301
Neurophysiol Clin (1991) 21, 301-311 © Elsevier, Paris
Revue
Sensory evoked potentials in herpes simplex encephalitis U Aguglia 1., G Farnarier 2, A Gambardella 1, A
Quattrone 1
1Clinica Neurologica, Facoltgt di Medicina, Catanzaro, Italy; 2Service d'Exploration Fonctionnelle du Systbme Nerveux CHU Timone, Marseille, France (Received 13 December 1990; accepted 28 July 1991)
Summary - Flash visual potentials (FEPs), somatosensory evoked potentials (SEPs) and auditory brain-
stem responses (ABR) were recorded in a 66-year-old patient presenting with clinical, EEG and CT brain scan features of herpes simplex encephalitis (HSE). At the time of evoked potential study (10 days after onset of the disease) the patient was treated with iv barbiturate on controlled respiration (lidocaine and phenytoin were not utilized) ; core temperature was 37°C and pupils were dilated and nonreactive. Cortical FEPs were not recognizable on 02 lead, whereas they were clearly evident on 01 with normal latency of early N1, P 1, N2 waves and delayed P2 component. SEPs showed normal peripheral and central conduction times, but N20 peak was bilaterally absent with unrecognizable (on P3) or delayed (on P4) N33 wave. No ABR (including wave I) were found on stimulation of the right ear, whereas delayed wave V with prolonged interpeak I - V latency was found on stimulation of the left ear. In conclusion, changes in sensory evoked potentials in HSE seem to be caused either by necrotic-hemorrhagic damage (with the disappearance of some cortical responses), by coma (with alterations in middle-latency cortical responses) and by increased intracranial pressure (with subsequent ABR abnormalities). sensory evoked potentials / herpes encephalitis
R~sum~ - Potentiels 6voqu6s sensoriels dans I'enc~phalite herp~tique (~ propos d'un cas). Les auteurs
rapportent les donndes des potentiels dvoquds multimodaux (visuels par flash: PEV, somesthdsiques par stimulation du nerf mddian : SEPs et auditifs prdcoces : ABR) qui ont ~t6 enregistrds chez un malade agd de 66 ans prdsentant un tableau clinique, EEG et scanographique d'encdphafite herpdtique (HSE). Le jour de l'enregistrement (JlO du d6but de la maladie) le patient dtait en coma barbiturique (sans lidocaine ni phenytoine), sous respiration contr6lde, en mydriase ardactive avec une tempdrature de 37°C. Les enregistrements des potentiels dvoquds ont donnd les rdsultats suivants : les rdponses visuelles corticales dtaient absentes sur la r~gion occipitale droite (02), tandis qu'elles dtaient bien structurdes avec des rdponses prdcoces (N1, P1 et N2) normales et une composante tardive (P2) retardde sur la rdgion occipitale gauche (01); les SEPs dtaient caract~risds par des r6ponses NIO et N13 de latence normale, alors que
* Clinica Neurologica, Policlinico Materdomini, Via Campanella, 88100 Catanzaro, Italy.
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la composante corticale N 2 0 dtait absente sur P3 et P4 et la eomposante ?433 dtait absente sur P4 et retardde sur P3 ; les A B R par stimulation de l'oreille droite dtaient absentes, les A B R par s~mulation de l'oreille gauche montraient un temps de conduction I - V allongd. En conclusion, les altdrations des potentiels dvoquds sensoriels clans I'HSE semblent dues ~t des ldsions ndcrosantes et hdmorragiques eortieo-souseorticales (avec disparition de certaines rdponses corticales), gt l'dtat de coma (avee altdration des composantes corticales de latence moyenne), ainsi qu'~ l'augmentation de la pression intracr~nienne (avec abolition e t / o u altdration des ABR).
potentiels ~voqu~s sensoriels / enc~phalite herp~tique
Introduction
Herpes simplex virus type 1 causes acute necrotizing encephalitis (HSE) with edema, necrosis and hemorrhage that selectively affects temporal and frontal lobes. EEG and MRI are the most sensitive non-invasive tests in early diagnosis of HSE (Schroth e t al, 1987 ; Loi and Gragasin, 1988). Sensory symptoms are not prominent in HSE. Sensory evoked potentials have been shown to be of use in demonstrating nonapparent sensory system abnormalities in patients with different central nervous system (CNS) diseases (Chiappa, 1990), including subacute encephalopathies (Aguglia e t al, 1989, 1990a, b). As far as we know, no evoked potential studies have been performed in patients suffering from HSE. In the present study, flash visual potentials (FEPs), somatosensory evoked potentials (SEPs) and auditory brainstem responses (ABR) have been recorded in a patient with HSE.
Case record
The patient, a 66-year-old right-handed male, had a past medical history of atherosclerotic heart disease, left ventricular myocardial infarction, essential arterial hypertension and bilateral atherosclerotic retinopathy with left retinal detachment. He presented with a 4-day history of bifrontal headache, fatigue, fever (38°C) and weakness of the left limbs. On the day of admission the patient was confused and somnolent with motor seizures involving both limbs on the left side associated with twitching of various parts of the body (mouth, left shoulder, left hand and foot). Visual field examination was not possible. Temperature was 40°C, blood pressure 190/110 and pulse 98/min. Routine laboratory testing revealed leucocytosis (28.000/mm 3) with lymphocytosis (56%0), increased erythrocyte sedimentation rate (80 mms, 1st h) and serum creatinine level (1.6 mg/dl), whereas serum electrolytes, calcium, phosphorus, liver enzymes and urinalysis were normal. Blood and urine cultures were negative. Cerebrospinal fluid (CSF) examination revealed an opening pressure of 250 mm water, with 17 leucocytes/ram 3 (58% polymorphonuclear cells, 26% lymphocytes, 16% monocytes), 20 erythrocytes/mm3, protein 58 mg/dl and glucose 82 mg/dl. Gram stain, acid fast stain and bacterial cultures were negative. CSF herpex simplex and varicella zoster viral titers were negative. Electrocardiogram revealed an old left ventricular infarction. The EEG showed continuous polymorphous delta activity of low amplitude in the right hemisphere associated with periodic sharp complexes occurring at 1.5 to 2.5-s intervals on P4; theta-delta activity with
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sporadic sharp waves was also recorded on P3. Myoclonic jerks recorded on the left deltoid muscle had no correlation with the periodic EEG complexes (fig 1). CT brain scan examination revealed bilateral hypodensities with contrast enhancement in the lenticular nuclei, external capsules and occipital lobes and a large hypodense area with contrast enhancement on the basal side of the right temporal lobe. At the time of the evoked potential study (day 10) the patient was treated with continuous iv injection of barbiturate (neither phenytoin nor lidocaine were utilised), on controlled respiration, the core temperature was 37°C, the pupils were dilated and non-reactive. Intracranial pressure and EEG were not monitored. The patient died on day 12. At post-mortem examination the temporal lobes appeared soft and swollen. In the right temporal lobe the necrotic tissue was haemorrhagic. The haematoma also involved the insula, capsula externa and occipital lobe of the right hemisphere. The brainstem was not examined. Microscopic examination showed rarefaction necrosis associated with microglial proliferation and sheets of lipid phagocytes and abundant lymphocytes and plasma cells in the meninges and around the vessels.
