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(BQ) Part 2 book Pediatric neurology presents the following contents: Differential effects of acute severehypoxia and chronic sublethal hypoxia on the neonatal brainstem; cerebrospinal fluid levels of cytokines andchemokines in patients with west syndrome, pediatric epilepsy, focal epilepsies and multipleindependent spike foci.
In: Pediatric Neurology Editors: P.N Lawson, E.A McCarthy, pp 91-114 ISBN: 978-1-61324-726-6 © 2012 Nova Science Publishers, Inc Chapter DIFFERENTIAL EFFECTS OF ACUTE SEVERE HYPOXIA AND CHRONIC SUBLETHAL HYPOXIA ON THE NEONATAL BRAINSTEM Ze Dong Jiang* and Andrew R Wilkinson Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom ABSTRACT Perinatal asphyxia and neonatal chronic lung disease (CLD) are two major problems in newborn infants, often leading to neurodevelopmental deficits or disabilities later in life Both problems are associated with hypoxia, but the nature of the hypoxia in the two problems is different The hypoxia after perinatal asphyxia is often acute, severe or lethal, and associated with ischaemia of the brain In contrast, the hypoxia in neonatal CLD is chronic or prolonged and sublethal Such differences may exert differential effects on the functional integrity and development of the neonatal brain, leading to different neuropathological changes and neurodevelopmental outcomes In recent years, some investigators have studied the functional integrity of the neonatal auditory brainstem in infants after perinatal asphyxia and neonatal CLD and have found differences in the effects of acute severe hypoxia and chronic sublethal hypoxia on the neonatal brainstem In infants after perinatal asphyxia, neural conduction and synaptic function are impaired in both peripheral and central regions of the brainstem, although the impairment is slightly more severe in the more central than the more peripheral regions In infants with neonatal CLD, however, neural conduction and synaptic function are impaired predominantly in the more central regions of the brainstem, whereas the more peripheral regions are relatively intact These findings indicate that perinatal asphyxia affects both the central and peripheral regions of the brainstem, while neonatal CLD affects predominantly the central regions, without appreciable effect on the peripheral regions This difference may be, at least partly, related to the different nature of hypoxia in the two clinical problems These findings shed light on the pathophysiology underlying neurological impairment and * Correspondence address: Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK E-mail address: zedong.jiang@paediatrics.ox.ac.uk 92 Ze Dong Jiang and Andrew R Wilkinson developmental deficits in neonatal CLD, related to chronic sublethal hypoxia, and after perinatal asphyxia, related to acute lethal hypoxia and the associated ischemia The knowledge obtained from these studies also provides valuable information for studying and implementing neuroprotective interventions or therapies for the two neonatal problems The interventions should target more central regions of the brain for infants with CLD, but target both peripheral and central regions of the brain for infants after perinatal asphyxia Recent studies have also found that in infants with perinatal asphyxia, the electrophysiological activity in the neonatal brainstem is significantly depressed, suggesting major neuronal injury and/or neuronal death after severe hypoxia-ischemia For these infants there is a need to intervene with radical neuroprotective measures (e.g brain cooling) as early as possible to reduce further neuronal injury and death and rescue severely injured neurons In infants with CLD, however, there was no noticeable depression of electrophysiological activity in the neonatal brainstem, suggesting no severe neuronal injury and/or neuronal death It appears that for infants with CLD there is no need to implement radical treatments, and well regulated supplemental oxygen may remain the most valuable therapy, along with other therapeutic adjuncts INTRODUCTION In newborn infants, asphyxia and chronic lung disease (CLD) are major perinatal problems, often leading to neurodevelopmental deficits or disabilities later in life Asphyxia occurring during the perinatal period is the most important cause of acquired brain damage in infants with subsequent life-long sequelae (Levene and Evans, 2005; Volpe, 2001) Many of the survivors have various degrees of learning difficulties, language deficits, attention deficit, hyperactivity disorders and cerebral palsy Neonatal CLD is one of the most common longterm complications in very low birthweight or very preterm infants (Greenough and Milner, 2005; Jeng et al., 2008) Although the primary pathology of CLD is related to lungs, approximately half of severe CLD survivors have neurodevelopmental deficits, which is a major concern of CLD survivors (Böhm and Katz-Salamon, 2003; Jeng et al., 2008; Karemaker et al., 2006; Katz-Salamon et al., 2000) Therefore, neonatal CLD and perinatal asphyxia are two major problems that have attracted considerable clinical attention The neonatal brain, particularly the cortex, is well known to be sensitive to arterial blood oxygen tension and hypoxia Neonatal CLD and perinatal asphyxia are both associated with hypoxia (Böhm and Katz-Salamon, 2003; Greenough and Milner, 2005; Jeng et al., 2008; Karemaker et al., 2006; Levene and Evans, 2005; Volpe, 2001) However, the nature of hypoxia in the two clinical problems is different The hypoxia in CLD is chronic or prolonged, and sublethal In contrast, the hypoxia in perinatal asphyxia is often acute, severe or lethal, and associated with ischaemia of the brain (Johnston et al., 2001; Levene and Evans, 2005; Volpe, 2001) Therefore, perinatal asphyxia and neonatal CLD may exert some different effects on the neonatal brain, resulting in differential neuropathological changes and neurodevelopmental outcome Understanding the mechanisms is important for studying and implementing neuroprotective interventions or therapies for infants with the two different clinical problems (Barks, 2008; Glass and Ferriero, 2007; Tin and Wiswell, 2008) The brainstem auditory evoked response (BAER) reflects electrophysiological activity of large numbers of neurons in the auditory brainstem in response to acoustic stimulation As a non-invasive objective test, the BAER has been an important tool to study the functional Differential Effects of Acute Severe Hypoxia 93 integrity and maturation of the neonatal, specifically auditory, brainstem and detect neural abnormalities in infants with various perinatal problems (Chiappa, 1991; Jiang, 2008,2010; Musiek et al., 2007; Wilkinson and Jiang, 2006) The BAER is sensitive to arterial blood oxygen tension and hypoxia (Inagaki et al., 1997; Jiang et al., 2005b,2006C; Sohmer et al., 1986) It has been used to assess the functional integrity of the auditory pathway and the brainstem in infants after hypoxia-ischemia (Hecox et al., 1981; Jiang, 1995,1998; Jiang and Tierney 1996; Jiang et al., 2001,2004; Karmel et al., 1988; Kileney et al., 1980) Nevertheless, there are some limitations in conventional BAER (i.e the BAER recorded using conventional average technique) to detect neuropathology that affects the auditory brainstem False-negative results are not uncommon Increase in the repetition rate of stimuli that elicit the BAER could enhance the detection of some neuropathology that affects the brainstem auditory pathway (Wilkinson and Jiang, 2006) However, in conventional evoked potential instruments (or averagers) the increase is limited by the need to prevent responses from overlapping one another More recently, a relative new technique - the maximum length