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Evoked potentials in amyotrophic lateral sclerosis
Clinical Neurophysiology of Motor Neuron Diseases Handbook of Clinical Neurophysiology, Vol. 4 A. Eisen (Ed.) q 2004 Elsevier B.V. All rights reserved
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CHAPTER 15
Evoked potentials in amyotrophic lateral sclerosis Reinhard Dengler* and Klaus Krampfl Department of Neurology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
15.1. Introduction Amyotrophic lateral sclerosis (ALS) is a motor system disorder characterized by selective degeneration of the upper and lower motor neuron sparing eye and sphincter muscles. There is, however, ample evidence for involvement of other peripheral and central neuronal systems and, in particular, of the sensory system (Averback and Crocker, 1982; Kato et al., 1996; Theys et al., 1999; Swash, 2000). Clinical and neuropathological signs of sensory involvement have been demonstrated in both sporadic and familial ALS (for review, see Eisen and Krieger, 1998; Swash, 2000). Several pathoanatomical studies have revealed abnormalities of the posterior columns or other ascending fiber tracts (Averback and Crocker, 1982; Kato et al., 1996). Patients with sensory symptoms, who were otherwise typical for ALS, have been described in several large case studies (Kondo and Hemmi, 1984; Gubbay et al., 1985; Li, 1990). In addition, clinical neurophysiological tests used in routine diagnosis may reveal impairment of peripheral as well as central sensory conduction in a proportion of ALS patients (Belsh, 1996; De Carvalho and Swash, 2000; Georgesco et al., 1997; Theys et al., 1999) raising differential diagnostic questions. There are numerous reports in the electrophysiological literature on abnormalities of sensory functions in ALS (Gubbay et al., 1985; Radtke et al., 1986; Subramaniam and Yiannikas, 1990; Shefner et al., 1991; Constantinovici, 1993; Georgesco et al., 1997). Especially studies utilizing somatosensory-evoked potentials (SEPs) detected subclinical impairment of central sensory * Correspondence to: Prof. Dr. Reinhard Dengler, Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. E-mail address: [email protected] (R. Dengler). Tel.: þ49-511-532-2391; fax: þ49-511-532-3115.
conduction in ALS patients. The data available fit with a degeneration of larger spinal ganglion neurons and their myelinated axons, which could sufficiently explain both moderate slowing of sensory conduction and reduction of sensory action potential amplitudes (Kawamura et al., 1981; Theys et al., 1999). Abnormalities, although usually minor, have also been described for auditory-evoked potentials (AEP) and for visual-evoked potentials (VEP). Most reports on SEPs and other EPs in ALS have been published in the 1980s and early 1990s while such studies have become rare in recent years or have focused mainly on cognitive brain potentials rather than classical EPs. A frequent shortcoming of the early studies is that patient classification may not be fully satisfying and that correlation of EP results with disease parameters such as severity or rate of progression may be difficult. The following chapter (i) describes some principles of EPs, especially SEPs; (ii) refers some essential studies on EPs in ALS; (iii) tries to evaluate the significance of EPs in the diagnosis and differential diagnosis of ALS. Methodological aspects will be discussed only in case of non-routine stimulation and recording techniques. There are numerous descriptions of EP techniques available which are recommended to the interested reader (e.g. Kimura and Yamada, 1982; Eisen and Krieger, 1998; Daube, 2000). 15.2. Somatosensory-evoked potentials 15.2.1. Principles of SEPs SEPs are responses to peripheral nerve or skin stimulation which can be recorded with surface
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electrodes at several sites along the peripheral and central sensory pathways. Median nerve and tibial nerve stimulation have been used most in routine diagnosis although other peripheral nerves may be also appropriate. Since the single responses are very small, repetitive stimulation and averaging techniques are necessary to differentiate EPs from the electrical background activity. Early and late SEP components can be distinguished, the first being representative for conduction in peripheral and central pathways and the second for central processing in secondary and tertiary centers. This review deals only with early SEPs. The different components of the SEPs reflect sequential activation of neural generators by the ascending volley (described in detail, e.g. by Aminoff and Eisen, 1998). A typical record of median SEPs elicited by nerve stimulation at the wrist and recorded from Erb’s point, neck (C7 spine) and the contralateral scalp (Cz-C3, 10/20 system) is illustrated in Fig. 1A. For the median nerve, the SEP component regularly recorded is the early cortical negativity N20 and for the tibial nerve the early positivity P40 (Fig. 1B). Both are neurally generated although they may reflect multiple and possibly independent thalamocortical projections. According to most authors, N20 is generated in the Brodman cortical area 3b in the posterior bank of the rolandic fissure while P40 is attributed to the primary sensory cortex. These two components are probably the parameters mostly used in clinical routine and in ALS differential diagnosis. For median SEPs, however, comparison of the latencies of the scalp potential N20 with that of the less frequently used components recorded from Erb’s point (N7) and from the neck (N14) (seventh, fifth, second cervical spine) are very useful for localization of an impairment of conduction in the central sensory pathways and for differentiation between peripheral and central conduction problems. The latency difference between N20 (scalp) and N14 (neck) in median SEP is called central conduction time and provides information on the function of the central sensory pathways. In tibial SEPs, the latency difference between the lumbar component L22 recorded from the second lumbar spine and the cortical component P40 can be used to assess conduction in the dorsal columns (Fig. 1B). For these reasons, it is strongly recommended to record scalp and spinal potentials simultaneously in all diagnostic SEP studies.
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Fig. 1. (A) Normal median SEP recorded from the scalp (N20, upper trace), C7 spine (N13/14, middle trace), and Erb’s point (N7, bottom trace) of a healthy control subject. Stimulation of the median nerve was applied at the wrist. (B) Normal tibial SEP recorded from the scalp (P40, upper trace), C2 spine (N30, middle trace), and L1 spine (N22, bottom trace) following stimulation of the posterior tibial nerve at the ankle.
Pathophysiologically, evaluation of early SEP components is a useful and well reproducible method of assessing the functional status of large diameter peripheral and central afferent fibers (Zanette et al., 1996). The peaks N20 and P40 (scalp) are very stable and are, therefore, mostly used in routine SEP tests. However, as said above, simultaneous recording of neck and lumbar components, respectively, is diagnostically very useful and is therefore strongly recommended for SEP studies in ALS.