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I
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Fig 1. EEG at admission (4 days after onset of the disease). Note continuous polymorphous delta activity of low amplitude in the right hemisphere associated with periodic sharp complexes occurring at 1.5 to 2.5-s intervals on P4. Note also theta-delta activity with sporadic sharp waves on P3. Myoclonic jerks recorded on the left deltoid muscle had no correlation with the periodic EEG complexes.
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Reactive changes were particularly intense immediately adjacent to the pia. These microscopic changes involved the temporal, parietal and occipital cortex, but did not affect the Gennari strip of the left calcarine cortex.
Evoked potential studies Recordings were performed at day 10 in a supine position either in darkness (FEPs and ERGs) or in a dimly-lit r o o m (ABR and SEPs). Surface silver chloride electrodes were utilized. Electrode impedance was kept < 5K13, usually below 3KD. At least 2 different trials were carried out to ensure response reproducibility. Results were analyzed in an off-line session and peak latencies were measured in ms using a cursor with digital display; amplitudes were measured in ~zV. The identified waveforms were traced by an X - Y plotter. Waves were labeled following guidelines of the American Electroencephalographic Society (1986) apart from the FEPs whose components were labeled according to Wright et al (1984), Katz et al (1989) and Aguglia et al (1991). Latencies of early (N1, P1, N2) and late (P2 and following) F E P components, latencies of ABR I - V and latencies of subcortical (N9, N13) and cortical (N20, P25, N33) SEPs were measured. The following amplitudes were considered : amplitude of the E R G b wave (from the first negative peak to the following large positive event), total FEP amplitude (from the higher negative peak to the lower positive trough), cortical SEP amplitudes (from the peak to the preceding wave) and ABR I / V amplitude ratio. As regards visual potentials, surface electrodes were placed on the inferior eyelids (ERG), 01, 02 (FEPs) and referred to linked earlobes. A ground electrode was applied to the forehead. Bilateral eye stimulation was performed. A flash stimulus of 0.35 J and 200 bts duration was produced once per s by a photostimulator placed 1 0 - 15 cm in front of the subject. One hundred and twenty-eight sweeps were averaged on 200 ms base-time. Bandpass was 1 . 0 - 2 5 0 Hz, with automatic artifact reject on. As regards SEPs, surface electrodes were placed on both ERB points (EP), earlobes, posterior midline neck over the CVII spinous process (CVII), on FZ, P3 and P4. The following montages on 3 channels were utilized : homolateral EP - contralateral EP, C V I I - contralateral earlobe, contralateral c o r t e x - F Z . The ground electrode was placed _-5 cm proximal to a bipolar stimulator which was located over the median nerve 1 cm above the wrist crease with a proximally oriented cathode. Left and right median nerve stimulation was performed separately. Electrical stimuli consisting of square pulses of 0.2 ms duration were delivered at 5 c/s. The intensity of electrical stimulation was adjusted to produce a minimal twitch of the thumb. Bandpass was 20 - 1.5 kHz, with an analysis time of 50 ms. A minimum o f 250 responses was required to obtain a reliable average with artifact reject on. As regards ABR, electrodes were attached at CZ and the earlobes, with FZ serving as a ground. Stimuli consisted of 100-dB H L clicks of alternating polarity at a rate
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305
of 10.2/s, presented monoaurally through earphones. A masking white noise (45 dB HL) was delivered to the unstimulated ear. Bandpass was 1 0 0 - 3 000; a minimum of 2048 clicks were averaged; time analysis was 10 ms. The control group consisted of 15 healthy subjects (9 females and 6 males), ranging in age from 45 - 69 years (mean 60 _+ 10 SD). The evoked responses were considered abnormal when values exceeded the upper normal limits (mean _+ 2 SD).
3O
R-ERG
I
L-ERG
7o
V 20
ms
01
63
I 180 Fig 2. Flash-evoked potentials by bilateral eye stimulation. Note delayed wave a on both eyes, unrecognizable cortical response on 02, well structured early components (N1, P1, N2) with delayed P2 component on 01.
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Results E R G s o f t h e p a t i e n t s h o w e d a b n o r m a l i t i e s in b o t h eyes : p r o l o n g e d l a t e n c y o f w a v e a, s m a l l a m p l i t u d e o f w a v e b, w i t h i n c r e a s e d l a t e n c y o f w a v e b in t h e left eye (fig 2 ; t a b l e I). C o r t i c a l F E P s w e r e o f s m a l l a m p l i t u d e a n d u n r e c o g n i z a b l e o n 02 l e a d , w h e r e a s t h e y w e r e c l e a r l y e v i d e n t o n 01 : t o t a l F E P a m p l i t u d e was 1 6 . 9 / z V , l a t e n c y o f t h e e a r l y w a v e s N1 P1 N 2 w e r e w i t h i n n o r m a l l i m i t s a n d t h e l a t e F E P c o m p o n e n t s c o n s i s t e d o f a d e l a y e d P 2 w a v e at 180 m s (fig 2 ; t a b l e I).