sequence (MLS) has been used to study the BAER and middle latency auditory response (Bell et al., 2001,2002,2006; Eysholdt and Schreiner, 1982; Jirsa, 2001; Jiang, 2008; Jiang et al., 2000; Lasky, 1997; Lasky et al., 1998; Lina-Granada et al., 1994; Musiek and Lee, 1997; Musiek et al., 2007; Picton et al., 1992) Unlike the uniformly spaced stimuli used in conventional BAER testing, the MLS uses patterned stimulus presentation to elicit evoked potentials This relatively new technique permits the overlapping of responses to successive stimuli, and allows presentation of stimuli at much higher rates than is possible with conventional methods The stimuli consist of distinct pulses of uniform polarity and amplitude occurring at pseudorandom time intervals Each pulse sequence is actually a series of pulses The nature of the stimuli and the newly developed processing technique make it unnecessary to wait for the response of each pulse to be completed before application of a new pulse Thus, pulses can be delivered at maximal rates of up to 1000/sec or even higher The higher rates provide a much stronger physiological/temporal challenge to auditory neurons, and permit a more-exhaustive sampling of physiological recovery or "fatigue" than is possible with conventional stimulation Such a stimulus ‘stress’ provides a potential to improve the detection of some neuropathology that may not be detected by presenting less stressful stimuli (i.e low-rate stimulation) using conventional averaging techniques With conventional BAER, we studied functional status of the neonatal auditory brainstem in infants with neonatal CLD (Jiang et al., 2006a,2007b), and infants after perinatal asphyxia (Jiang et al., 2001,2004,2006b) We have also studied the two clinical problems using MLS BAER (Jiang, 2008,2010; Jiang et al., 2000,2003,2009b,c; Wilkinson et al., 2007) More recently, in order to identify any differences in the functional integrity of the neonatal brainstem between the infants with neonatal CLD and those with perinatal asphyxia, we have compared MLS BAER results between the two major perinatal problems (Jiang et al., 2009a,2010) Detailed analysis was carried out, respectively, for MLS BAER wave latencies and interpeak intervals, reflecting neural conduction in the auditory brainstem, and for MLS BAER wave amplitudes, reflecting brainstem auditory electrophysiology, mainly neuronal function of the auditory brainstem These studies have exposed some very interesting findings, suggesting that there are differential pathophysiological changes in the brainstem between neonatal CLD and perinatal asphyxia, which may have important clinical implications 94 Ze Dong Jiang and Andrew R Wilkinson DIFFERENCES IN IMPAIRED BRAINSTEM CONDUCTION BETWEEN ACUTE SEVERE HYPOXIA AND CHRONIC SUBLETHAL HYPOXIA In both conventional BAER and MLS BAER, the major variables that reflect the functional integrity of the auditory brainstem are wave V latency and interpeak intervals, particularly I-V interval (Wilkinson and Jiang-, 2006) The typical and major abnormality in various clinical problems is an increase in I–V interpeak interval, suggesting impaired nerve conduction and synaptic transmission in the auditory brainstem (Chiappa, 1990; Jiang, 2008; Jiang et al., 2004; Wilkinson and Jiang, 2006) Such abnormalities are often more evident at higher than at lower repetition rates of click stimuli This is particularly obvious in MLS BAER (Jiang, 2008; Jiang et al., 2005a; Wilkinson and Jiang, 2006) The I–V interval, socalled brainstem conduction time, is the most commonly used BAER variable reflecting functional status, specifically neural conduction, of the auditory brainstem (Chiappa, 1990; Jiang, 2008; Wilkinson and Jiang, 2006) This interval is comprised of two sub-components — the early components I–III interval and the later component III–V interval The two smaller intervals reflect functional status of the more peripheral and the more central regions, respectively, of the brainstem (Jiang, 2008,2010; Jiang et al., 2009d) Our previous BAER studies have shown that in some neuropathology the I–III and III–V intervals and, particularly, their ratio (i.e III–V/I–III interval ratio that reflects their relative change) can uncover some abnormalities that cannot be shown by examining the I–V interval only (Jiang, 2008; Jiang et al., 2002,2009d) In recent years, we examined wave latencies and interpeak intervals in MLS BAER in infants with neonatal CLD or after perinatal asphyxia and compared the results between the two clinical problems (Jiang et al., 2010) Particular attention was paid to the analysis of I–III and III–V intervals and III–V/I–III interval ratio to detect any differences between neonatal CLD and perinatal asphyxia in neural conduction of the more central (III–V interval) and the more peripheral regions (I–III interval) of the auditory brainstem These analyses allowed us to gain some new insights into the effects of the two conditions on the functional integrity, related to neural conduction and synaptic transmission, of the neonatal auditory brainstem We recruited 117 term newborn infants after perinatal asphyxia They had clinical signs of hypoxic–ischaemic encephalopathy (hypotonia with reduced or no spontaneous movements, increased threshold for primitive reflexes, lethargy or coma, absence or very weak suck and requirement of tube feeds, or seizures), other signs of hypoxia (e.g frequent depression and failure of breathing spontaneously at birth), and depression of Apgar score (≤ at min) (Levene and Evans, 2005; Volpe, 2001) These infants also had meconium staining of the amniotic fluid and/or umbilical cord blood pH < 7.10 We also recruited 43 very preterm Infants with CLD, who met the following criteria of CLD: requirement for supplementary oxygen or ventilatory support beyond 36 weeks of postconceptional age to maintain PaO2 >50 mm Hg, clinical signs of chronic lung respiratory disease, and radiographic evidence of CLD (persistent strands of density in both lungs) None had any other major perinatal complications or problems that may affect the central nervous system All were studied at term date (i.e 38–42 weeks postconceptional age) Differential Effects of Acute Severe Hypoxia 95 Figure Sample recordings of MLS BAER, recorded with click intensity ≥ 40 dB above BAER threshold at term age, from a normal term infant (A), a very preterm infant with neonatal CLD (B), and an term infant after perinatal asphyxia (C) Compared to that in normal term infant, III–V interval is increased markedly in the infant with CLD, and moderately in the infant after asphyxia I–III interval in the infant with CLD is similar to that in the normal infant, whereas the interval in the infant after asphyxia is moderately increased As a result, III–V/I–III interval ratio is increased significantly in the infants with CLD These differences are more significant at higher (e.g 455/s) than at lower click rates (e.g 91/s) In addition, the infant with CLD does not show any major amplitude reduction for all MLS BAER waves, but the infant after asphyxia shows a major amplitude reduction, particularly for wave V and at very high rates (455 and 910/s) The latencies of waves I, III, and V were measured Interpeak intervals of I–V, I–III and III–V, and III–V/I–III interval ratio were then calculated Figure shows sample recordings of MLS BAER made from each of the healthy term infants (as term controls), infants with neonatal CLD, and infant after perinatal asphyxia 96 Ze Dong Jiang and Andrew R Wilkinson Differences in Brainstem Neural Conduction between CLD and Asphyxia Findings in MLS BAER wave Latencies and Intervals Compared to the normal controls, wave I latency in the infants with neonatal CLD was slightly longer at all click rates 