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15.2.2. Somatosensory-evoked potentials in ALS Several authors (Cosi et al., 1984; Radtke et al., 1986; Cascino et al., 1988; Subramaniam and Yiannikas, 1990; Zanette et al., 1990; Zanette et al., 1996; Ogata et al., 2001) have studied scalp and spinal SEPs after median or tibial nerve stimulation in ALS mostly using routine electrode placements. Some studies, however, used electrode placements different from the usual C3-Fz (median SEP) and Cz-Fz (tibial SEP) montage (Zanette et al., 1990) and produced results, which may be interesting, but are difficult to compare. In the following section we refer to SEP studies in ALS in more detail which appear representative for the spectrum of findings in the literature. Radtke et al. (1986) found abnormalities in 2 out of 16 patients in median SEP and in 7 out of 16 in tibial SEP by re-evaluation of 17 well-documented ALS patients studied by SEP. The main abnormality was uni- or bilateral slowing of central conduction. Additional use of VEPs and AEPs increased the yield of abnormal EPs up to 47%. Cosi et al. (1984) addressed the issue of subclinical involvement of the sensory system in ALS studying median and tibial SEPs in 45 patients. The latency of the neck component N13 of the median SEPs was slightly but significantly prolonged as well as the latency of the scalp potential N19 while amplitudes were not significantly reduced. The central conduction time was significantly increased with 11 out of 47 values exceeding þ 3 SD. Tibial SEPs also showed significantly increased latencies and, in addition, marked reductions of amplitude. The authors conclude that there is a pathological slowing of conduction along the central sensory pathways in ALS. Similar results were obtained in a smaller series of 10 patients (Constantinovici, 1989) and in another series of 32 patients (Matheson et al., 1986). The latter study revealed abnormalities of tibial SEPs in 19 out of 32 patients and of median SEPs in 11 out of 32. The abnormal scalp potential latencies were associated with prolongation of central conduction time although in six patients there was also slowing of peripheral conduction. Georgesco et al. (1997) studied the sensory system in 24 ALS patients by electroneurography of several lower limb nerves and tibial SEPs. Although normal results in electroneurography were a prerequisite for inclusion in the study marked alterations of the scalp
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components of the SEPs were found for all nerves tested. The authors discussed abnormal central sensory transmission above the lumbar level (N22) or cortical abnormalities. Facco et al. (1989) made an attempt to localize the level of conduction impairment in the somatosensory pathways in 16 ALS patients focusing on the analysis of the brachio-cervical and cervico-cortical segments. For that purpose, the N9 – N13 and the N13 – N20 intervals of median SEPs were measured. The results disclosed a significantly prolonged N9 – N13 interval and no significant delay of N13 –N20. These data would point to a predominant impairment of cervical somatosensory pathways and a fairly normal cervicocortical conduction. Comparison with other SEP studies in ALS, however, is difficult as the authors used a non-cephalic reference and a four-channel montage. A prospective study on the time course of sensory involvement in ALS was carried out by Gregory et al. (1993). The authors investigated the clinical status of the sensory system, sensory nerve action potentials and median SEPs and repeated the assessments after 6 –18 months. Mild sensory symptoms had been noticed in two out of 19 patients and none had sensory signs in the first examination. Sensory nerve action potentials decreased and median SEPs latencies (scalp) increased significantly during the course of the disease. The authors conclude that significant subclinical deterioration of sensory function occurs in ALS and parallels motor neuron degeneration. In a study on the evolution of motor and sensory deficits in ALS, Theys et al. (1999) found a significant slowing of the peripheral conduction time of median SEPs as represented by the N9 latency (Erb’s point). A higher level of significance was achieved when the N9 – N20 latency (scalp) was determined, which includes peripheral cervical and central sensory conduction. In contrast to the above study by Gregory et al., these values showed no significant change in the follow-up examination after 6 months. Therefore, the authors concluded that there is a significant subclinical sensory involvement in ALS which, however, appeared to be non-progressive. A study focusing on the impairment of cortical generators of SEPs was carried out by Zanette et al. (1996) in 29 ALS patients. These authors compared the results of tibial SEP measurements in ALS patients, i.e. patients with signs of upper motor neuron involvement, with those obtained in patients
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suffering from progressive muscle atrophy (PMA), i.e. patients with pure nuclear signs. In ALS patients, three main modalities of changes were detected mainly affecting the amplitudes and the field distribution of the early P40 and N37 cortical potentials. None of these changes was observed in PMA patients. The authors applied special recording techniques, placing electrodes over Cz, C3, C4, and Fz and using an ipsilateral earlobe reference. This must be stressed as the placement of the electrodes is crucial in recording early cortical potentials evoked by lower extremity stimulation. Different patterns of changes were seen in the SEPs of 22 out of 29 patients. The most prevalent type of change comprised an abnormal or even absent P40 and a normal N37 component over the contralateral scalp. Another type of change more frequently observed in severely affected patients consisted of the selective absence of early cortical SEPs, probably reflecting a more extensive loss of pyramidal cells. In contrast to the first type, the latter correlated well with major changes of motor-evoked potentials. Altogether, the study provides evidence for slight involvement of central sensory conduction and, in particular, for impairment of cortical SEP generation in ALS. The authors suggest that SEP changes in ALS are predominately cortical and that neuronal loss in the somatosensory cortex may selectively affect the generator sites of SEPs to lower limb stimulation. There are some reports on SEPs in the special variant of ALS endemic in Guam and in the Kii peninsula in Japan, which is frequently associated with a parkinsonism – dementia complex. Studies in the Guamanian population revealed abnormal central conduction by means of tibial SEPs in some patients all of which had the parkinsonism – dementia complex (Ahlskog et al., 1999). No changes in the latency and size of conventional SEPs were found in ALS patients with the Kii variant (Machii et al., 2003). However, employing a protocol with varying interstimulus intervals, they found indication of disinhibition or hyperexcitability of the somatosensory cortex in these patients. This observation may be in line with the hypothesis of a general hyperexcitability of the cortex in ALS, at least, in early stages (Ince, 2000). In an editorial to this article, Shibasaki (2003) discussed these findings with respect to similar observations in disorders such as myoclonus epilepsy, Alzheimer’s disease with myoclonus, Parkinson’s, Huntington’s and others. He suggests that further studies employing
