco, 1980; Goldie et al, 1981; Maugui~re et al, 1982; Ganes a n d N a k s t a d , 1984; Dear and Godfrey, 1985; Steinhart and Weiss, 1985; Belsh and Chokroverty, 1987; Garcia-Larrea et al, 1987; Facco et al, 1988a; Ganes and Lundar, 1988; Facco et al, 1990; Machado et al, 1991). ABRs are absent in some 70% of cases, while in the others, wave I is still present (fig 8). The absence of wave I depends upon cochlear ischemia due to the arrest of cerebral circulation, the ear being supplied by posterior intracranial circulation (Braunstein et al, 1978; Kricheff et al, 1978). Although in brain death, absent ABRs usually are, as a matter of fact, a sign of arrest of cerebra[ circulation, paradoxically they cannot show the death of the brainstem but only the damage of the ear: one cannot mle out a preserved brainstem function (Brunko et al, 1985; Maugui~re et al, 1988). The absence of wave I in most brain dead patients led many authors to assign a limited value to ABRs; however this limit may be overcome by serial monitoring during preterminal states, thus showing the progressive disappearance of waves (Garcia-Larrea et al, 1987). On the contrary, ABRs retain all their value in the exclusion of false positives (when peripheral lesions of the ear are excluded), since in patients appearing to be brain dead due to sedation', hypothermia or unknown toxic or metabolic factors, the waves are preserved. SEPs are far more reliable than ABRs, with the cervical N9-N13 present in most, if not all patients. There are two SEP patterns of brain death: a) absence of components following P13; b) dissociation N13/P13 (namely, preserved cervical N13 with absent far-field scalp-recorded P13-14; fig 8). The latter is the most paradigmatic picture of brainstem death, clearly showing the arrest of conduction at the cervicomedullary junction, and is present in some 50% of cases (Facco et al, 1990). The former shows a residual activity in the lower brain stem, but this does not seem to contradict the concept of death of brainstem as a functional unit; in fact, the persistence of P13 in some 50% of cases probably reflects the preservation of cervicomedullary junction observed on autopsy in 57% of brain dead patients by Walker et al (1975). The exclusion of cervical spinal cord lesions is of paramount importance, since these may yield a dissociation N13/P13-14 (Maugui~re et al, 1983). It is worth

Evoked potentials in coma

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sence of wave I only. B) Absence of ABRs response. C) Dissociation of N13/P13 (namely, preserved cervical N13 and absent far-field P13) in SEPs recording.

remarking once again that the use o f a non-cephalic reference is essential, otherwise patients with preserved brain stem function (absent N20 and present N18, like the case s h o w n in figure 7) cannot be discriminated f r o m dead ones. In conclusion: a) A B R s m a y confirm the diagnosis of brain death only in a minority o f cases, unless serial monitoring is performed in preterminal states, whereas SEPs are able to do it in most, if not all, cases; b) A B R s , although less reliable,keep all their value in the exclusion o f false positives; c) A B R s and SEPs allow to check brainstem function w h e n lesion o f the eyes prevents the evaluation o f brain stem reflexes; and d) A B R s and SEPs allow a direct, objective c o n f i r m a t i o n o f brain death a n d m a y i m p r o v e the s a f e t y o f d i a g n o s i s , since t h e y s e l d o m d i s c l o s e a preserved brainstem function in clinically brain dead patients (Anziska and Cracco, 1980; F a c c o et al 1988a).

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