21–910/s, but without any statistical significance The latency in the infants after perinatal asphyxia was similar to that in the controls at all click rates When comparison was made between the two study groups of infants, wave I latency was slightly longer in the infants with CLD than in the infants after asphyxia, though this did not reach statistical significance Wave III latency in the infants with CLD was slightly longer than in the normal controls at all click rates between 21 and 910/s However, the latency in the infants after asphyxia was significantly longer than in the controls at 227–910/s clicks The latency was similar in the two study groups at lower click rates, and tended to be longer at higher rates in the infants after asphyxia than in the infants with CLD In contrast to wave I and III latencies, the major wave latency in the BAER — wave V latency was significantly longer than in the controls for both the infants with CLD and those after asphyxia This occurred at all click rates 21–910/s (Figure 2), though was more significant at higher than at lower click rates The extent of prolongation in the latency was similar in the CLD infant and the infants after perinatal asphyxia at all rates, without any significant difference between the two study groups (Figure 2) 11.0 Wave V latency (ms) 10.0 9.0 8.0 7.0 NT C LD 6.0 A sp 21 91 227 455 910 Click Rate (/s) Figure Boxplot of BAER wave V latency (bold line across the box, median; box, 25th and 75th centile; extensions, the largest and smallest values) at various click rates in very preterm infants with neonatal CLD, term infants after perinatal asphyxia (Asp), and normal term (NT) infants as controls The data are recorded with click intensity ≥ 40 dB above BAER threshold at term age These are also the case for all Figures 3-10 The p values (*p < 0.05) shown in the figure are for the comparison between CLD and asphyxiated infants Wave V latency is similar in the CLD and asphyxia groups, although the latency in both groups is significantly longer than in normal infants (C) Differential Effects of Acute Severe Hypoxia 97 The I–V interval in both the CLD and the asphyxiated infants was significantly longer than in the controls at all click rates 21–910/s (Figure 3) The difference for the two study groups from the controls was increased linearly with the increase in click rate The increase in the interval was similar in the CLD and asphyxiated infants, without any significant differences between the two groups at any click rates (Figure 3) This was similar to that of the wave V latency To detect any differences in the functional status between the peripheral and central regions of the auditory brainstem and any differences between CLD and asphyxia, we also analyzed the I-III and III-V intervals, and the III-V/I-III interval ratio This allowed us to detect any differences between neonatal CLD and perinatal asphyxia that may not be shown by conventionally analysing the I–V interval only The I–III interval in the infants with CLD was similar to that in the controls at all click rates 21–910/s However, the interval in the infants after asphyxia was significantly longer than in the controls at all rates (Figure 4) The difference was more significant at higher than at lower rates There was a major difference in the I–III interval between the two study groups; the interval, though similar in the two groups at 21/s in conventional BAER, was significantly longer in the infants after asphyxia than in infants with CLD at all rates 91–910/s in MLS BAER The difference was increased with the increase in click rate In contrast, the III–V interval in infants with CLD was significantly longer than in the controls at all click rates 21–910/s (Figure 5) The difference between infants with CLD and the controls was increased linearly with increasing click rate For the infants after asphyxia, the III–V interval was also significantly longer than in the controls, particularly at higher rates (Figure 5), but the increase was relatively less significant than that in infants with CLD When comparison was made between the two study groups, the III–V interval tended to be longer in the infants with CLD than in the infants after asphyxia, and the difference was increased with the increase in click rate, reaching statistical significance at higher rates 277–910/s (Figure 5) 8.5 I-V interval (ms) 7.5 6.5 5.5 4.5 NT C LD A sp 3.5 21 91 227 455 910 Click Rate (/s) Figure Boxplot of I-V interpeak interval at various click rates in very preterm infants with neonatal CLD, term infants after perinatal asphyxia (Asp), and normal term (NT) infants as controls The interval is similar in CLD infants and asphyxiated infants, although the interval in both groups is significantly longer than in normal controls 98 Ze Dong Jiang and Andrew R Wilkinson 4.8 I-III interval (ms) 4.2 * * 3.6 * * * * * * * * 3.0 2.4 NT CLD Asp 1.8 21 91 227 455 910 Click Rate (/s) Figure Boxplot of I-III interpeak interval at various click rates in very preterm infants with neonatal CLD, term infants after perinatal asphyxia (Asp), and normal term (NT) infants as controls The p values (*p < 0.05, **p < 0.01; ***p < 0.001) are for the comparison between CLD and asphyxiated infants The interval in asphyxiated infants is significantly longer than in CLD infants whose I–III interval is similar to that in normal controls, at all click rates 21–910/s 4.5 * III-V interval (ms) 3.9 * * 3.3 2.7 2.1 NT C LD 1.5 A sp 21 91 227 455 910 Click Rate (/s) Figure Boxplot of III-V interpeak interval at various click rates in very preterm infants with neonatal CLD, term infants after perinatal asphyxia (Asp), and normal term (NT) infants as controls The p values (*p < 0.05) are for the comparison between CLD and asphyxiated infants The interval in CLD infants is significantly longer than in asphyxiated infants at all 21–910/s, although the interval in both groups is significantly longer than in normal controls Differential Effects of Acute Severe Hypoxia 99 We further analysed the III–V/I–III interval ratio — a BAER variable that may detect some abnormality that could not be shown by analysing the I–V, I-III and III-V intervals (Jiang et al., 2009d) For the infants with CLD, the interval ratio was significantly greater than in the normal controls, and the difference between the two groups was increased linearly with increasing click rate (Figure 6) For the infants after asphyxia, III–V/I–III interval ratio was only slightly greater than in the controls, although there was a statistically significant difference at 455/s Comparison between the two study groups revealed that the interval ratio was significantly greater in the infants with CLD than in the infants after asphyxia at all click rates 1.8 III-V/I-III interval ratio 1.5 1.2 * * * * * * * * * * * * * * NT CLD Asp 21 91 227 455 910 Click Rate (/s) Figure Boxplot of the III–V/I–III interval ratio at various click rates in very preterm infants with neonatal CLD, term infants after perinatal asphyxia (Asp), and normal term (NT) infants as controls The p values (**p < 0.01, ***p < 0.001) are for the comparison between CLD and asphyxiated infants The interval ratio in CLD infants, which is significantly greater than in normal controls at all click rates 21–910/s, is significantly greater than in asphyxiated infants whose interval ratio is similar to that in normal controls at 21–227/s and is greater than in controls at 455 and 910/s, at all click rates 21–910/s Impaired Brainstem Neural Conduction and Differences between Asphyxia and CLD In the BAER, wave V latency and I–V intervals are the two most widely used variables that reflect neural conduction, related to myelination and synaptic function, in the brainstem or central auditory pathway (Jiang, 2008) The two variables were increased similarly in our CLD and asphyxiated infants, suggesting similar degree of impairment in neural conduction in the auditory brainstem However, a more detailed analysis revealed that there were major differences between the two clinical problems In the infants with CLD, no apparent abnormalities were found in wave III latency and the I–III interval (Figure 4), suggesting no appreciable abnormality in the more peripheral regions of the brainstem In the infants after 100 Ze Dong Jiang and Andrew R Wilkinson perinatal asphyxia, however, wave III latency tended to increase and, in particular, the I–III interval was increased significantly at all click rates, suggesting impaired neural conduction in the more peripheral regions of the brainstem On the other hand, there was a major increase in the III–V interval (Figure 5) and the III–V/I–III interval ratio in both the CLD and asphyxiated infants, but the increase was more significant in the infants with CLD than in the infants after asphyxia Apparently, there is major impairment in neural conduction in the more central regions of the brainstem in the two clinical problems, but the impairment is more severe in neonatal CLD than in perinatal asphyxia Such differential changes in the earlier sub-component (I–III interval) and the later sub-component (III–V interval) of the I–V interval are almost the other way around in the two clinical problems, resulting in a similar increase in the I–V interval (and wave V latency) The I–III interval was significantly longer in the infants after perinatal asphyxia than in the infants with neonatal CLD, while the III–V interval was somewhat the other way around, i.e the interval was longer in CLD than in asphyxia Such differential changes in the two intervals leads to a significant greater III–V/I–III interval ratio in the infants with CLD than in the infants after asphyxia Differences in Brainstem Synaptic Transmission between CLD and Asphyxia Findings in MLS BAER Wave Latency- and Interval-Rate Functions For those variables that were correlated significantly with click rate, the latency-, interval-, and amplitude-rate functions were obtained by regression analysis The slope for each function was then calculated to assess click rate-dependent changes (i.e changes in BAER variables with varying click rate) For each MLS BAER variable-rate function that was significantly greater than zero at the 0.05 level or better, the slope was compared between the study and control groups to detect any difference The slopes of latency-rate functions for waves I and III in the infants with CLD were similar to those in the normal controls In the infants after asphyxia the slope of latency-rate function for wave I was also similar to the controls, while the slope for wave III was slightly steeper than in the controls, with no statistical significance However, the slopes of latencyrate functions for wave V in both the CLD and the asphyxiated infants were significantly steeper than in the controls This was also the case for the slope of the I–V interval-rate function The slope of the I–III interval-rate function in the infants with CLD was similar to that in the controls, while the slope in the infants after asphyxia was slightly steeper than in the controls The slopes of the III–V interval-rate function and the III–V/I–III interval ratiorate functions in the two study groups were all steeper than in the control group, which was more significant in the infants with CLD than in the infants after asphyxia Comparison between the CLD and the asphyxiated infants did not show any significant differences in the slopes of wave I and V latency-rate functions and the I–V interval-rate function The slope of wave III latency-rate function was slightly steeper in the infants after asphyxia than in the infants with CLD, with no statistical significance The slope of the I–III interval-rate function was significantly steeper in the infants after asphyxia than in the infants with CLD (p < 0.05) On the contrary, the slope of the III–V interval-rate function in the infants with CLD was slightly steeper than in the infants after asphyxia The slope of the III– 172 Tomoyuki Takano neuronal migration disorders (Blume, 1978; Mizukawa, 1992; Noriega-Sanchez and Markand, 1976), thus suggesting variable and widespread occurrence of neuropathological findings Most patients have significant cognitive and motor deficits: motor disturbances in 40 to 45% and mental retardation in 68 to 82% Noriega- Sanchez and Markand (1976) and Blume (1978) found most patients with multiple independent spike foci to have multiple seizure types, including various types of generalized seizures, which occur with high frequency and prove refractory to medication Multiple independent spikes appear as paroxysms of brief multiple spike and waves, irregular spike and waves, or sharp waves during interictal state However, ictal EEG findings in patients with multiple independent spike foci, which have been reported in association with certain seizure types, have not been entirely clarified Mizukawa (1992) reported ictal EEGs in 17 patients with tonic spasms, that is, desynchronization in 9, recruiting rhythm in 1, and rapid synchronization in Diffuse polyspike and wave or irregular spike and wave are also reported in myoclonic seizures Yamatogi and Ohtahara (1981) suggested that these ictal EEG patterns are similar to those of generalized motor seizures seen in patients with Lennox- Gastaut syndrome Some researchers have proposed that this electroclinical syndrome with multiple independent spike foci with severe epilepsy should be called Markand-Blume-Ohtahara syndrome, because of extensive studies on multiple independent spike foci by Markand and Blume for defining its clinical correlates, and by Ohtahara for integrating clinical characteristics with other epileptic encephalopathies (Yamatogi and Ohtahara, 2003, 2006) Interictal multiple independent spikes were observed in patients with focal epilepsies in the current series (temporal lobe epilepsy in 1, and frontal lobe epilepsy in 2) Two cases had past histories of profound brain insult before the appearance of multiple independent spike foci such as PVL and viral encephalitis with widespread neuropathological findings It is suggested that these etiological backgrounds are closely associated with the multiple cortical excitability producing multiple independent spike foci, resulting in generalized epileptiform discharges Focal Epilepsies and Multiple Independent Spike Foci 173 Figure A: Ictal EEG of TLE (Case 4) Epileptic discharges started from the rapid rhythms on the bilateral Fp and F at the sudden onset of tonic seizure of the left arm (*), followed by rhythmic sharp wave discharges of the left arm and leg during the clonic phase, seconds later (**) B: Ictal EEG of PLE (Case 8) Low voltage rhythmic alpha wave activity was continuously observed during the somatosensory seizure accompanied by severe abdominal pain (*) Ictal discharges attenuated (**) or activated (***) in proportion to the decrease or increase of the abdominal pain REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] Blume WT Clinical and electroencephalographic correlates of the multiple independent spike foci pattern in children Ann Neurol 1978; 4: 541-7 Engel J Jr Functional explorations of the human epileptic brain and their therapeutic implications.Electroencephalogr Clin Neurophysiol 1990; 76: 296-316 Engel J Jr, Pedley TA Introduction: what is epilepsy? In: Engel Jr J, Pedley TA, editors Epilepsy: a comprehensive textbook Philadelphia: Lippincott Williams & Wilkins; 2008 p 1-7 Engel J Jr, Dichter MA, Schwartzkroin PA Introduction: Basic mechanisms of human epilepsy In: Engel Jr J, Pedley