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more advanced electrophysiological techniques might settle the issue of functional disinhibition of motor and sensory cortical systems in ALS and ALS variants. Systematic studies distinguishing between SEP changes in sporadic and familial ALS have not been carried out. In their report on three children suffering from recessive familial childhood primary lateral sclerosis with associated gaze paresis, a rare inherited form of primary lateral sclerosis, Gascon et al. (1995) described SEP changes which may point to a cortical dysfunction. Low-amplitude and poorly configurated scalp components associated with normal central conduction times were observed whereas peripheral sensory conduction was unchanged. A problem of major clinical importance is the early differential diagnosis between ALS and cervical spondylotic myelopathy since early symptoms and signs of these two disorders can be very similar. Although the diagnostic value of imaging techniques has improved considerably with respect to recent developments in CT and MRI, frequently there remain diagnostic situations that require sensitive functional tests of the integrity of motor and sensory conduction. In a longitudinal study, De Carvalho et al. (1995) studied 43 patients with an initial diagnosis of ALS in order to ascertain the percentage of patients with spinal cord compression and to evaluate the usefulness of SEPs in early diagnosis. Thirty-three patients had a final diagnosis of ALS and eight of spinal cord compression. Of those with ALS, only three had an abnormal central conduction time while this was the case in seven out of eight patients with compressive myelopathy. It is important to stress that the patients included in the study had no demonstrable sensory deficits. The mean duration of neurological symptoms ranged around 3 years in both conditions. The study underlines the usefulness of SEPs in the differential diagnosis between ALS and spinal cord compression in patients with pure motor signs. In the individual case, however, SEP findings alone are not sufficient to make the diagnosis (Aalfs et al., 1993; Kang and Fan, 1995) and must be discussed thoroughly in conjunction with clinical information and imaging results. 15.2.3. Value of SEPs in ALS In summary, there is evidence of progressive sensory pathway involvement in ALS as
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demonstrated by an increase of changes of SEPs in the course of the disease. The latencies of the cortical components N20 (median SEPs) and P40 (tibial SEPs) and of the neck (N14) or lumbar potentials (N22) can be easily determined and are appropriate parameters to reveal the involvement of the sensory system in the degenerative process in ALS (Matheson et al., 1986; Radtke et al., 1986; Subramaniam and Yiannikas, 1990; Shefner et al., 1991; Gregory et al., 1993; Georgesco et al., 1994; Zanette et al., 1996; Theys et al., 1999). The most common abnormalities are prolonged latencies of the scalp potentials and an increase of the central conduction time pointing to an impairment of conduction in the dorsal columns and lemniscal pathways (Cosi et al., 1984; Gregory et al., 1993; Theys et al., 1999). These changes are generally mild and occur in a limited number of patients, at least, in the early stages of the disease. More pronounced and focal abnormalities of SEPs should draw the attention to other diagnoses such as spinal cord compression or inflammatory neurological diseases and to the rare x-chromosomal bulbospinal muscle atrophy (Kennedy Syndrome). In our labs, diagnostic median and tibial SEPs are carried out at least once in the course of the disease and are usually normal in line with the literature. Mild changes of peripheral and central conduction are accepted and are not used as argument against ALS as long as the other clinical and lab findings fit with this diagnosis. 15.3. Visual-evoked potentials in ALS Normal VEPs from both eyes of a healthy control are illustrated in Fig. 2. The latencies of the cortical P100 components (ca. 110 ms) are bilaterally in the normal range as well as the amplitudes without relevant side-to-side differences. Several groups have reported normal or minimally changed VEPs in ALS using the routine patternreversal technique (Radtke et al., 1986; Ghezzi et al., 1989; Palma et al., 1993). Other authors have described that the individual latencies of the diagnostically important P100 (P1) component in ALS patients were still within normal range although there was a significant group difference between ALS patients and normal controls (Subramaniam et al., 1990). In a series of 32 ALS patients (Matheson et al., 1986), four patients were described to have
Fig. 2. Normal VEPs recorded from a healthy subject following pattern-reversal stimulation. The latency of the P100 positivity is within the normal range and there are no significant side-to-side differences of latencies and amplitudes.
abnormalities of VEPs with three of them showing changes of minor degree only. Another group (Munte et al., 1998a) found significant group differences when comparing averages of 14 ALS patients and of 14 control subjects. There was a marked reduction of the P1 amplitude of the VEPs that held true for the individual ALS patients, too. They discussed their findings with respect to the different technique used to evoke the responses. In their study, a luminance change stimulus and not a checker board pattern reversal was used. There is evidence that the P1 component evoked by luminance changes is generated by extrastriate temporo-occipital areas whereas the P1 after pattern-reversal stimuli is generated in the primary visual cortex. Thus, the study points to an involvement of the cortical visual system in the disease process. Recording of VEPs is not part of the routine diagnosis in ALS. Pathological results are not an argument against ALS in otherwise typical patients although they need an explanation. 15.4. Auditory-evoked potentials in ALS Studies of AEPs in ALS have been carried out less frequently than those using SEPs. Fig. 3 illustrates an example of a normal brainstem AEP elicited by stimulation of either ear. The first two peaks (I –II) represent the peripheral conduction time of the signal while the latencies of the latter ones (III – V) are
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15.5. Event-related potentials, cognitive potentials
Fig. 3. Normal AEP recording from a healthy subject following stimulation of either ear (upper and lower trace, respectively). Latencies of the consecutive negative peaks I– V are detected as indicated. Various interpeak latencies can be used as measures for localization of central conduction or processing failure.
prolonged in case of impairment of the central conduction of auditory signals. Amplitudes can be measured and compared for significant side differences. In their comprehensive study on EPs in ALS, Radke et al. (1986) recorded AEPs in 12 patients and observed abnormal results in two out of the 12. Both patients had prominent oropharyngeal symptoms at the time of diagnosis. One patient had a delay in the I– V interpeak latency bilaterally. The second patient, who complained of a sensory deficit around one ear, had a mild to moderate prolongation of the latencies of the AEP components at this side with normal conduction on the other side. There were no further changes in the AEPs in follow-up examinations. The AEP abnormalities in the patients with marked bulbar symptoms gave rise to the hypothesis that the auditory sensory pathways may be pathophysiologically involved in the disease process. In another study (Matheson et al., 1986), four out of 32 ALS patients showed abnormal AEPs. These four patients also revealed abnormal SEPs following both median and tibial nerve stimulation. In summary AEPs are not an obligatory part of the routine diagnostic work-up in ALS patients. Pathological values may occasionally be observed and cannot be used as argument against the diagnosis in otherwise typical patients.