Table I. Values of sensory evoked potentials in one patient with herpes simplex encephalitis and in controls. Patient ERG
Wave a lat Wave b lat Wave b ampl
(ms) (ms) ~V)
JEEPs
(ms) (ms) (ms) (ms) ~V)
SEPs
N10 lat N13 lat N20 lat P25 lat N33 lat N10-N13 NI3-N20 N13-P25 P25 N33
R-Eye
L-Eye
30.0 48.0 8.4
31.0 70.0 9.8
02
N1 lat P1 lat N2 lat P2 lat Total ampl
(ms) (ms) (ms) (ms) (ms) lat (ms) lat (ms) lat (ms) ampl (#V) ampl ~V)
ABR
Wave I lat Wave II lat Wave III lat Wave IV lat Wave V lat I-V lat I/V ratio
(ms) (ms) (ms) (ms) (ms) (ms) ~V)
Controls: mean (SD)
? ? ? ? 1.8
O1
L-Med
10.2 13.1 ? ? 2.9 ? 12.4 6.7 ?
10.0 12.8 ? 25.0 43.0 2.8 ,.9 12.2 8.2 8.4
R-Ear
L-Ear
? ? ? ? ? ? ?
02
47.5 63.0 109.0 180.0 16.9
R-Med
25.5
R-Eye
19.6 (2.0) 42.0 (5.8) 39.5 (14.2)
1,5 ? ? ? 7.6 6.1 0.4
47.2 73.0 100.3 133.2 10.6
(6.5) (5.2) (11.2) (16.7) (4.0)
R-Med
',
10.0 13.5 19.0 25.0 35.0 3.5 5.5 11.5 5.4 4.6
(0.6) (0.7) (1.0) (1.6) (3.2) (0.5) (0.7) (1.3) (2.6) (3.8)
R-Ear
1,7 2.8 3.7 5.1 5,7 4.0 0,3
(0.2) (0.2) (0.2) (0.3) (0.2) (0.2) (0.2)
L-Eye
19.9 (2.2) 43.0 (6.0) 37.9 (13.8) 01
46.7 70.5 100.2 128.8 12.3
(8.4) (6.0) (10.8) (14.8) (4.5)
L-Med
9.8 13.6 19.1 25.2 34.8 3.6 5.5 11.6 5.6 4.2
(0.7) (0.7) (1.0) (1.7) (3.0) (0.6) (0.7) (1.5) (3.0) (3.5)
L-Ear
1.7 2.7 3.5 5.1 5.6 3.9 0.4
(0.2) (0.2) (0.2) (0.3) (0.3) (0.2) (0.2)
ERG: electroretinograms ; FEP : flash-evoked visual potentials ; SEP : somatosensory evoked potentials ; ABR: auditory brainstem responses; Med: median nerve stimulation (R: right, L; left).
A
EP in herpes simplex encephalitis
~~
p
Z 5.91 ~
-
F
307
43
Z
5ms CVII-AI 12.8
25
B
19.6
_
?
~
/
10.2 Fig 3. Somatosensory evoked potentials by stimulation of median nerves. A and B : left and right median nerve stimulation, respectively. Note important abnormalities in cortical responses: 19.5 and 19.6 denote the hypothetic latencies of N20 peaks that are actually absent on both sides (A and B); the N33 wave is delayed (A) and unrecognizable (B).
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SEPs showed normal peripheral and cervical potentials with normal interpeak latencies N10-N13 and N13-P25 (table I). Significant abnormalities were found at the cortical level: lack of N20 peak (on both P3 and P4 leads), as well as unrecognizable (on P3) and delayed (on P4) N33 wave. Only a clearly evident positive wave was recorded with a latency of 25 and 25.5 ms on P4-FZ and P3-FZ montages, respectively (fig 3). No ABR (including wave I) were found on stimulation of the right ear, whereas unrecognizable waves II, III, IV with delayed wave V and prolonged interpeak I - V latency were found on stimulation of the left ear (fig 4; table I).
Discussion and conclusion Although in this study no immunologic a n d / o r virologic investigations were carried out (on serum, L C R a n d / o r brain) evidencing an HSE viral infection, the clinical, EEG, CT brain scan and pathologic examination were consistent with the diagnosis of HVE (Blackwood and Corsellis, 1976; Schroth et al, 1987 ; Lai and Gragasin, 1988). Flash-evoked potential studies revealed pathological ERG, mostly on the left eye, which was probably related to the past history of bilateral retinopathy and left retinal detachment. Extinction of the cortical visual responses on 02 was consistent with the h e m a t o m a destroying the right temporal lobe (ie geniculostriate radiations) and occipital cortex. Cortical visual responses recorded on 01 showed normal latency of the early waves and delayed latency of the late components. Similar alterations have also been described in patients presenting with c o m a (Rodin et al, 1985) or severe dementia (Aguglia et al, 1989, 1990, 1991). According to recent neurophysiological studies (Aguglia et al, 1991), early F E P waves should be generated in layer IV (Gen-
G,M.
66 y e s
1.5
7.6
CZ-A1
1 mS CZ-A2
Fig 4. Auditory brainstem responses by stimulation of left ear. Note presence of wave I on homolateral montage (CZ-A1) and delayed wave V on both homolateral (CZ-A1) and contralateral (CZ-A2)montages.