TA, editors Epilepsy: a comprehensive textbook Philadelphia: Lippincott Williams & Wilkins; 2008 p 495-507 Mizukawa M Severe epilepsy with multiple independent spike foci: a clinical and electroencephalographic study [in Japanese] J JpnEpilSoc 1992; 10: 78-87 Noriega-Sanchez A, Markand ON Clinical and electroencephalographic correlation of independent multifocal spike discharges Neurology 1976; 26: 667-72 Yamatogi Y, Ohtahara S Age-dependent epileptic encephalopathy: a longitudinal study Folia PsychiatrNeurolJpn 1981; 35: 321-31 Yamatogi Y, Ohtahara S Severe epilepsy with multiple independent spike foci J Clin Neurophysiol 2003; 20: 442-8 174 [9] Tomoyuki Takano Yamatogi Y, Ohtahara S Multiple independent spike foci and epilepsy, with special reference to a new epileptic syndrome of “severe epilepsy with multiple independent spike foci” Epilepsy Res 2006; 70S: S96-104 uploaded by [stormrg] INDEX A ABR interpeak latency intervals, x, 131, 137 access, 152 accounting, 48 acetylcholinesterase, 63, 117 acid, 47, 59, 60, 61, 64, 70, 152, 153 acidosis, 40 acne, 153 acoustic stimulation, vii, 1, 2, 4, 92 ACTH, 157, 158, 159, 160, 161, 162 action potential, 46 activity level, viii, 66, 76, 81 acute lethal hypoxia, ix, 92, 102, 110 AD, 66, 67, 75, 111, 130 adaptation, 6, 37, 113 adenoma, 148 ADHD, 85 adjunctive therapy, 153, 154 adjustment, 149 adolescents, 54, 71, 72, 73, 85, 151, 154 adrenocorticotropic hormone, 158, 159 adulthood, 48, 53, 72, 146 adults, x, 12, 14, 16, 18, 37, 46, 52, 54, 71, 72, 80, 85, 86, 87, 113, 115, 118, 120, 123, 124, 129, 133, 135, 151, 153, 154 advancements, 122 adverse effects, 40, 48, 49, 52, 53 aetiology, 85 aggression, 48, 61 agonist, 47 alpha wave, 170, 171, 173 alters, 51, 54 American Psychiatric Association, 82 amnesia, 42, 54, 57, 147 amniotic fluid, 94 amplitude, 4, 6, 8, 9, 10, 11, 12, 13, 15, 16, 18, 21, 22, 23, 24, 25, 32, 35, 93, 95, 100, 103, 104, 105, 106, 107, 108, 109, 119, 120, 121, 124, 136, 137, 149 amygdala, 41, 42, 44, 45, 50, 71, 73, 78, 88 anatomy, 70 anesthesiologist, 152 anger, 76 angiogram, 151 antagonism, 64 anticonvulsant, 49, 62, 64, 149, 152, 153, 154, 162 antiepileptic drugs, viii, 39, 40, 55, 61, 63, 167 antisense, 50 anxiety, 151 APA, 82 Apgar score, vii, 2, 3, 19, 26, 36, 70, 94, 112 aphasia, 151 aplastic anemia, 153 apnea, 40 apoptosis, viii, 39, 49, 51, 63, 64, 108 apraxia, 148 arousal, 71, 79 arrest, 158 arrests, 147 arteriovenous malformation, 150 artery, 151 aspartate, 57 asphyxia, vii, viii, ix, 2, 3, 36, 37, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114 assessment, viii, 6, 8, 41, 56, 57, 60, 65, 75, 79, 81, 85, 128, 133, 140, 141, 158, 161 assessment models, 41 astrogliosis, 71 ataxia, x, 131, 132, 148 atonic, 147, 150 atrophy, 50, 54, 107, 148, 159 attentional disengagement, 75 attribution, 57 audit, 56 auditory abnormalities, vii, 2, 3, 12 176 Index auditory cortex, x, 115, 121, 124, 125, 130, 137 auditory evoked potentials, x, 7, 37, 111, 128, 130, 131, 142 auditory nerve, 114 auditory stimuli, 135, 139 autism, vii, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 81, 82, 83, 84, 85, 86, 87, 88, 89, 132 Autism spectrum disorder (ASD), viii, 65 autistic development, 75 automatisms, 147, 150 autosomal dominant, 146 awareness, 41, 67, 147, 150 axons, 47, 71, 118 B background noise, bacteria, 103 basal forebrain, 116 base, 41 basic research, 154 behavioral change, 55 behavioral disorders, 116 behavioral manifestations, 74 behavioral problems, 151 behaviors, 48, 66, 67, 68, 75, 76, 81, 85, 129, 130, 132 Belgium, 65 benign, 43, 49, 57, 59, 146 bias, 80 Bilateral, 58 bilirubin, 31, 32, 34, 37, 38 biological motion, 80, 86 birth weight, 70, 77, 78, 125, 130, 159 births, 33, 35, 132 birthweight, 35, 111, 128 bleeding, 70 blindness, 116 blood, 40, 44, 92, 93, 94, 152 blood flow, 44 blood urea nitrogen, 152 bone, 133 bowel, 33 brain activity, 142 brain damage, 3, 22, 23, 26, 34, 59, 61, 92, 102, 114, 118 brain growth, 45, 50, 62, 84 brain size, 72, 85, 88 brain stem, 38, 113, 142 brain structure, 70, 82, 114 brainstem, vii, ix, x, 1, 2, 3, 4, 6, 7, 8, 12, 13, 17, 18, 19, 20, 21, 22, 23, 24, 26, 30, 31, 32, 33, 34, 35, 36, 37, 38, 91, 92, 93, 94, 97, 99, 101, 102, 103, 107, 108, 109, 110, 111, 112, 113, 114, 121, 131, 132, 135, 137, 140, 141, 142 brainstem auditory evoked response (BAER), vii, 1, 2, 92 brainstem auditory pathway, vii, 1, 2, 3, 4, 6, 7, 12, 13, 17, 19, 20, 31, 34, 93, 101 breathing, 94, 139 bronchopulmonary dysplasia, 28, 38, 114 C calcium, 47, 61, 153 canals, candidates, 148, 151 carbamazepine, 41, 61, 62, 63, 153 caregivers, 146, 148, 149, 150 causality, 57 cavernous hemangiomas, 150 cell culture, 63 cell cycle, 64 cell death, 23, 50, 63, 71, 108 central nervous system (CNS), 22, 37, 40, 94, 101, 113, 114, 125, 137, 161, 162, 163, 171 cerebellum, 44, 50, 54, 63, 71, 83, 88 cerebral blood flow, 137 cerebral cortex, ix, 114, 115, 118, 120, 125, 126 cerebral edema, 159 cerebral function, 6, 22 cerebral hypoxia, 23, 114 cerebral palsy, 68, 81, 92, 103, 113, 116, 141 cerebrospinal fluid, xi, 157, 158, 162, 163 cerebrum, 126 challenges, 133 channel blocker, 153, 154 chemical, chemokines, 160, 161 Chicago, 114 child bearing, 52, 53 childhood, vii, viii, x, 39, 41, 42, 43, 44, 56, 57, 59, 72, 82, 87, 120, 122, 145, 146, 147, 148, 149, 153, 155 China, 141 chloral, 133, 138 cholesterol, 50 cholinesterase, 125, 126 chromosomal abnormalities, 69 chronic hypoxia, 32 chronic lung disease (CLD), vii, viii, 2, 3, 28, 36, 37, 91, 92, 111, 112, 113, 114 circulation, 152 classification, 145 clinical application, 7, 34, 37, 114, 129 clinical diagnosis, 135 Index clinical neurophysiology, vii, 118 clinical problems, ix, 3, 7, 12, 31, 34, 91, 92, 93, 94, 99, 102 clinical symptoms, 74, 158, 162 clinical syndrome, 69 clinical trials, 154 cloning, 59 closure, 51 CNS, 6, 79, 156, 161, 163 cochlea, 120, 121 coding, 69 cognition, vii, viii, 39, 40, 41, 49, 55, 56, 57, 126, 132 cognitive abilities, 67 cognitive deficit, 40, 41, 44 cognitive deficits, 40, 41, 44 cognitive development, 124 cognitive domains, 40 cognitive dysfunction, 55, 128 cognitive function, 41, 43, 44, 49, 52, 54, 55, 56, 57, 58, 62, 73, 120, 124, 128, 130 cognitive impairment, viii, 39, 40, 41, 45, 51, 52, 53, 54, 58 cognitive map, 42 cognitive performance, 43 cognitive process, ix, 43, 115 cognitive processing, ix, 43, 115 cognitive profile, 40, 52 cognitive slowing, 153 collateral, 60 color, 139 coma, 94, 152 combination therapy, 110 communication, viii, x, 65, 66, 67, 68, 71, 73, 80, 81, 82, 83, 131, 132, 140 communication skills, viii, 66, 80, 82 communicative behaviors, 75, 132, 140 communities, 80 community, viii, 65, 74, 78, 80 comorbidity, viii, 65 complex partial seizure, 147, 153, 154, 170 complexity, 79 compliance, 133 complications, 7, 17, 20, 31, 33, 36, 54, 70, 92, 94, 112, 150 compounds, 61 comprehension, 77 computation, 45 computer, 4, 44, 133 conception, 52, 53 concordance, 69 conduction, ix, 18, 23, 36, 37, 38, 91, 93, 94, 99, 102, 109, 112, 113, 122, 133 177 conductive hearing loss, 133 configuration, 142 congenital malformations, 40, 48, 52, 53 connectivity, 44, 73, 77, 118 conscious sedation, 133 consciousness, 3, 147, 152, 159 consolidation, 42, 56, 57 construction, 85 contingency, 86 control group, 100, 134, 137, 138, 139, 158 controversial, 123 controversies, 110 conversations, 140 conversion disorder, 148 cooling, ix, 6, 36, 92, 110, 111, 112 coordination, 67, 75, 76 corpus callosum, 71, 73, 82, 118, 119, 154 correlation, 6, 22, 35, 38, 83, 112, 119, 124, 173 correlations, 124, 163 cortex, ix, 42, 44, 45, 64, 71, 73, 78, 87, 92, 115, 116, 117, 119, 120, 121, 126, 128, 166, 171 cortical neurons, 118 cortical pathway, 117, 118, 124, 126 corticosteroids, 44 cost, 154 cost constraints, 154 creatinine, 152 critical