There is evidence from clinical, neuropsychological and neuropathological studies that the neurodegenerative process in ALS extends beyond the primary motor cortex and involves cortical regions important for cognitive functions (Wikstrom et al., 1982; Horoupian et al., 1984; Iwasaki et al., 1990; Neary et al., 1990). Psychological deficits, frequently of the frontal lobe type, are reported to become prevalent in about 2– 5% of patients with sporadic ALS. Since a general limitation of classical psychological testing of cognitive function in ALS is interference with physical disability of the patients, neurophysiological assessment of higher order functions has also been employed. Event-related potentials (ERPs), especially the “P300” late component, have the potential to monitor changes of cognitive functions and have been studied in ALS using simple as well as more complex visual and auditory tasks. Gil et al. (1995) were among the first to analyze auditory ERPs in ALS investigating 20 patients and as many matched controls. They found no differences in the latencies of the early N100 and P200 waves, but could show a significant delay of the P300 latency in 60% of the ALS patients. Additionally, the patients underwent classical neuropsychological testing producing significantly lower scores than the controls. To our knowledge, this study was the first to demonstrate the usefulness of ERPs in testing cognitive function in ALS, especially in the course of the disease, as problems arising from progression of motor deficits or speech difficulties could be circumvented. Paulus et al. (2002) investigated auditory and visual ERPs in 16 ALS patients in a combined neuropsychological and neurophysiological study. They were able to carry out a more subtle differentiation of the cognitive dysfunction of their patients by using a comprehensive battery of neuropsychological tests covering intelligence, executive functions, attention, memory, word fluency, visuo-motor and visual-constructive skills. A significant impairment of executive functions and attention was observed in the group of ALS patients associated with a significant correlation to prolonged latencies of visual and auditory P300 waves. The study provided further evidence for the usefulness of ERPs in assessing cognitive functions in ALS patients and
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demonstrated a close relationship between cognitive deficits and neurophysiological changes. Frontal lobe functions were tested by means of ERPs in eight ALS patients without clinical signs of cognitive impairment by Vieregge et al. (1999). An auditory task was used in order to test for changes in selective attention as a typical frontal lobe feature. ALS patients showed significantly smaller amplitude differences between the responses to attended and to unattended tones than the controls which was taken as neurophysiological evidence of impairment of selective attention in ALS. ERP studies were also used to analyze memory deficits in ALS (Mu¨nte et al., 1998a,b). Eight ALS patients and as many age-matched controls were subjected to a two-phase recognition memory test. During the first phase, words were repeatedly presented on a video-screen. During the second phase (1 h later) a second list containing old and new words was presented while ERPs were recorded (Fig. 4). A significantly different waveform of the ERPs in response to repeated and new words between ALS patients and controls was found indicating an alteration of memory processing in ALS. The same group studied visual search behavior of ALS patients (Mu¨nte et al., 1999). Comparing 13
patients with sporadic ALS and as many controls, target detection rates in parallel tasks were found to be normal in ALS. A significant slowing of the performance was shown in serial tasks associated with alterations of the ERP recordings. Changes of an early attention-sensitive ERP component pointed to an attention deficit underlying the impairment of visual search behavior in ALS. Kotchoubey et al. (2003) used ERPs in almost completely immobile ALS patients with sustained artificial ventilation to investigate cortical plasticity. The results were compared with records obtained from patients with tetraplegia due to high-level spinal cord injury and from healthy controls. The time course of ERPs upon the presentation of words belonging to different association fields was analyzed over 10 regions of interest on the scull. This approach allowed brain mapping of ERP differences between the two patient groups and the controls. In summary, the analysis revealed that activation of visual information processing plays an important compensatory role in both ALS and spinal cord injured patients. In conclusion, ERPs appear to be an easily accessible and reliable monitor of specific changes of cognitive functions in the disease course of ALS. The above reports indicate changes of cortical functions beyond the motor cortex and are in line with results from neuropathological and functional imaging studies (Ludolph et al., 1992; Brooks et al., 2000; Turner and Leigh, 2000; Konrad et al., 2002). The future will probably belong to studies combining the advantages of ERP techniques and of functional magnetic resonance imaging (fMRI), i.e. high temporal resolution of ERPs and high spatial resolution of fMRI.
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Fig. 4. ERPs (grand average) recorded from the scalp at Cz and Pz electrode positions (10/20 system) in response to single words presented on a monitor. Thick and dotted lines indicate ERPs following first and repeated presentations, respectively. Patients with ALS fail to show a more positive ERP waveform following correct recognition of repeated words pointing to an alteration of memory processing (modified from Mu¨nte et al., 1998b).
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Kondo, K and Hemmi, I (1984) Clinical statistics in 515 fatal cases of motor neuron disease: determinants of course. Neuroepidemiology, 3: 129–148. Konrad, C, Henningsen, H, Bremer, J, Mock, B, Deppe, M, Buchinger, C, Turski, P, Knecht, S and Brooks, B (2002) Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp. Brain Res., 143: 51– 56. Kotchoubey, B, Dubischar, A, Mack, H, Kaiser, J and Birbaumer, N (2003) Electrocortical and behavioral effects of chronic immobility on word processing. Brain Res. Cogn. Brain Res., 17: 188– 199. Li, TM, Alberman, E and Swash, M (1990) Clinical features and associations of 560 cases of motor neuron disease. J. Neurol. Neurosurg. Psychiatry, 53: 1043 –1045. Ludolph, AC, Langen, KJ, Regard, M, Herzog, H, Kemper, B, Kuwert, T, Bottger, IG and Feinendegen, L (1992) Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol. Scand., 85: 81– 89. Machii, K, Ugawa, Y, Kokubo, Y, Sasaki, R and Kuzuhara, S (2003) Somatosensory evoked potential recovery in kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (kii AlS/PDC). Clin. Neurophysiol., 114: 564 – 568. Matheson, JK, Harrington, HJ and Hallett, M (1986) Abnormalities of multimodality evoked potentials in amyotrophic lateral sclerosis. Arch. Neurol., 43: 338– 340. Mu¨nte, TF, Troger, MC, Nusser, I, Wieringa, BM, Johannes, S, Matzke, M and Dengler, R (1998a) Alteration of early components of the visual evoked potential in amyotrophic lateral sclerosis. J. Neurol., 245: 206 – 210. Mu¨nte, TF, Troger, M, Nusser, I, Wieringa, BM, Matzke, M, Johannes, S and Dengler, R (1998b) Recognition memory deficits in amyotrophic lateral sclerosis assessed with event-related brain potentials. Acta Neurol. Scand., 98: 110– 115. Mu¨nte, TF, Troger, MC, Nusser, I, Wieringa, BM, Matzke, M, Johannes, S and Dengler, R (1999) Abnormalities of visual search behaviour in ALS patients detected with event-related brain potentials. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 1: 21–27. Neary, D, Snowden, JS, Mann, DM, Northen, B, Goulding, PJ and Macdermott, N (1990) Frontal lobe dementia and motor neuron disease. J. Neurol. Neurosurg. Psychiatry, 53: 23 – 32. Ogata, K, Tobimatsu, S, Furuya, H and Kira, J (2001) Sporadic amyotrophic lateral sclerosis showing abnormal somatosensory evoked potentials: a report of three cases. Fukuoka Igaku Zasshi, 92: 242– 250.