EP in herpes simplex encephalitis
309
nari's strip) of the striate cortex by activation of geniculostriate input, whereas late FEP components would be generated in the extrastriate cortex. If this is the case, then in our patient there should be functional preservation of either the geniculocalcarine pathway and Gennari's strip in the left hemisphere associated with impairment of the extrastriate visual cortex. SEP studies showed no abnormalities in subcortical sensory pathways and significant alterations in cortical responses. Firstly, the lack of N20 peak requires consideration. Abolition of parietal N20-P25 components, but preservation of frontal N30 wave have been recorded in patients with complete parietal lesions (Maugui~re et al, 1983). Unfortunately, because of the bipolar parietal-frontal montage, we were unable to differentiate the parietal P25 wave from the frontal N30 component. Therefore, it could not be excluded that the parietal positive wave had a negative contribution from the frontal lead (N30 component). If this had been the case, then our patient would have had bilateral lack of both N20 and P25 waves with preservation of N30 components, ie a massive bilateral parietal lesion. Nonetheless, the pathologicals study failed to show significant necrotic changes or destructive lesions in the parietal lobes (only minor microscopic changes were found in the subpial cortical layers). Some authors (Synek e t a l , 1988; Sinek and Trubuhovich, 1991) have stressed the malignant significance of cortical SEPs characterized by a single, clearly evident positive wave with a virtually absent N20 peak on contralateral p a r i e t a l - f r o n t a l montage. These authors hypothesized that the scalp potentials recorded in these patients represent thalamic activity that becomes recordable at the scalp level in the absence of potentials from the sensory cortex due to severe cortical a n d / o r subcortical lesions leading to functional suppression o f the somatosensory cortex. We are unable to confirm such a hypothesis, but can we confirm that this kind of cortical SEP signifies a malignant outcome. Finally, alterations in middlelatency (N33) components were observed. There is evidence that middle-latency SEP components are generated primarily through corticocortical and transcortical conduction (Stohr et al, 1983 ; Yamada et al, 1983). Alterations in middle-latency SEP components have also been observed in patients with phenobarbital coma (Newlon et al, 1983), dysmetabolic (Chu and Yang, 1988) or subacute spongiform (Aguglia et al, 1989, 1990) encephalopathies, thus suggesting a non-specific alteration of the cerebral cortical function in our patient. ABR studies by stimulation of the right ear revealed no recognizable response including wave I, thus suggesting a peripheral hearing loss on the right side. Stimulation of the left ear produced evident I and V waves with increased I - V interpeak latency: this alteration indicated dysfunction in the auditory nerve and/or in the lateral pons (Picton, 1986). Transient prolongation of I - V interpeak latency or abolition of ABR has been recorded in comatose patients treated with lidocaine (Garcia-Larrea et al, 1988) as well as in patients presenting with phenytoin intoxication (Hirose et al, 1986). Nonetheless, neither lidocaine nor phenytoin were given to the patient described in this study. It is well known that increased intracranial pressure may interfere with the eighth nerve and cochlear blood supply and provoke alterations in
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ABR, including absence of response (including wave I) or prolongation of I - V interpeak latency (Stone et al, 1988; Chiappa, 1990). Although intra6ranial pressure was not monitored on day 10 (at the time of ABR recording) the latter was found to be increased (250 m m water) on day 5. Therefore, it seems reasonable to assume that very high intracranial pressure ( p r o b a b l y due to the large right temporal - occipital hematoma) could induce ABR dysfunctions at the peripheral level (cochlea a n d / o r eighth nerve) in our patient. In conclusion, changes in sensory evoked potentials in HSE seem to be caused either by destructive anatomical damage (ie, hematoma destroying geniculocalcarine pathways a n d / o r calcarine cortex with absence of cortical FEPs), by coma (with alterations in middle-latency EPs) and by increased intracranial pressure (with subsequent ABR abnormalities).
References Aguglia U, Oliveri RL, Gambardella A, Zappia M, Quattrone A (1989) Combined neurophysiologic studies in CreutzfeldtJacob disease: a case report. Clin Electroencephalogr, 20, 103 - 110 Aguglia U, Farnarier G, Regis H, Oliveri RL, Quattrone A (1990) Sensory evoked potentials in Creutzfeld-Jacob disease. Eur Neurol, 30, 157- 161 Aguglia U, Gambarelli D, Farnarier G, Quattrone A (1991) Different susceptibility of geniculo-striate and extrageniculate visual pathways to human CreutzfeldJacob disease. A combined neurophysiologic-neuropathologic study. Eleetroencephalogr Clin Neurophysiol 78, 413 -423 American Electroencephalographic Society (1986) Guidelines for clinical evoked potentials studies. J Clin Neurophysiol 3 (Suppl 1), 4 3 - 92 Blackwood W, Corsellis JAN (1976) GreenfieM's Neuropathology. Edward Arnold, London, 297- 302 Chiappa KH (1990) Evoked Potentials in Clinical Medicine. Raven Press, NY, 267 - 272 Chu NS, Yang SS (1988) Portal-systemic
encephalopathy: alterations in somatosensory and brainstem auditory evoked potentials. J Neurol Sci 84, 41 - 50 Garcia-Larrea L, Artru F, Bertrand O, Pernier J, Maugui~re F (1988) Transient druginduced abolition of BAEPs in coma. Neurology 38, 1487 - 1489 Katz B, Rimmer S, Iragui V, Katzman R (1989) Abnormal pattern electroretinogram in Alzheimer's disease: evidence for retinal ganglion cell degeneration? Ann Neurol 26, 221 - 225 Hirose G, Kitagawa Y, Chujo T, Oda R, Kataoka S, Takado M (1986) Acute effects of phenytoin on brainstem auditory evoked potentials : clinical and experimental • study. Neurology 36, 1521 - 1524 Lai CW, Gragasin ME (1988) Electroencephalography in herpes simplex encephalitis. J Clin Neurophysiol 5, 87 - 103 Maugui6re F, Desmet JE, Courjon J (1983) Astereognosis and dissociated loss of frontal or parietal components of somatosensory evoked potentials in hemispheric lesions. Detailed correlations with clinical signs and computerized tomographic scanning. Brain, 106, 271-311 Newlon PG, Greenberg RP, Enas GC, Becker DP (1983) Effects of therapeutic phenobarbital coma on multimodality evoked