period, 2, 22, 77, 118 CSF, xi, 157, 158, 159, 160, 161, 162, 163 CT, 44, 85, 130, 163 culture, 63 cures, 158 cycles, 127 cytokines, xi, 157, 158, 160, 161, 162 D damages, 102 data analysis, data collection, 6, 75 decay, 138 decay times, 138 deconvolution, 4, 35, 38 defects, viii, 39, 46, 48, 64, 73 deficiency, 54, 70 deficit, 92, 141 Delta, 120 dementia, 148 dendrites, 47, 50, 63, 117, 118 dendritic spines, 118 dendritogenesis, vii, 39, 40 Denmark, 48 depolarization, 43, 45, 46, 122 178 depression, ix, 23, 36, 42, 53, 92, 94, 107, 109, 112, 114 depth, xi, 145, 150 destruction, 33, 108 desynchronization, 172 detectable, 49 detection, vii, viii, 1, 3, 4, 6, 7, 12, 19, 20, 22, 26, 31, 32, 34, 35, 66, 80, 81, 82, 83, 86, 93, 123, 124, 130, 135, 159 developing brain, 45, 46, 50, 53, 61, 63, 64, 102, 113 developmental change, 16, 139 developmental disorder, 70, 77, 78, 81, 85, 87, 89 developmental psychopathology, 56 deviation, 75 diagnostic criteria, viii, 65 diet, 53 differential diagnosis, 67, 140 diffusion, 83 diplopia, 153 disability, 67, 80, 81, 86, 124, 130, 141 discharges, xi, 40, 42, 44, 54, 57, 58, 149, 150, 154, 165, 167, 169, 170, 171, 172, 173 discontinuity, 118, 119 discrimination, 41, 61, 123, 127, 129, 130, 135, 138, 139, 142 discrimination learning, 61 diseases, vii, 1, 69, 111, 162 disorder, viii, x, 33, 43, 54, 58, 65, 66, 67, 69, 71, 78, 83, 84, 85, 86, 87, 89, 131, 132, 135, 138, 140, 143 distress, viii, 66, 70, 76, 81 distribution, 102, 117, 119, 151 dizygotic, 69, 84 dizygotic twins, 69, 84 dizziness, 153, 154 DNA, 44, 50 dominance, 46, 60, 151 dopamine, 50 Down syndrome, 133, 134, 140, 141 down-regulation, 46 drug treatment, 55 drug withdrawal, 61 drugs, 40, 44, 49, 52, 53, 55, 61, 63, 64, 85, 166 DSM, 66, 67, 68 DWI, 83 dysarthria, 148 dyslexia, 130 dysplasia, 35, 111 dystonia, 148 dystonic posturing, 147, 150 Index E EAE, 163 editors, 36, 37, 56, 112, 114, 127, 128, 173 education, 48, 83 EEG, x, xi, 40, 43, 44, 45, 52, 54, 56, 57, 58, 118, 119, 120, 124, 126, 127, 128, 130, 145, 148, 149, 150, 152, 158, 165, 166, 167, 168, 169, 170, 171, 173 EEG activity, 43, 45, 58, 119, 126, 127 EEG patterns, 126, 172 effusion, 141 Egypt, 39 elaboration, 117, 124 electrodes, 7, 120, 122, 135, 139, 150, 167 electroencephalogram, 2, 118, 166 electroencephalography, 54, 145, 158 electrographic seizures, 162 electrophysiological activity, vii, ix, 1, 2, 23, 46, 92, 109 emergency, 52 emission, 7, 141 emotion, 71, 76 emotion regulation, 76 emotional information, 42 encephalitis, xi, 147, 154, 165, 166, 167, 171, 172 encephalopathy, xi, 22, 26, 94, 111, 113, 114, 157, 158, 161, 163, 171, 173 encoding, 41, 42, 45, 137, 138, 140 energy, 23, 44, 120 England, 125 enlargement, 72, 73 environment, viii, 19, 66, 76, 78, 82, 121 environmental change, 79 environmental stimuli, 63 epidemiologic, 87 epilepsy, vii, x, xi, 39, 40, 41, 43, 44, 45, 48, 51, 52, 53, 54, 55, 56, 57, 58, 60, 62, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 158, 161, 162, 165, 166, 167, 172, 173, 174 epilepsy syndromes, x, 52, 55, 145, 148, 153 epileptogenesis, 44, 45, 162 equipment, ERPs, 122, 123, 124, 139 etiology, viii, 65, 68, 152, 157, 161, 167 event-related potential, 42, 123, 128, 130, 143 evidence, viii, x, 23, 51, 58, 61, 65, 69, 71, 73, 74, 77, 80, 83, 86, 87, 89, 94, 114, 115, 117, 125, 126, 129, 133, 134, 135, 136, 140, 141, 149, 162 evoked potential, ix, x, 2, 4, 7, 32, 35, 38, 93, 107, 115, 118, 120, 122, 128, 129, 132, 135, 137, 140, 141, 143 evolution, 58 Index exchange transfusion, 32 excitability, xi, 46, 50, 63, 165, 172 excitation, 40, 44, 51 exclusion, 67 executive function, 41 executive functioning, 41 experimental autoimmune encephalomyelitis, 161, 163 experimental condition, 103 experimental design, 77 exposure, viii, 39, 40, 48, 49, 50, 61, 62, 63, 64, 70, 78 extracellular signal regulated kinases, 51 eye movement, 75 F facial expression, 68 faith, 41 false negative, false positive, 82 families, 74 family history, x, 48, 145, 147 fascia, 47 FDA, 152, 153, 154 fear, 76, 147 febrile seizure, 146, 147 female rat, 67 fetal alcohol syndrome, 70 fetal distress, 70 fetal growth, 35, 38 fetus, 32, 40, 52, 53, 119 fiber, 47, 60, 61, 117 fibers, 47, 49, 60, 61, 116, 117, 118, 119, 121, 122, 125 Finland, 49 first generation, 153 fixation, 75 flexibility, 41 fluid, 162, 163 fMRI, 60 focal seizure, 146, 147 formation, 2, 59, 61, 116, 117, 121, 122, 137 freedom, 154 frontal cortex, 71, 78, 83, 88 frontal lobe, xi, 41, 44, 45, 56, 73, 83, 146, 149, 165, 167, 172 functional integrity of the brainstem, vii, 1, 2, 24, 31 Functional Magnetic Resonance Imaging, 151 functional MRI, 60, 118, 146, 151 179 G GABA, 46, 49, 50, 51, 59, 60, 63, 153 gait, 148 gene expression, 51, 60 generalized seizures, 146, 147, 154, 170, 172 generalized tonic-clonic seizure, 58, 158, 170 genes, 51, 69, 70, 73, 132, 140 genetic factors, viii, 65 genetic linkage, 89 genetic syndromes, 133 genetics, 53, 70, 140 genome, 69 gestation, ix, 18, 27, 28, 36, 48, 50, 115, 116, 119, 121, 125, 126 gestational age, 17, 35, 38, 70, 78, 87, 88, 119, 127 gestures, 66, 68, 76, 81 glia, 46, 73 glial cells, 158 glioma, 51 glucose, 44, 54, 58, 151, 159 glutamate, 46, 47, 49, 51, 59, 60 gray matter, xi, 72, 114, 141, 165, 167 grids, 75, 150 growth, vii, x, 2, 3, 32, 38, 39, 46, 47, 54, 61, 63, 69, 70, 73, 74, 77, 84, 102, 114, 117, 118, 122, 125, 131, 132, 140 growth factor, 46 growth rate, 69, 73 guidelines, 89 H habituation, 63 hair, 134, 153 hair loss, 153 hallucinations, 147, 150 happiness, 68 HDAC, 64 head trauma, 147 health, 80, 81, 82 health care, 80, 81, 82 health care professionals, 80, 81, 82 hearing impairment, 134, 141 hearing loss, x, 111, 132, 133, 134, 135, 136, 140, 141, 142 heat shock protein, 111 hemiparesis, 151 hemisphere, 119, 150, 166, 171 hemoglobin, 151 hemorrhage, 52, 53, 70, 130 hepatic failure, 153 180 Index hepatotoxicity, 152 heterogeneity, 69 hippocampus, 41, 42, 43, 44, 45, 50, 51, 56, 57, 59, 60, 61, 64, 146, 162 hirsutism, 153 histochemistry, 117 histology, 116 histone, 51 histone deacetylase, 51 history, viii, x, 65, 87, 126, 140, 145, 146, 147, 148, 152, 154, 167 HM, 35 human, 22, 26, 35, 37, 40, 44, 54, 56, 57, 61, 63, 102, 111, 112, 113, 114, 117, 118, 121, 123, 125, 126, 127, 128, 129, 130, 142, 163, 173 human brain, 63, 117, 118, 123, 126, 142 human development, 128, 130 Hunter, 54, 133 hybridization, 86 hydrocephalus, 171 hydrocortisone, 113 hyperactivity, 48, 92, 153 hyperbilirubinemia, vii, 2, 3, 31, 32, 35 hyperplasia, 83, 153 hyperthermia, 23, 26 hyperthyroidism, 61 hyperventilation, x, 131, 132, 141 hypoglycemia, 152 hypothermia, 23, 110, 111 hypothesis, 56, 70 hypoxemia, 102, 108, 114 hypoxia, vii, viii, ix, 2, 3, 6, 7, 13, 15, 20, 21, 22, 23, 24, 25, 26, 30, 31, 35, 36, 37, 40, 70, 91, 92, 93, 94, 101, 102, 103, 107, 108, 109, 110, 111, 112, 113, 114 I ID, 127 identification, viii, 10, 34, 65, 67, 80, 82, 83, 123 idiopathic, 58, 68, 147, 149 IFN, 157, 159, 160, 161, 163 IL-13, xi, 157, 159, 160 IL-17, xi, 157, 159, 160 IL-8, xi, 157, 159, 160, 161 imitation, 66, 74, 75, 76, 81, 89 immune response, 163 immunity, 162 immunohistochemistry, 37 immunoreactivity, 162 impairments, 45, 49, 68, 78, 102, 116 improvements, 158 impulses, 119 in utero, 40, 48, 50, 70 in vivo, 54, 122 incidence, 78, 133, 140, 146 incubator, 120 indexing, 129 indirect bilirubin, 38 individuals, x, 43, 68, 69, 77, 78, 84, 132, 134, 140 induction, 42, 43, 45, 51, 64, 161 inefficiency, 108, 109 INF, xi, 157, 159 infancy, 40, 42, 66, 74, 78, 83, 85, 86, 88, 89, 120, 123, 130, 149, 155, 166 infection, 33, 70, 159, 163, 171 inflammation, 33, 71, 163 influenza, 159, 163 influenza a, 163 influenza-associated encephalopathy (IE), xi, 157, 158 information processing, 43, 45, 57, 83, 128, 138 informed consent, xi, 157, 159 