303 Palma, V, Guadagnino, M, Brescia Morra, V and Nolfe, G (1993) Multimodality evoked potentials in sporadic amyotrophic lateral sclerosis: a statistical approach. Electromyogr. Clin. Neurophysiol., 33: 167 –171. Paulus, KS, Magnano, I, Piras, MR, Solinas, MA, Solinas, G, Sau, GF and Aiello, I (2002) Visual and auditory event-related potentials in sporadic amyotrophic lateral sclerosis. Clin. Neurophysiol., 113: 853 – 861. Radtke, RA, Erwin, A and Erwin, CW (1986) Abnormal sensory evoked potentials in amyotrophic lateral sclerosis. Neurology, 36: 796 – 801. Shefner, JM, Tyler, R and Krarup, C (1991) Abnormalities in the sensory action potential in patients with amyotrophic lateral sclerosis. Muscle Nerve, 14: 1242– 1246. Shibasaki, H (2003) Is somatosensory function abnormal in amyotrophic lateral sclerosis/parkinsonism-dementia complex in Kii Peninsula? Clin. Neurophysiol., 114: 775 – 776. Subramaniam, JS and Yiannikas, C (1990) Multimodality evoked potentials in motor neuron disease. Arch. Neurol., 47: 989 – 994. Swash, M (2000) Clinical features and diagnosis of amyotrophic lateral sclerosis. In: RH Brown, V Meininger and M Swash (Eds.), Amyotrophic Lateral Sclerosis. Martin Dunitz, London, UK. Theys, PA, Peeters, E and Robberecht, W (1999) Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques. J. Neurol., 246: 438 – 442. Turner, MR and Leigh, PN (2000) Positron emission tomography (PET) – its potential to provide surrogate markers in ALS. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 1 (Suppl. 2): 17 – 22. Vieregge, P, Wauschkuhn, B, Heberlein, I, Hagenah, J and Verleger, R (1999) Selective attention is impaired in amyotrophic lateral sclerosis – a study of event-related EEG potentials. Brain Res. Cogn. Brain Res., 8: 27 – 35. Wikstrom, J, Paetau, A, Palo, J, Sulkava, R and Haltia, M (1982) Classic amyotrophic lateral sclerosis with dementia. Arch. Neurol., 39: 681 – 683. Zanette, G, Polo, A, Gasperini, M, Bertolasi, L and De Grandis, D (1990) Far-field and cortical somatosensory evoked potentials in motor neuron disease. Muscle Nerve, 13: 47 – 55. Zanette, G, Tinazzi, M, Polo, A and Rizzuto, N (1996) Motor neuron disease with pyramidal tract dysfunction involves the cortical generators of the early somatosensory evoked potential to tibial nerve stimulation. Neurology, 47: 932 – 938.
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CHAPTER 15
Evoked potentials in amyotrophic lateral sclerosis Reinhard Dengler* and Klaus Krampfl Department of Neurology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
15.1. Introduction Amyotrophic lateral sclerosis (ALS) is a motor system disorder characterized by selective degeneration of the upper and lower motor neuron sparing eye and sphincter muscles. There is, however, ample evidence for involvement of other peripheral and central neuronal systems and, in particular, of the sensory system (Averback and Crocker, 1982; Kato et al., 1996; Theys et al., 1999; Swash, 2000). Clinical and neuropathological signs of sensory involvement have been demonstrated in both sporadic and familial ALS (for review, see Eisen and Krieger, 1998; Swash, 2000). Several pathoanatomical studies have revealed abnormalities of the posterior columns or other ascending fiber tracts (Averback and Crocker, 1982; Kato et al., 1996). Patients with sensory symptoms, who were otherwise typical for ALS, have been described in several large case studies (Kondo and Hemmi, 1984; Gubbay et al., 1985; Li, 1990). In addition, clinical neurophysiological tests used in routine diagnosis may reveal impairment of peripheral as well as central sensory conduction in a proportion of ALS patients (Belsh, 1996; De Carvalho and Swash, 2000; Georgesco et al., 1997; Theys et al., 1999) raising differential diagnostic questions. There are numerous reports in the electrophysiological literature on abnormalities of sensory functions in ALS (Gubbay et al., 1985; Radtke et al., 1986; Subramaniam and Yiannikas, 1990; Shefner et al., 1991; Constantinovici, 1993; Georgesco et al., 1997). Especially studies utilizing somatosensory-evoked potentials (SEPs) detected subclinical impairment of central sensory * Correspondence to: Prof. Dr. Reinhard Dengler, Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. E-mail address: [email protected] (R. Dengler). Tel.: þ49-511-532-2391; fax: þ49-511-532-3115.
conduction in ALS patients. The data available fit with a degeneration of larger spinal ganglion neurons and their myelinated axons, which could sufficiently explain both moderate slowing of sensory conduction and reduction of sensory action potential amplitudes (Kawamura et al., 1981; Theys et al., 1999). Abnormalities, although usually minor, have also been described for auditory-evoked potentials (AEP) and for visual-evoked potentials (VEP). Most reports on SEPs and other EPs in ALS have been published in the 1980s and early 1990s while such studies have become rare in recent years or have focused mainly on cognitive brain potentials rather than classical EPs. A frequent shortcoming of the early studies is that patient classification may not be fully satisfying and that correlation of EP results with disease parameters such as severity or rate of progression may be difficult. The following chapter (i) describes some principles of EPs, especially SEPs; (ii) refers some essential studies on EPs in ALS; (iii) tries to evaluate the significance of EPs in the diagnosis and differential diagnosis of ALS. Methodological aspects will be discussed only in case of non-routine stimulation and recording techniques. There are numerous descriptions of EP techniques available which are recommended to the interested reader (e.g. Kimura and Yamada, 1982; Eisen and Krieger, 1998; Daube, 2000). 15.2. Somatosensory-evoked potentials 15.2.1. Principles of SEPs SEPs are responses to peripheral nerve or skin stimulation which can be recorded with surface
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electrodes at several sites along the peripheral and central sensory pathways. Median nerve and tibial nerve stimulation have been used most in routine diagnosis although other peripheral nerves may be also appropriate. Since the single responses are very small, repetitive stimulation and averaging techniques are necessary to differentiate EPs from the electrical background activity. Early and late SEP components can be distinguished, the first being representative for conduction in peripheral and central pathways and the second for central processing in secondary and tertiary centers. This review deals only with early SEPs. The different components of the SEPs reflect sequential activation of neural generators by the ascending volley (described in detail, e.g. by Aminoff and Eisen, 1998). A typical record of median SEPs elicited by nerve stimulation at the wrist and recorded from Erb’s point, neck (C7 spine) and the contralateral scalp (Cz-C3, 10/20 system) is illustrated in Fig. 1A. For the median nerve, the SEP component regularly recorded is the early cortical negativity N20 and for the tibial nerve the early positivity P40 (Fig. 1B). Both are neurally generated although they may reflect multiple and possibly independent thalamocortical projections. According to most authors, N20 is generated in the Brodman cortical area 3b in the posterior bank of the rolandic fissure while P40 is attributed to the primary sensory cortex. These two components are probably the parameters mostly used in clinical routine and in ALS differential diagnosis. For median SEPs, however, comparison of the latencies of the scalp potential N20 with that of the less frequently used components recorded from Erb’s point (N7) and from the neck (N14) (seventh, fifth, second cervical spine) are very useful for localization of an impairment of conduction in the central sensory pathways and for differentiation between peripheral and central conduction problems. The latency difference between N20 (scalp) and N14 (neck) in median SEP is called central conduction time and provides information on the function of the central sensory pathways. In tibial SEPs, the latency difference between the lumbar component L22 recorded from the second lumbar spine and the cortical component P40 can be used to assess conduction in the dorsal columns (Fig. 1B). For these reasons, it is strongly recommended to record scalp and spinal potentials simultaneously in all diagnostic SEP studies.