EP in herpes simplex encephalitis potentials recorded from head-injured patients. Neurosurgery 12, 6 1 3 - 6 1 9 Picton TW (1986) Abnormal brainstem auditory evoked potentials : a tentative classification. In: Evoked Potentials (Cracco RQ, Bodis-Wollner I, eds) AR Liss, NY, 373 - 378 Rodin E, Tahir S, Austin D, Andaya L (1985) Brainstem death. Clin Electroeneephalogr 16, 6 3 - 7 1 Schroth G, Gawehn J, Thron A, Vallbracht A, Voigt K (1987) Early diagnosis of herpes simplex encephalitis by RMN. Neurology 37, 1 7 9 - 183 Synek VM, Wilson JL, Macdonald GM, Synek BJL (1988) Unusual scalp recorded somatosensory evoked potentials after removal of a large intraventricular meningioma. Clin Electroencephalogr 19, 7 4 - 7 7 Synek VM, Trubuhovich RV (1991) Impor-
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tant abnormalities in recordings of somatosensory evoked potentials in coma. Clin Electroencephalogr 22, 118 - 126 Stohr M, Dichgans J, Vogt K, Buettner UW (1983) The significance of somatosensory evoked potentials for localization of unilateral lesions within the cerebral hemispheres. J Neurol Sci 61, 4 9 - 63 Stone JL, Ghaly RF, Hughes JR (1988) Evoked potentials in head injury and states of increased intracranial pressure. J Clin Neurophysiol 5, 1 3 5 - 160 Yamada T, Kimura J, Wilkinson JT, Kayamori R (1983) Short- and long-latency median SEPs with a localized neurological lesion. Arch Neurol 40, 2 1 5 - 220 Wright CE, Harding GFA, Orwing A (1984) Presenile dementia. The use of flash and pattern VEP in diagnosis. Electroencephalogr Clin Neurophysiol 57, 4 0 5 - 415
Neurophysiol Clin (1991) 21, 301-311 © Elsevier, Paris
Revue
Sensory evoked potentials in herpes simplex encephalitis U Aguglia 1., G Farnarier 2, A Gambardella 1, A
Quattrone 1
1Clinica Neurologica, Facoltgt di Medicina, Catanzaro, Italy; 2Service d'Exploration Fonctionnelle du Systbme Nerveux CHU Timone, Marseille, France (Received 13 December 1990; accepted 28 July 1991)
Summary - Flash visual potentials (FEPs), somatosensory evoked potentials (SEPs) and auditory brain-
stem responses (ABR) were recorded in a 66-year-old patient presenting with clinical, EEG and CT brain scan features of herpes simplex encephalitis (HSE). At the time of evoked potential study (10 days after onset of the disease) the patient was treated with iv barbiturate on controlled respiration (lidocaine and phenytoin were not utilized) ; core temperature was 37°C and pupils were dilated and nonreactive. Cortical FEPs were not recognizable on 02 lead, whereas they were clearly evident on 01 with normal latency of early N1, P 1, N2 waves and delayed P2 component. SEPs showed normal peripheral and central conduction times, but N20 peak was bilaterally absent with unrecognizable (on P3) or delayed (on P4) N33 wave. No ABR (including wave I) were found on stimulation of the right ear, whereas delayed wave V with prolonged interpeak I - V latency was found on stimulation of the left ear. In conclusion, changes in sensory evoked potentials in HSE seem to be caused either by necrotic-hemorrhagic damage (with the disappearance of some cortical responses), by coma (with alterations in middle-latency cortical responses) and by increased intracranial pressure (with subsequent ABR abnormalities). sensory evoked potentials / herpes encephalitis
R~sum~ - Potentiels 6voqu6s sensoriels dans I'enc~phalite herp~tique (~ propos d'un cas). Les auteurs
rapportent les donndes des potentiels dvoquds multimodaux (visuels par flash: PEV, somesthdsiques par stimulation du nerf mddian : SEPs et auditifs prdcoces : ABR) qui ont ~t6 enregistrds chez un malade agd de 66 ans prdsentant un tableau clinique, EEG et scanographique d'encdphafite herpdtique (HSE). Le jour de l'enregistrement (JlO du d6but de la maladie) le patient dtait en coma barbiturique (sans lidocaine ni phenytoine), sous respiration contr6lde, en mydriase ardactive avec une tempdrature de 37°C. Les enregistrements des potentiels dvoquds ont donnd les rdsultats suivants : les rdponses visuelles corticales dtaient absentes sur la r~gion occipitale droite (02), tandis qu'elles dtaient bien structurdes avec des rdponses prdcoces (N1, P1 et N2) normales et une composante tardive (P2) retardde sur la rdgion occipitale gauche (01); les SEPs dtaient caract~risds par des r6ponses NIO et N13 de latence normale, alors que
* Clinica Neurologica, Policlinico Materdomini, Via Campanella, 88100 Catanzaro, Italy.
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U Aguglia et al
la composante corticale N 2 0 dtait absente sur P3 et P4 et la eomposante ?433 dtait absente sur P4 et retardde sur P3 ; les A B R par stimulation de l'oreille droite dtaient absentes, les A B R par s~mulation de l'oreille gauche montraient un temps de conduction I - V allongd. En conclusion, les altdrations des potentiels dvoquds sensoriels clans I'HSE semblent dues ~t des ldsions ndcrosantes et hdmorragiques eortieo-souseorticales (avec disparition de certaines rdponses corticales), gt l'dtat de coma (avee altdration des composantes corticales de latence moyenne), ainsi qu'~ l'augmentation de la pression intracr~nienne (avec abolition e t / o u altdration des ABR).
potentiels ~voqu~s sensoriels / enc~phalite herp~tique
Introduction
Herpes simplex virus type 1 causes acute necrotizing encephalitis (HSE) with edema, necrosis and hemorrhage that selectively affects temporal and frontal lobes. EEG and MRI are the most sensitive non-invasive tests in early diagnosis of HSE (Schroth e t al, 1987 ; Loi and Gragasin, 1988). Sensory symptoms are not prominent in HSE. Sensory evoked potentials have been shown to be of use in demonstrating nonapparent sensory system abnormalities in patients with different central nervous system (CNS) diseases (Chiappa, 1990), including subacute encephalopathies (Aguglia e t al, 1989, 1990a, b). As far as we know, no evoked potential studies have been performed in patients suffering from HSE. In the present study, flash visual potentials (FEPs), somatosensory evoked potentials (SEPs) and auditory brainstem responses (ABR) have been recorded in a patient with HSE.