inhibition, 43, 44, 57, 58 initiation, 161 injections, 158 injuries, 102, 108 injury, ix, 44, 52, 58, 59, 61, 79, 92, 110, 113, 116 inositol, 59 institutions, 70 integration, 8, 42 integrity, vii, ix, 1, 2, 3, 24, 31, 34, 85, 91, 93, 94, 102, 109, 120, 128, 135, 136 intelligence, 35, 56, 57, 62 intensive care unit, 7, 33, 120 interference, viii, 39 interferon, 158 interferon (IFN), 158 Intervals, 96 intervention, viii, 6, 22, 23, 65, 78, 81, 82, 83, 89, 110 intestine, 70 intrauterine growth restriction, vii, 2, intrauterine growth retardation, 32 inversion, 69 ipsilateral, 8, 150 IQ scores, 48 iron, 53, 54 irritability, 74, 77, 153, 154 ischemia, vii, ix, 2, 3, 6, 7, 13, 15, 20, 21, 22, 23, 24, 25, 26, 30, 31, 35, 37, 92, 93, 111, 113, 114 isolation, 53, 159 issues, 35, 53, 77, 134, 151 Italy, 115 Index J Japan, 157, 165 Jordan, 142 K K+, 42, 46 ketones, 44 L lactic acid, 148 laminar, 117 lamination, 116, 124, 125 language development, 132 language impairment, 137, 142 language skills, x, 67, 76, 130, 131, 132, 140 latency, viii, x, 3, 6, 7, 9, 10, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 26, 27, 28, 29, 31, 33, 35, 37, 38, 65, 77, 82, 93, 94, 96, 97, 99, 100, 101, 109, 110, 111, 114, 120, 121, 122, 128, 131, 135, 136, 137, 138, 139, 142, 143 lead, 40, 102, 109 leakage, learning, viii, 39, 40, 41, 42, 43, 47, 48, 56, 60, 67, 71, 86, 88, 92, 133, 142 learning difficulties, 92 learning disabilities, 88 learning process, 40 learning skills, 67 learning task, viii, 39, 40, 43, 48 left hemisphere, 46, 170 lesions, 37, 45, 46, 107, 108, 111, 114, 137, 143, 150, 154 lethargy, 94 ligand, 163 light, ix, 91, 128 limbic system, 61 lipids, 45 lithium, 49 localization, 146, 148, 149, 150, 161, 162 loci, 69, 89, 132, 140 locomotor, 48 longitudinal study, 55, 111, 173 long-term memory, 41, 42 low birthweight, 28, 36, 92, 112 LTD, 42, 51, 57 lumbar puncture, 159 lung disease, vii, viii, 2, 3, 28, 36, 37, 91, 92, 111, 112, 113, 114 181 M magnetic field, 128 magnetic fields, 128 magnetic resonance, 44, 86, 87, 118, 146, 151 magnetic resonance imaging, 44, 86, 118, 146, 151 magnets, 150 majority, x, 51, 70, 77, 117, 131, 132, 134, 139 malabsorption, 70 man, 128 management, x, 20, 22, 24, 81, 83, 145, 146, 148, 152, 153 mapping, 150, 154 Mars, 74, 87 masking, 142, 149 mastoid, 8, 135, 138 materials, 76 matrix, 116 matter, 41, 73, 77, 83, 102, 117, 166 maturation process, x, 115 maximum length sequence (MLS), vii, 1, 3, 35, 93 MCP, xi, 157, 159, 160 MCP-1, xi, 157, 159, 160 measles, 70 measurement, 7, 10, 11, 23, 34, 77, 88, 105, 120, 124, 133 measurements, 8, 12, 13, 16, 24, 29, 103, 105, 121, 132, 133, 134, 135, 138, 140, 142 meconium, 94 media, 133, 141 median, 25, 96, 121 medical, viii, 6, 48, 66, 74, 79, 80, 86, 140, 143, 148, 154, 155, 158 medication, viii, 39, 40, 55, 57, 148, 150, 172 medicine, x, 127, 128, 145 membranes, 50, 108 memory, viii, 39, 40, 41, 42, 43, 45, 47, 53, 54, 56, 57, 58, 67, 71, 84, 123, 130, 150, 151 memory formation, 41, 43 memory performance, 42, 58 memory processes, viii, 39 meningitis, 103, 111, 146, 159 mental age, 80 mental development, 33, 113 mental processes, 41 mental retardation, 66, 67, 68, 69, 116, 172 messages, 53 meta-analysis, 72, 87, 88 Metabolic, 58 metabolic acidosis, 153 metabolism, 23, 44, 45, 54, 58, 59, 151 methodology, 119, 120, 124, 139 mice, 50, 63, 64, 88, 162 182 Index migration, viii, 39, 49, 50, 51, 116, 172 minicolumn, 74 MIP, xi, 157, 159, 160 modelling, 37, 113 models, 7, 26, 42, 47, 49, 64, 69, 83, 114, 124, 130, 158 molecules, 71, 162 mongolism, 141 monozygotic twins, 69 morbidity, 32, 33, 54 morphology, 121, 122, 124, 136, 137, 139, 149 Moses, 83, 84 motor behavior, 67, 79 motor skills, x, 131, 132 MR, 58, 126 MRI, 44, 52, 54, 58, 71, 72, 73, 77, 84, 146, 150, 151 mRNA, 158, 163 multiple sclerosis, 161, 163 mutant, 88 mutation, 73, 132, 135, 140 mutations, x, 69, 73, 88, 131, 132, 135, 140 myelin, 45, 59, 102, 120 myelin basic protein, 102 myelinogenesis, vii, 39, 40, 122 myoclonus, 148, 155 myopathy, 148 neurons, vii, ix, 1, 2, 4, 6, 23, 43, 45, 47, 50, 54, 60, 61, 63, 71, 92, 93, 101, 102, 107, 108, 109, 110, 116, 117, 118, 120, 127, 137 neuropathy, 148 neuroprotection, 23, 46, 110, 111, 114 neuropsychology, 127 neurotoxicity, 31, 32, 38, 61, 63 neurotransmission, 50, 120 neurotransmitter, 42, 44, 51 neurotransmitters, 49, 101 New England, 130 New Zealand, 125 newborn infants, viii, 20, 26, 31, 91, 92, 94, 123, 125, 126 NICU children, viii, 66, 74 NK cells, 161 NMDA receptors, 51, 64 non-invasively electrophysiological examination, vii, 1, norepinephrine, 50 normal children, 77 novel stimuli, 139 nuclei, 50, 71, 108 nucleus, 2, 41, 50, 108, 125, 154 nurses, 80, 81 O N Na+, 42, 46 nausea, 147 necrosis, 45, 108, 163 negativity, 123, 127, 129, 130 neglect, 83, 150 neocortex, 71, 117 neonatal necrotizing enterocolitis, vii, 2, neonates, viii, 6, 7, 12, 20, 22, 26, 28, 33, 35, 36, 37, 40, 66, 79, 85, 112, 116, 118, 120, 123, 124, 127, 129, 152 nerve, 2, 6, 23, 94, 121, 154 nerve conduction velocity, nervous system, 40, 46, 116, 161 Netherlands, 125 neural function, 13, 22, 30, 31, 32, 33 neural system, 42, 76, 78 neural systems, 42, 76, 78 neurodegeneration, 50, 63, 64 neurodevelopmental deficits, viii, 32, 33, 45, 91, 92 neurodevelopmental disorders, 66 neuroimaging, 81, 118, 122 neuroinflammation, 89 neuronal apoptosis, 49, 51 neuronal ceroid lipofuscinoses, 148, 149 occipital cortex, 121, 171 occipital lobe, xi, 73, 150, 165, 166, 167 occipital lobe epilepsy (OLE), xi, 165, 167 occipital regions, 150 olfaction, 41 open angle glaucoma, 153 operant conditioning, 48 operations, 75 otitis media, 133 otoacoustic emissions, x, 35, 37, 131, 132, 134, 140 outpatient, 149 overlap, 2, overproduction, 126 ox, 1, 91, 151 oxidative stress, 46, 59, 158, 161 oxygen, ix, 92, 93, 94, 110 P pain, 148, 155, 170, 171, 173 palliative, 154 parallel, 2, 38, 87, 117, 118, 121, 122 parenting, 78 parenting styles, 78 Index parents, 40, 70, 74, 75, 78, 146, 148, 149, 150 parietal cortex, 44 parietal lobe, xi, 148, 150, 165, 166, 167 parietal lobe epilepsy (PLE), xi, 165, 167 partial seizure, 147, 148, 153, 154, 170, 171 pathogenesis, 158 pathology, 3, 6, 31, 38, 83, 92, 114 pathophysiological, viii, 22, 28, 30, 65, 93, 166 pathophysiology, ix, xi, 23, 30, 36, 44, 91, 109, 110, 112, 157, 158, 161, 162, 166 pathways, ix, 38, 43, 68, 80, 108, 115, 116, 117, 118, 120, 121, 122, 130, 135, 136, 139 pediatric epilepsy, x, 145, 151, 154 peer relationship, 68 perceptual learning, 142 perinatal, vii, ix, x, 2, 3, 6, 7, 17, 20, 21, 22, 23, 24, 25, 26, 30, 31, 32, 33, 35, 36, 37, 48, 52, 53, 62, 87, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 124, 125, 131, 132 peripheral blood, 163 peripheral blood mononuclear cell, 163 periventricular leukomalacia (PVL), xi, 165, 167 permit, 6, 93 PET, 44, 54, 151 PET scan, 151 pH, 94 pharmacokinetics, 52, 53 pharmacological treatment, xi, 145 phenobarbitone, 40 phenomenology, 126, 127 phenotype, 70, 78, 83, 85, 163 phenylketonuria, 69 phenytoin, 41, 61, 63, 152, 153 Philadelphia, 54, 114, 128, 173 photosensitivity, 147 Physiological, 127 physiology, 126, 127 PI3K, 69, 73 pigs, 26 pilot study, 162 pitch, 129, 142 placebo, 55 plasma levels, 162 plasticity, 41, 43, 44, 45, 46, 51, 57, 60, 142 pleasure, 66, 68, 76 PM, 167 polarity, ix, 4, 93, 115, 120, 121, 122, 124 polymorphisms, 84 pons, 88 population, xi, 22, 32, 33, 39, 53, 85, 88, 107, 125, 134, 136, 140, 145, 162 positron, 44, 54, 146 183 positron emission tomography, 44, 54, 146 posterior cortex, 44 postnatal exposure, 48 preadolescents, 73 precipitation, 166 prefrontal cortex, 78, 125, 126, 127 pregnancy, 40, 48, 50, 51, 52, 53, 116 premature infant, 116, 118, 119, 120, 121, 124, 126, 127 prematurity, 111, 118 preparation, preschool, vii, 39, 78, 