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Fig. 1. (A) Normal median SEP recorded from the scalp (N20, upper trace), C7 spine (N13/14, middle trace), and Erb’s point (N7, bottom trace) of a healthy control subject. Stimulation of the median nerve was applied at the wrist. (B) Normal tibial SEP recorded from the scalp (P40, upper trace), C2 spine (N30, middle trace), and L1 spine (N22, bottom trace) following stimulation of the posterior tibial nerve at the ankle.
Pathophysiologically, evaluation of early SEP components is a useful and well reproducible method of assessing the functional status of large diameter peripheral and central afferent fibers (Zanette et al., 1996). The peaks N20 and P40 (scalp) are very stable and are, therefore, mostly used in routine SEP tests. However, as said above, simultaneous recording of neck and lumbar components, respectively, is diagnostically very useful and is therefore strongly recommended for SEP studies in ALS.
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15.2.2. Somatosensory-evoked potentials in ALS Several authors (Cosi et al., 1984; Radtke et al., 1986; Cascino et al., 1988; Subramaniam and Yiannikas, 1990; Zanette et al., 1990; Zanette et al., 1996; Ogata et al., 2001) have studied scalp and spinal SEPs after median or tibial nerve stimulation in ALS mostly using routine electrode placements. Some studies, however, used electrode placements different from the usual C3-Fz (median SEP) and Cz-Fz (tibial SEP) montage (Zanette et al., 1990) and produced results, which may be interesting, but are difficult to compare. In the following section we refer to SEP studies in ALS in more detail which appear representative for the spectrum of findings in the literature. Radtke et al. (1986) found abnormalities in 2 out of 16 patients in median SEP and in 7 out of 16 in tibial SEP by re-evaluation of 17 well-documented ALS patients studied by SEP. The main abnormality was uni- or bilateral slowing of central conduction. Additional use of VEPs and AEPs increased the yield of abnormal EPs up to 47%. Cosi et al. (1984) addressed the issue of subclinical involvement of the sensory system in ALS studying median and tibial SEPs in 45 patients. The latency of the neck component N13 of the median SEPs was slightly but significantly prolonged as well as the latency of the scalp potential N19 while amplitudes were not significantly reduced. The central conduction time was significantly increased with 11 out of 47 values exceeding þ 3 SD. Tibial SEPs also showed significantly increased latencies and, in addition, marked reductions of amplitude. The authors conclude that there is a pathological slowing of conduction along the central sensory pathways in ALS. Similar results were obtained in a smaller series of 10 patients (Constantinovici, 1989) and in another series of 32 patients (Matheson et al., 1986). The latter study revealed abnormalities of tibial SEPs in 19 out of 32 patients and of median SEPs in 11 out of 32. The abnormal scalp potential latencies were associated with prolongation of central conduction time although in six patients there was also slowing of peripheral conduction. Georgesco et al. (1997) studied the sensory system in 24 ALS patients by electroneurography of several lower limb nerves and tibial SEPs. Although normal results in electroneurography were a prerequisite for inclusion in the study marked alterations of the scalp
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components of the SEPs were found for all nerves tested. The authors discussed abnormal central sensory transmission above the lumbar level (N22) or cortical abnormalities. Facco et al. (1989) made an attempt to localize the level of conduction impairment in the somatosensory pathways in 16 ALS patients focusing on the analysis of the brachio-cervical and cervico-cortical segments. For that purpose, the N9 – N13 and the N13 – N20 intervals of median SEPs were measured. The results disclosed a significantly prolonged N9 – N13 interval and no significant delay of N13 –N20. These data would point to a predominant impairment of cervical somatosensory pathways and a fairly normal cervicocortical conduction. Comparison with other SEP studies in ALS, however, is difficult as the authors used a non-cephalic reference and a four-channel montage. A prospective study on the time course of sensory involvement in ALS was carried out by Gregory et al. (1993). The authors investigated the clinical status of the sensory system, sensory nerve action potentials and median SEPs and repeated the assessments after 6 –18 months. Mild sensory symptoms had been noticed in two out of 19 patients and none had sensory signs in the first examination. Sensory nerve action potentials decreased and median SEPs latencies (scalp) increased significantly during the course of the disease. The authors conclude that significant subclinical deterioration of sensory function occurs in ALS and parallels motor neuron degeneration. In a study on the evolution of motor and sensory deficits in ALS, Theys et al. (1999) found a significant slowing of the peripheral conduction time of median SEPs as represented by the N9 latency (Erb’s point). A higher level of significance was achieved when the N9 – N20 latency (scalp) was determined, which includes peripheral cervical and central sensory conduction. In contrast to the above study by Gregory et al., these values showed no significant change in the follow-up examination after 6 months. Therefore, the authors concluded that there is a significant subclinical sensory involvement in ALS which, however, appeared to be non-progressive. A study focusing on the impairment of cortical generators of SEPs was carried out by Zanette et al. (1996) in 29 ALS patients. These authors compared the results of tibial SEP measurements in ALS patients, i.e. patients with signs of upper motor neuron involvement, with those obtained in patients