Case record
The patient, a 66-year-old right-handed male, had a past medical history of atherosclerotic heart disease, left ventricular myocardial infarction, essential arterial hypertension and bilateral atherosclerotic retinopathy with left retinal detachment. He presented with a 4-day history of bifrontal headache, fatigue, fever (38°C) and weakness of the left limbs. On the day of admission the patient was confused and somnolent with motor seizures involving both limbs on the left side associated with twitching of various parts of the body (mouth, left shoulder, left hand and foot). Visual field examination was not possible. Temperature was 40°C, blood pressure 190/110 and pulse 98/min. Routine laboratory testing revealed leucocytosis (28.000/mm 3) with lymphocytosis (56%0), increased erythrocyte sedimentation rate (80 mms, 1st h) and serum creatinine level (1.6 mg/dl), whereas serum electrolytes, calcium, phosphorus, liver enzymes and urinalysis were normal. Blood and urine cultures were negative. Cerebrospinal fluid (CSF) examination revealed an opening pressure of 250 mm water, with 17 leucocytes/ram 3 (58% polymorphonuclear cells, 26% lymphocytes, 16% monocytes), 20 erythrocytes/mm3, protein 58 mg/dl and glucose 82 mg/dl. Gram stain, acid fast stain and bacterial cultures were negative. CSF herpex simplex and varicella zoster viral titers were negative. Electrocardiogram revealed an old left ventricular infarction. The EEG showed continuous polymorphous delta activity of low amplitude in the right hemisphere associated with periodic sharp complexes occurring at 1.5 to 2.5-s intervals on P4; theta-delta activity with
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sporadic sharp waves was also recorded on P3. Myoclonic jerks recorded on the left deltoid muscle had no correlation with the periodic EEG complexes (fig 1). CT brain scan examination revealed bilateral hypodensities with contrast enhancement in the lenticular nuclei, external capsules and occipital lobes and a large hypodense area with contrast enhancement on the basal side of the right temporal lobe. At the time of the evoked potential study (day 10) the patient was treated with continuous iv injection of barbiturate (neither phenytoin nor lidocaine were utilised), on controlled respiration, the core temperature was 37°C, the pupils were dilated and non-reactive. Intracranial pressure and EEG were not monitored. The patient died on day 12. At post-mortem examination the temporal lobes appeared soft and swollen. In the right temporal lobe the necrotic tissue was haemorrhagic. The haematoma also involved the insula, capsula externa and occipital lobe of the right hemisphere. The brainstem was not examined. Microscopic examination showed rarefaction necrosis associated with microglial proliferation and sheets of lipid phagocytes and abundant lymphocytes and plasma cells in the meninges and around the vessels.
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Fig 1. EEG at admission (4 days after onset of the disease). Note continuous polymorphous delta activity of low amplitude in the right hemisphere associated with periodic sharp complexes occurring at 1.5 to 2.5-s intervals on P4. Note also theta-delta activity with sporadic sharp waves on P3. Myoclonic jerks recorded on the left deltoid muscle had no correlation with the periodic EEG complexes.
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Reactive changes were particularly intense immediately adjacent to the pia. These microscopic changes involved the temporal, parietal and occipital cortex, but did not affect the Gennari strip of the left calcarine cortex.
Evoked potential studies Recordings were performed at day 10 in a supine position either in darkness (FEPs and ERGs) or in a dimly-lit r o o m (ABR and SEPs). Surface silver chloride electrodes were utilized. Electrode impedance was kept < 5K13, usually below 3KD. At least 2 different trials were carried out to ensure response reproducibility. Results were analyzed in an off-line session and peak latencies were measured in ms using a cursor with digital display; amplitudes were measured in ~zV. The identified waveforms were traced by an X - Y plotter. Waves were labeled following guidelines of the American Electroencephalographic Society (1986) apart from the FEPs whose components were labeled according to Wright et al (1984), Katz et al (1989) and Aguglia et al (1991). Latencies of early (N1, P1, N2) and late (P2 and following) F E P components, latencies of ABR I - V and latencies of subcortical (N9, N13) and cortical (N20, P25, N33) SEPs were measured. The following amplitudes were considered : amplitude of the E R G b wave (from the first negative peak to the following large positive event), total FEP amplitude (from the higher negative peak to the lower positive trough), cortical SEP amplitudes (from the peak to the preceding wave) and ABR I / V amplitude ratio. As regards visual potentials, surface electrodes were placed on the inferior eyelids (ERG), 01, 02 (FEPs) and referred to linked earlobes. A ground electrode was applied to the forehead. Bilateral eye stimulation was performed. A flash stimulus of 0.35 J and 200 bts duration was produced once per s by a photostimulator placed 1 0 - 15 cm in front of the subject. One hundred and twenty-eight sweeps were averaged on 200 ms base-time. Bandpass was 1 . 0 - 2 5 0 Hz, with automatic artifact reject on. As regards SEPs, surface electrodes were placed on both ERB points (EP), earlobes, posterior midline neck over the CVII spinous process (CVII), on FZ, P3 and P4. The following montages on 3 channels were utilized : homolateral EP - contralateral EP, C V I I - contralateral earlobe, contralateral c o r t e x - F Z . The ground electrode was placed _-5 cm proximal to a bipolar stimulator which was located over the median nerve 1 cm above the wrist crease with a proximally oriented cathode. Left and right median nerve stimulation was performed separately. Electrical stimuli consisting of square pulses of 0.2 ms duration were delivered at 5 c/s. The intensity of electrical stimulation was adjusted to produce a minimal twitch of the thumb. Bandpass was 20 - 1.5 kHz, with an analysis time of 50 ms. A minimum o f 250 responses was required to obtain a reliable average with artifact reject on. As regards ABR, electrodes were attached at CZ and the earlobes, with FZ serving as a ground. Stimuli consisted of 100-dB H L clicks of alternating polarity at a rate
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of 10.2/s, presented monoaurally through earphones. A masking white noise (45 dB HL) was delivered to the unstimulated ear. Bandpass was 1 0 0 - 3 000; a minimum of 2048 clicks were averaged; time analysis was 10 ms. The control group consisted of 15 healthy subjects (9 females and 6 males), ranging in age from 45 - 69 years (mean 60 _+ 10 SD). The evoked responses were considered abnormal when values exceeded the upper normal limits (mean _+ 2 SD).
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I 180 Fig 2. Flash-evoked potentials by bilateral eye stimulation. Note delayed wave a on both eyes, unrecognizable cortical response on 02, well structured early components (N1, P1, N2) with delayed P2 component on 01.
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Results E R G s o f t h e p a t i e n t s h o w e d a b n o r m a l i t i e s in b o t h eyes : p r o l o n g e d l a t e n c y o f w a v e a, s m a l l a m p l i t u d e o f w a v e b, w i t h i n c r e a s e d l a t e n c y o f w a v e b in t h e left eye (fig 2 ; t a b l e I). C o r t i c a l F E P s w e r e o f s m a l l a m p l i t u d e a n d u n r e c o g n i z a b l e o n 02 l e a d , w h e r e a s t h e y w e r e c l e a r l y e v i d e n t o n 01 : t o t a l F E P a m p l i t u d e was 1 6 . 9 / z V , l a t e n c y o f t h e e a r l y w a v e s N1 P1 N 2 w e r e w i t h i n n o r m a l l i m i t s a n d t h e l a t e F E P c o m p o n e n t s c o n s i s t e d o f a d e l a y e d P 2 w a v e at 180 m s (fig 2 ; t a b l e I).