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suffering from progressive muscle atrophy (PMA), i.e. patients with pure nuclear signs. In ALS patients, three main modalities of changes were detected mainly affecting the amplitudes and the field distribution of the early P40 and N37 cortical potentials. None of these changes was observed in PMA patients. The authors applied special recording techniques, placing electrodes over Cz, C3, C4, and Fz and using an ipsilateral earlobe reference. This must be stressed as the placement of the electrodes is crucial in recording early cortical potentials evoked by lower extremity stimulation. Different patterns of changes were seen in the SEPs of 22 out of 29 patients. The most prevalent type of change comprised an abnormal or even absent P40 and a normal N37 component over the contralateral scalp. Another type of change more frequently observed in severely affected patients consisted of the selective absence of early cortical SEPs, probably reflecting a more extensive loss of pyramidal cells. In contrast to the first type, the latter correlated well with major changes of motor-evoked potentials. Altogether, the study provides evidence for slight involvement of central sensory conduction and, in particular, for impairment of cortical SEP generation in ALS. The authors suggest that SEP changes in ALS are predominately cortical and that neuronal loss in the somatosensory cortex may selectively affect the generator sites of SEPs to lower limb stimulation. There are some reports on SEPs in the special variant of ALS endemic in Guam and in the Kii peninsula in Japan, which is frequently associated with a parkinsonism – dementia complex. Studies in the Guamanian population revealed abnormal central conduction by means of tibial SEPs in some patients all of which had the parkinsonism – dementia complex (Ahlskog et al., 1999). No changes in the latency and size of conventional SEPs were found in ALS patients with the Kii variant (Machii et al., 2003). However, employing a protocol with varying interstimulus intervals, they found indication of disinhibition or hyperexcitability of the somatosensory cortex in these patients. This observation may be in line with the hypothesis of a general hyperexcitability of the cortex in ALS, at least, in early stages (Ince, 2000). In an editorial to this article, Shibasaki (2003) discussed these findings with respect to similar observations in disorders such as myoclonus epilepsy, Alzheimer’s disease with myoclonus, Parkinson’s, Huntington’s and others. He suggests that further studies employing
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more advanced electrophysiological techniques might settle the issue of functional disinhibition of motor and sensory cortical systems in ALS and ALS variants. Systematic studies distinguishing between SEP changes in sporadic and familial ALS have not been carried out. In their report on three children suffering from recessive familial childhood primary lateral sclerosis with associated gaze paresis, a rare inherited form of primary lateral sclerosis, Gascon et al. (1995) described SEP changes which may point to a cortical dysfunction. Low-amplitude and poorly configurated scalp components associated with normal central conduction times were observed whereas peripheral sensory conduction was unchanged. A problem of major clinical importance is the early differential diagnosis between ALS and cervical spondylotic myelopathy since early symptoms and signs of these two disorders can be very similar. Although the diagnostic value of imaging techniques has improved considerably with respect to recent developments in CT and MRI, frequently there remain diagnostic situations that require sensitive functional tests of the integrity of motor and sensory conduction. In a longitudinal study, De Carvalho et al. (1995) studied 43 patients with an initial diagnosis of ALS in order to ascertain the percentage of patients with spinal cord compression and to evaluate the usefulness of SEPs in early diagnosis. Thirty-three patients had a final diagnosis of ALS and eight of spinal cord compression. Of those with ALS, only three had an abnormal central conduction time while this was the case in seven out of eight patients with compressive myelopathy. It is important to stress that the patients included in the study had no demonstrable sensory deficits. The mean duration of neurological symptoms ranged around 3 years in both conditions. The study underlines the usefulness of SEPs in the differential diagnosis between ALS and spinal cord compression in patients with pure motor signs. In the individual case, however, SEP findings alone are not sufficient to make the diagnosis (Aalfs et al., 1993; Kang and Fan, 1995) and must be discussed thoroughly in conjunction with clinical information and imaging results. 15.2.3. Value of SEPs in ALS In summary, there is evidence of progressive sensory pathway involvement in ALS as
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demonstrated by an increase of changes of SEPs in the course of the disease. The latencies of the cortical components N20 (median SEPs) and P40 (tibial SEPs) and of the neck (N14) or lumbar potentials (N22) can be easily determined and are appropriate parameters to reveal the involvement of the sensory system in the degenerative process in ALS (Matheson et al., 1986; Radtke et al., 1986; Subramaniam and Yiannikas, 1990; Shefner et al., 1991; Gregory et al., 1993; Georgesco et al., 1994; Zanette et al., 1996; Theys et al., 1999). The most common abnormalities are prolonged latencies of the scalp potentials and an increase of the central conduction time pointing to an impairment of conduction in the dorsal columns and lemniscal pathways (Cosi et al., 1984; Gregory et al., 1993; Theys et al., 1999). These changes are generally mild and occur in a limited number of patients, at least, in the early stages of the disease. More pronounced and focal abnormalities of SEPs should draw the attention to other diagnoses such as spinal cord compression or inflammatory neurological diseases and to the rare x-chromosomal bulbospinal muscle atrophy (Kennedy Syndrome). In our labs, diagnostic median and tibial SEPs are carried out at least once in the course of the disease and are usually normal in line with the literature. Mild changes of peripheral and central conduction are accepted and are not used as argument against ALS as long as the other clinical and lab findings fit with this diagnosis. 15.3. Visual-evoked potentials in ALS Normal VEPs from both eyes of a healthy control are illustrated in Fig. 2. The latencies of the cortical P100 components (ca. 110 ms) are bilaterally in the normal range as well as the amplitudes without relevant side-to-side differences. Several groups have reported normal or minimally changed VEPs in ALS using the routine patternreversal technique (Radtke et al., 1986; Ghezzi et al., 1989; Palma et al., 1993). Other authors have described that the individual latencies of the diagnostically important P100 (P1) component in ALS patients were still within normal range although there was a significant group difference between ALS patients and normal controls (Subramaniam et al., 1990). In a series of 32 ALS patients (Matheson et al., 1986), four patients were described to have
Fig. 2. Normal VEPs recorded from a healthy subject following pattern-reversal stimulation. The latency of the P100 positivity is within the normal range and there are no significant side-to-side differences of latencies and amplitudes.
abnormalities of VEPs with three of them showing changes of minor degree only. Another group (Munte et al., 1998a) found significant group differences when comparing averages of 14 ALS patients and of 14 control subjects. There was a marked reduction of the P1 amplitude of the VEPs that held true for the individual ALS patients, too. They discussed their findings with respect to the different technique used to evoke the responses. In their study, a luminance change stimulus and not a checker board pattern reversal was used. There is evidence that the P1 component evoked by luminance changes is generated by extrastriate temporo-occipital areas whereas the P1 after pattern-reversal stimuli is generated in the primary visual cortex. Thus, the study points to an involvement of the cortical visual system in the disease process. Recording of VEPs is not part of the routine diagnosis in ALS. Pathological results are not an argument against ALS in otherwise typical patients although they need an explanation. 15.4. Auditory-evoked potentials in ALS Studies of AEPs in ALS have been carried out less frequently than those using SEPs. Fig. 3 illustrates an example of a normal brainstem AEP elicited by stimulation of either ear. The first two peaks (I –II) represent the peripheral conduction time of the signal while the latencies of the latter ones (III – V) are
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15.5. Event-related potentials, cognitive potentials
Fig. 3. Normal AEP recording from a healthy subject following stimulation of either ear (upper and lower trace, respectively). Latencies of the consecutive negative peaks I– V are detected as indicated. Various interpeak latencies can be used as measures for localization of central conduction or processing failure.
prolonged in case of impairment of the central conduction of auditory signals. Amplitudes can be measured and compared for significant side differences. In their comprehensive study on EPs in ALS, Radke et al. (1986) recorded AEPs in 12 patients and observed abnormal results in two out of the 12. Both patients had prominent oropharyngeal symptoms at the time of diagnosis. One patient had a delay in the I– V interpeak latency bilaterally. The second patient, who complained of a sensory deficit around one ear, had a mild to moderate prolongation of the latencies of the AEP components at this side with normal conduction on the other side. There were no further changes in the AEPs in follow-up examinations. The AEP abnormalities in the patients with marked bulbar symptoms gave rise to the hypothesis that the auditory sensory pathways may be pathophysiologically involved in the disease process. In another study (Matheson et al., 1986), four out of 32 ALS patients showed abnormal AEPs. These four patients also revealed abnormal SEPs following both median and tibial nerve stimulation. In summary AEPs are not an obligatory part of the routine diagnostic work-up in ALS patients. Pathological values may occasionally be observed and cannot be used as argument against the diagnosis in otherwise typical patients.
There is evidence from clinical, neuropsychological and neuropathological studies that the neurodegenerative process in ALS extends beyond the primary motor cortex and involves cortical regions important for cognitive functions (Wikstrom et al., 1982; Horoupian et al., 1984; Iwasaki et al., 1990; Neary et al., 1990). Psychological deficits, frequently of the frontal lobe type, are reported to become prevalent in about 2– 5% of patients with sporadic ALS. Since a general limitation of classical psychological testing of cognitive function in ALS is interference with physical disability of the patients, neurophysiological assessment of higher order functions has also been employed. Event-related potentials (ERPs), especially the “P300” late component, have the potential to monitor changes of cognitive functions and have been studied in ALS using simple as well as more complex visual and auditory tasks. Gil et al. (1995) were among the first to analyze auditory ERPs in ALS investigating 20 patients and as many matched controls. They found no differences in the latencies of the early N100 and P200 waves, but could show a significant delay of the P300 latency in 60% of the ALS patients. Additionally, the patients underwent classical neuropsychological testing producing significantly lower scores than the controls. To our knowledge, this study was the first to demonstrate the usefulness of ERPs in testing cognitive function in ALS, especially in the course of the disease, as problems arising from progression of motor deficits or speech difficulties could be circumvented. Paulus et al. (2002) investigated auditory and visual ERPs in 16 ALS patients in a combined neuropsychological and neurophysiological study. They were able to carry out a more subtle differentiation of the cognitive dysfunction of their patients by using a comprehensive battery of neuropsychological tests covering intelligence, executive functions, attention, memory, word fluency, visuo-motor and visual-constructive skills. A significant impairment of executive functions and attention was observed in the group of ALS patients associated with a significant correlation to prolonged latencies of visual and auditory P300 waves. The study provided further evidence for the usefulness of ERPs in assessing cognitive functions in ALS patients and
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demonstrated a close relationship between cognitive deficits and neurophysiological changes. Frontal lobe functions were tested by means of ERPs in eight ALS patients without clinical signs of cognitive impairment by Vieregge et al. (1999). An auditory task was used in order to test for changes in selective attention as a typical frontal lobe feature. ALS patients showed significantly smaller amplitude differences between the responses to attended and to unattended tones than the controls which was taken as neurophysiological evidence of impairment of selective attention in ALS. ERP studies were also used to analyze memory deficits in ALS (Mu¨nte et al., 1998a,b). Eight ALS patients and as many age-matched controls were subjected to a two-phase recognition memory test. During the first phase, words were repeatedly presented on a video-screen. During the second phase (1 h later) a second list containing old and new words was presented while ERPs were recorded (Fig. 4). A significantly different waveform of the ERPs in response to repeated and new words between ALS patients and controls was found indicating an alteration of memory processing in ALS. The same group studied visual search behavior of ALS patients (Mu¨nte et al., 1999). Comparing 13
patients with sporadic ALS and as many controls, target detection rates in parallel tasks were found to be normal in ALS. A significant slowing of the performance was shown in serial tasks associated with alterations of the ERP recordings. Changes of an early attention-sensitive ERP component pointed to an attention deficit underlying the impairment of visual search behavior in ALS. Kotchoubey et al. (2003) used ERPs in almost completely immobile ALS patients with sustained artificial ventilation to investigate cortical plasticity. The results were compared with records obtained from patients with tetraplegia due to high-level spinal cord injury and from healthy controls. The time course of ERPs upon the presentation of words belonging to different association fields was analyzed over 10 regions of interest on the scull. This approach allowed brain mapping of ERP differences between the two patient groups and the controls. In summary, the analysis revealed that activation of visual information processing plays an important compensatory role in both ALS and spinal cord injured patients. In conclusion, ERPs appear to be an easily accessible and reliable monitor of specific changes of cognitive functions in the disease course of ALS. The above reports indicate changes of cortical functions beyond the motor cortex and are in line with results from neuropathological and functional imaging studies (Ludolph et al., 1992; Brooks et al., 2000; Turner and Leigh, 2000; Konrad et al., 2002). The future will probably belong to studies combining the advantages of ERP techniques and of functional magnetic resonance imaging (fMRI), i.e. high temporal resolution of ERPs and high spatial resolution of fMRI.
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Fig. 4. ERPs (grand average) recorded from the scalp at Cz and Pz electrode positions (10/20 system) in response to single words presented on a monitor. Thick and dotted lines indicate ERPs following first and repeated presentations, respectively. Patients with ALS fail to show a more positive ERP waveform following correct recognition of repeated words pointing to an alteration of memory processing (modified from Mu¨nte et al., 1998b).
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