Table I. Values of sensory evoked potentials in one patient with herpes simplex encephalitis and in controls. Patient ERG
Wave a lat Wave b lat Wave b ampl
(ms) (ms) ~V)
JEEPs
(ms) (ms) (ms) (ms) ~V)
SEPs
N10 lat N13 lat N20 lat P25 lat N33 lat N10-N13 NI3-N20 N13-P25 P25 N33
R-Eye
L-Eye
30.0 48.0 8.4
31.0 70.0 9.8
02
N1 lat P1 lat N2 lat P2 lat Total ampl
(ms) (ms) (ms) (ms) (ms) lat (ms) lat (ms) lat (ms) ampl (#V) ampl ~V)
ABR
Wave I lat Wave II lat Wave III lat Wave IV lat Wave V lat I-V lat I/V ratio
(ms) (ms) (ms) (ms) (ms) (ms) ~V)
Controls: mean (SD)
? ? ? ? 1.8
O1
L-Med
10.2 13.1 ? ? 2.9 ? 12.4 6.7 ?
10.0 12.8 ? 25.0 43.0 2.8 ,.9 12.2 8.2 8.4
R-Ear
L-Ear
? ? ? ? ? ? ?
02
47.5 63.0 109.0 180.0 16.9
R-Med
25.5
R-Eye
19.6 (2.0) 42.0 (5.8) 39.5 (14.2)
1,5 ? ? ? 7.6 6.1 0.4
47.2 73.0 100.3 133.2 10.6
(6.5) (5.2) (11.2) (16.7) (4.0)
R-Med
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10.0 13.5 19.0 25.0 35.0 3.5 5.5 11.5 5.4 4.6
(0.6) (0.7) (1.0) (1.6) (3.2) (0.5) (0.7) (1.3) (2.6) (3.8)
R-Ear
1,7 2.8 3.7 5.1 5,7 4.0 0,3
(0.2) (0.2) (0.2) (0.3) (0.2) (0.2) (0.2)
L-Eye
19.9 (2.2) 43.0 (6.0) 37.9 (13.8) 01
46.7 70.5 100.2 128.8 12.3
(8.4) (6.0) (10.8) (14.8) (4.5)
L-Med
9.8 13.6 19.1 25.2 34.8 3.6 5.5 11.6 5.6 4.2
(0.7) (0.7) (1.0) (1.7) (3.0) (0.6) (0.7) (1.5) (3.0) (3.5)
L-Ear
1.7 2.7 3.5 5.1 5.6 3.9 0.4
(0.2) (0.2) (0.2) (0.3) (0.3) (0.2) (0.2)
ERG: electroretinograms ; FEP : flash-evoked visual potentials ; SEP : somatosensory evoked potentials ; ABR: auditory brainstem responses; Med: median nerve stimulation (R: right, L; left).
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10.2 Fig 3. Somatosensory evoked potentials by stimulation of median nerves. A and B : left and right median nerve stimulation, respectively. Note important abnormalities in cortical responses: 19.5 and 19.6 denote the hypothetic latencies of N20 peaks that are actually absent on both sides (A and B); the N33 wave is delayed (A) and unrecognizable (B).
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SEPs showed normal peripheral and cervical potentials with normal interpeak latencies N10-N13 and N13-P25 (table I). Significant abnormalities were found at the cortical level: lack of N20 peak (on both P3 and P4 leads), as well as unrecognizable (on P3) and delayed (on P4) N33 wave. Only a clearly evident positive wave was recorded with a latency of 25 and 25.5 ms on P4-FZ and P3-FZ montages, respectively (fig 3). No ABR (including wave I) were found on stimulation of the right ear, whereas unrecognizable waves II, III, IV with delayed wave V and prolonged interpeak I - V latency were found on stimulation of the left ear (fig 4; table I).
Discussion and conclusion Although in this study no immunologic a n d / o r virologic investigations were carried out (on serum, L C R a n d / o r brain) evidencing an HSE viral infection, the clinical, EEG, CT brain scan and pathologic examination were consistent with the diagnosis of HVE (Blackwood and Corsellis, 1976; Schroth et al, 1987 ; Lai and Gragasin, 1988). Flash-evoked potential studies revealed pathological ERG, mostly on the left eye, which was probably related to the past history of bilateral retinopathy and left retinal detachment. Extinction of the cortical visual responses on 02 was consistent with the h e m a t o m a destroying the right temporal lobe (ie geniculostriate radiations) and occipital cortex. Cortical visual responses recorded on 01 showed normal latency of the early waves and delayed latency of the late components. Similar alterations have also been described in patients presenting with c o m a (Rodin et al, 1985) or severe dementia (Aguglia et al, 1989, 1990, 1991). According to recent neurophysiological studies (Aguglia et al, 1991), early F E P waves should be generated in layer IV (Gen-
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1.5
7.6
CZ-A1
1 mS CZ-A2
Fig 4. Auditory brainstem responses by stimulation of left ear. Note presence of wave I on homolateral montage (CZ-A1) and delayed wave V on both homolateral (CZ-A1) and contralateral (CZ-A2)montages.
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nari's strip) of the striate cortex by activation of geniculostriate input, whereas late FEP components would be generated in the extrastriate cortex. If this is the case, then in our patient there should be functional preservation of either the geniculocalcarine pathway and Gennari's strip in the left hemisphere associated with impairment of the extrastriate visual cortex. SEP studies showed no abnormalities in subcortical sensory pathways and significant alterations in cortical responses. Firstly, the lack of N20 peak requires consideration. Abolition of parietal N20-P25 components, but preservation of frontal N30 wave have been recorded in patients with complete parietal lesions (Maugui~re et al, 1983). Unfortunately, because of the bipolar parietal-frontal montage, we were unable to differentiate the parietal P25 wave from the frontal N30 component. Therefore, it could not be excluded that the parietal positive wave had a negative contribution from the frontal lead (N30 component). If this had been the case, then our patient would have had bilateral lack of both N20 and P25 waves with preservation of N30 components, ie a massive bilateral parietal lesion. Nonetheless, the pathologicals study failed to show significant necrotic changes or destructive lesions in the parietal lobes (only minor microscopic changes were found in the subpial cortical layers). Some authors (Synek e t a l , 1988; Sinek and Trubuhovich, 1991) have stressed the malignant significance of cortical SEPs characterized by a single, clearly evident positive wave with a virtually absent N20 peak on contralateral p a r i e t a l - f r o n t a l montage. These authors hypothesized that the scalp potentials recorded in these patients represent thalamic activity that becomes recordable at the scalp level in the absence of potentials from the sensory cortex due to severe cortical a n d / o r subcortical lesions leading to functional suppression o f the somatosensory cortex. We are unable to confirm such a hypothesis, but can we confirm that this kind of cortical SEP signifies a malignant outcome. Finally, alterations in middlelatency (N33) components were observed. There is evidence that middle-latency SEP components are generated primarily through corticocortical and transcortical conduction (Stohr et al, 1983 ; Yamada et al, 1983). Alterations in middle-latency SEP components have also been observed in patients with phenobarbital coma (Newlon et al, 1983), dysmetabolic (Chu and Yang, 1988) or subacute spongiform (Aguglia et al, 1989, 1990) encephalopathies, thus suggesting a non-specific alteration of the cerebral cortical function in our patient. ABR studies by stimulation of the right ear revealed no recognizable response including wave I, thus suggesting a peripheral hearing loss on the right side. Stimulation of the left ear produced evident I and V waves with increased I - V interpeak latency: this alteration indicated dysfunction in the auditory nerve and/or in the lateral pons (Picton, 1986). Transient prolongation of I - V interpeak latency or abolition of ABR has been recorded in comatose patients treated with lidocaine (Garcia-Larrea et al, 1988) as well as in patients presenting with phenytoin intoxication (Hirose et al, 1986). Nonetheless, neither lidocaine nor phenytoin were given to the patient described in this study. It is well known that increased intracranial pressure may interfere with the eighth nerve and cochlear blood supply and provoke alterations in
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ABR, including absence of response (including wave I) or prolongation of I - V interpeak latency (Stone et al, 1988; Chiappa, 1990). Although intra6ranial pressure was not monitored on day 10 (at the time of ABR recording) the latter was found to be increased (250 m m water) on day 5. Therefore, it seems reasonable to assume that very high intracranial pressure ( p r o b a b l y due to the large right temporal - occipital hematoma) could induce ABR dysfunctions at the peripheral level (cochlea a n d / o r eighth nerve) in our patient. In conclusion, changes in sensory evoked potentials in HSE seem to be caused either by destructive anatomical damage (ie, hematoma destroying geniculocalcarine pathways a n d / o r calcarine cortex with absence of cortical FEPs), by coma (with alterations in middle-latency EPs) and by increased intracranial pressure (with subsequent ABR abnormalities).
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encephalopathy: alterations in somatosensory and brainstem auditory evoked potentials. J Neurol Sci 84, 41 - 50 Garcia-Larrea L, Artru F, Bertrand O, Pernier J, Maugui~re F (1988) Transient druginduced abolition of BAEPs in coma. Neurology 38, 1487 - 1489 Katz B, Rimmer S, Iragui V, Katzman R (1989) Abnormal pattern electroretinogram in Alzheimer's disease: evidence for retinal ganglion cell degeneration? Ann Neurol 26, 221 - 225 Hirose G, Kitagawa Y, Chujo T, Oda R, Kataoka S, Takado M (1986) Acute effects of phenytoin on brainstem auditory evoked potentials : clinical and experimental • study. Neurology 36, 1521 - 1524 Lai CW, Gragasin ME (1988) Electroencephalography in herpes simplex encephalitis. J Clin Neurophysiol 5, 87 - 103 Maugui6re F, Desmet JE, Courjon J (1983) Astereognosis and dissociated loss of frontal or parietal components of somatosensory evoked potentials in hemispheric lesions. Detailed correlations with clinical signs and computerized tomographic scanning. Brain, 106, 271-311 Newlon PG, Greenberg RP, Enas GC, Becker DP (1983) Effects of therapeutic phenobarbital coma on multimodality evoked
EP in herpes simplex encephalitis potentials recorded from head-injured patients. Neurosurgery 12, 6 1 3 - 6 1 9 Picton TW (1986) Abnormal brainstem auditory evoked potentials : a tentative classification. In: Evoked Potentials (Cracco RQ, Bodis-Wollner I, eds) AR Liss, NY, 373 - 378 Rodin E, Tahir S, Austin D, Andaya L (1985) Brainstem death. Clin Electroeneephalogr 16, 6 3 - 7 1 Schroth G, Gawehn J, Thron A, Vallbracht A, Voigt K (1987) Early diagnosis of herpes simplex encephalitis by RMN. Neurology 37, 1 7 9 - 183 Synek VM, Wilson JL, Macdonald GM, Synek BJL (1988) Unusual scalp recorded somatosensory evoked potentials after removal of a large intraventricular meningioma. Clin Electroencephalogr 19, 7 4 - 7 7 Synek VM, Trubuhovich RV (1991) Impor-
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tant abnormalities in recordings of somatosensory evoked potentials in coma. Clin Electroencephalogr 22, 118 - 126 Stohr M, Dichgans J, Vogt K, Buettner UW (1983) The significance of somatosensory evoked potentials for localization of unilateral lesions within the cerebral hemispheres. J Neurol Sci 61, 4 9 - 63 Stone JL, Ghaly RF, Hughes JR (1988) Evoked potentials in head injury and states of increased intracranial pressure. J Clin Neurophysiol 5, 1 3 5 - 160 Yamada T, Kimura J, Wilkinson JT, Kayamori R (1983) Short- and long-latency median SEPs with a localized neurological lesion. Arch Neurol 40, 2 1 5 - 220 Wright CE, Harding GFA, Orwing A (1984) Presenile dementia. The use of flash and pattern VEP in diagnosis. Electroencephalogr Clin Neurophysiol 57, 4 0 5 - 415