84, 129 preschool children, 78, 84, 129 preschoolers, 78 preservation, 46 preterm infants, vii, 17, 18, 19, 20, 23, 24, 25, 27, 28, 29, 30, 33, 36, 37, 38, 87, 92, 96, 97, 98, 99, 103, 104, 105, 106, 112, 113, 116, 117, 122, 125, 126, 127, 128, 130 prevention, 67, 124 primate, 126 principles, 37, 63, 114 probands, 69 problem solving, 41, 67 processing deficits, 137 professionals, viii, 65, 82 prognosis, x, 125, 145 pro-inflammatory, 161 project, 69, 79 proliferation, viii, 39, 45, 49, 51 propagation, 166, 171 protection, 50 protein kinase C, 42, 50 protein kinases, 50, 51 proteins, 59 proteolipid protein, 45 psychiatry, 89, 140, 141 psychobiology, 57 psychologist, 151 psychopathology, 56, 68 psychopathy, 82 psychosocial functioning, viii, 39, 40, 43 PTEN, 69, 73 pumps, 50 pyramidal cells, 60 Q quality of life, xi, 145 quantification, 142 questionnaire, 76, 85, 89 184 Index R radioactive isotopes, 151 ratio analysis, 35 RE, 37, 113, 114, 140 reactions, viii, 66, 76, 81, 161 reactivity, 44, 63, 76, 81 reasoning, 41 recall, 49, 74, 75 reception, 137 receptors, 42, 45, 46, 49, 51, 57, 59, 61, 120, 153 reciprocity, 68 recognition, 41, 42, 56, 74, 78, 80, 84, 86, 130, 139, 140 recommendations, 41, 51, 53 recovery, 4, 5, 6, 22, 23, 26, 44, 93, 152 recovery process, recovery processes, recruiting, viii, 65, 172 recurrence, 52, 166 reflexes, 94 Registry, 62 regression, 27, 28, 29, 30, 100, 105, 106, 107 regression analysis, 27, 28, 29, 30, 100, 105, 106, 107 rehabilitation, 82 rehabilitation program, 82 reinforcement, 135 rejection, 9, 136, 138 relevance, 114 reliability, 11 repression, 51 requirements, 44 researchers, 172 resection, 154 resistance, 66, 67 resolution, 69, 162 resources, 82 response, vii, x, 1, 2, 3, 4, 6, 7, 10, 22, 34, 35, 36, 37, 38, 50, 51, 62, 66, 70, 74, 89, 92, 93, 101, 110, 111, 112, 113, 114, 117, 120, 121, 122, 123, 128, 131, 132, 133, 135, 136, 137, 138, 139, 140, 141, 142, 143, 157, 158, 159, 160, 161 responsiveness, 71, 76 retardation, 62, 66, 67, 69, 141, 148 retina, 120, 139 retrograde amnesia, 57 Rett Syndrome (RTT), x, 131, 132 RH, 141 rhythm, 172 right hemisphere, 170 right ventricle, 50 risk, viii, 9, 10, 17, 18, 19, 20, 24, 28, 32, 33, 36, 37, 40, 48, 51, 52, 53, 65, 67, 70, 75, 76, 77, 78, 79, 81, 82, 83, 87, 89, 114, 116, 125 risk factors, 28, 40, 48, 87, 114, 125 risks, viii, 39, 51, 52, 53 RNA, 50 rodents, 50, 158 routines, 68 S safety, 110, 152 school, vii, 39, 40, 48, 52, 113, 124, 133 schooling, 53 science, 122, 127, 128, 142 sclerosis, 40, 54, 55, 58, 69, 73, 146, 147, 148, 149, 151, 154, 171 second generation, 153 sedatives, seizure, viii, xi, 39, 40, 42, 43, 47, 49, 50, 52, 57, 59, 61, 145, 147, 148, 150, 151, 152, 154, 158, 161, 165, 166, 167, 168, 170, 171, 172, 173 self esteem, 53 semantic memory, 57 sensation, 41, 147, 148, 150, 170 sensations, 41, 147, 148 sensitivity, 4, 6, 9, 70, 80, 82, 133, 136 sensorineural hearing loss, 134 sensory memory, 123, 127, 129 sensory modalities, 122 sensory modality, 123 sensory systems, 120, 127 sentence comprehension, 86 septum, 50 serotonin, 50 serum, 37, 49, 152, 158, 161, 162 services, 81, 82 sex, 134, 142, 167 shock, 148 short-term memory, 41 showing, 5, 43, 67, 71, 80, 158, 170 sibling, 74, 75, 77, 78, 84 siblings, viii, 48, 65, 75, 76, 77, 78, 81, 88 side effects, 40, 52, 153 signalling, 64 signals, 49, 51, 120, 138 signs, viii, 26, 65, 66, 74, 75, 80, 81, 82, 83, 89, 94 silver, simulation, 88 skin, sleep deprivation, 147 social behavior, viii, 65 social cognition, 85, 87 Index social development, 66, 133 social events, 80 social impairment, 69, 88 socioeconomic status, 48, 87, 130 sodium, 151, 153, 158 somnolence, 154 SP, 116, 117, 125 spatial learning, viii, 39, 48, 49 special education, 48 speculation, speech, x, 123, 126, 128, 129, 132, 135, 137, 148 speech sounds, 123, 126, 128 spina bifida, 153 spinal cord, 50, 141 Spring, 57 sprouting, 2, 44, 45, 47, 49, 60, 61 SS, 141 standard deviation, 12, 14, 48, 134 standard error, 13, 15, 16, 17, 18, 19, 27, 28, 29, 30 state, 35, 43, 44, 45, 47, 79, 80, 89, 140, 151, 166, 171, 172 state control, 79 states, 57, 79, 119 status epilepticus, 40, 58, 59, 60, 61, 147, 152, 153 stigma, 53 stimulation, vii, viii, x, 1, 2, 4, 6, 8, 17, 18, 19, 20, 26, 34, 35, 37, 38, 42, 66, 79, 92, 93, 109, 115, 117, 120, 121, 122, 123, 138, 154 stimulus, 3, 4, 6, 8, 10, 11, 22, 37, 38, 41, 75, 79, 84, 93, 101, 103, 120, 121, 123, 128, 129, 135, 137, 138, 139 storage, 41 storms, xi, 157, 158 stratification, 117 stress, 6, 78, 93, 147 stress test, stroke, 146, 154 structure, 3, 71, 83, 116 substrate, 117 substrates, 44 surveillance, 80, 82, 83 survival, 50, 116, 119 survival rate, 116, 119 survivors, 92 susceptibility, 45, 69 swelling, 47 symmetry, 79 symptoms, 44, 74, 80, 84, 85, 148 synapse, 73, 117 synaptic plasticity, 42, 43, 58, 117 synaptic strength, 42 synaptic transmission, 4, 6, 22, 38, 94, 101 synaptogenesis, vii, 39, 40, 45, 47, 69, 117 185 synchronization, 86, 122, 172 syndrome, x, xi, 40, 44, 58, 61, 62, 67, 69, 80, 82, 83, 84, 85, 86, 88, 131, 133, 140, 141, 142, 143, 145, 146, 147, 148, 149, 150, 153, 154, 157, 158, 159, 162, 163, 165, 166, 167, 172, 174 synthesis, 44, 46, 50, 56, 57, 101, 153 T T cell, 162 target, ix, 30, 64, 75, 92, 110, 116, 123 target behavior, 75 taste aversion, 61 taxonomy, 56 teams, 75 techniques, vii, x, 1, 3, 4, 6, 78, 93, 115, 118, 124, 132, 140, 151 technology, 69 temperament, viii, 66, 74, 76, 81, 85, 88 temporal lobe, xi, 41, 42, 44, 54, 55, 56, 57, 58, 60, 73, 137, 146, 147, 149, 154, 162, 165, 167, 172 temporal lobe epilepsy, xi, 54, 55, 57, 58, 60, 146, 147, 149, 162, 165, 167, 172 temporal window, 139 tension, 92, 93 teratogen, 64 terminals, 47, 117 test procedure, 133 testing, 4, 5, 38, 43, 56, 70, 93, 134, 136, 138, 139, 140, 145, 151, 152, 159 test-retest reliability, 76 textbook, 173 Th1 polarization, 163 thalamus, 41, 125, 154 therapeutic interventions, 22 therapy, ix, 40, 49, 52, 62, 83, 92, 110, 152, 153, 162 time frame, 22 tin, 148 tinnitus, 147 tissue, 46, 50, 74, 85 TNF, xi, 157, 158, 159, 160, 161 TNF-α, xi, 157, 159, 160, 161 toddlers, 55, 80, 86, 87 tones, 123, 135, 139, 142 tonic, xi, 43, 146, 147, 150, 153, 157, 158, 161, 162, 168, 169, 170, 171, 172, 173 tonic-clonic seizures, 162, 170 toxic effect, 32, 50 toxicity, 49, 52, 59, 61, 63 toxicology, 152 training, 80, 81, 142, 143 trajectory, 118 transforming growth factor, 163 186 Index translocation, 87 transmission, 42, 94, 101 transport, 44 treatment, xi, 23, 26, 31, 32, 48, 50, 52, 53, 55, 60, 61, 70, 110, 113, 114, 145, 152, 153, 157, 158 tremor, 148, 153 trial, 79 triggers, 42 tumor, 158, 163 tumor necrosis factor, 158, 163 tumors, 146, 148, 150, 154 twins, 69 tympanometry, x, 131, 132, 133, 135, 136, 140 visual attention, viii, 66, 75, 76, 77, 79, 81, 85, 86 visual environment, 77 visual modality, 139 visual processing, 80, 83, 87, 139 visual stimuli, 139 visual stimulus, 75, 79 visual system, 80 vitamin B6, 158 vitamin K, 52, 53 vocalizations, 66, 77 vomiting, 147 vulnerability, 45, 47, 57 W U UK, 1, 48, 91 umbilical cord, 94 underlying genetic abnormalities, x, 145 undernutrition, 32 uniform, 4, 93 United, 1, 53, 67, 84, 91 United Kingdom, 1, 67, 91 United States, 53, 67, 84 USA, 7, 35, 36, 37, 48, 57, 111, 112, 114, 131, 145 V vaccine, 70 Valencia, 155 variables, viii, 11, 14, 16, 17, 18, 19, 20, 22, 24, 29, 31, 33, 39, 40, 94, 99, 100, 101, 103, 109, 141 variations, 22, 69, 79, 86 ventricle, 88 Verbal IQ, 49 vertigo, 153 vesicle, 42 videos, 74, 87 videotape, viii, 65, 74, 75, 81 viral infection, 158, 163 virus infection, 159 vision, 41, 150, 153 visual acuity, 80 waking, 119 Washington, 82 water, 48, 49 weight gain, 153 weight loss, 153 West syndrome (WS), xi, 157, 158, 165, 167 white matter, vii, 39, 73, 83, 84, 85, 102, 107, 117, 137, 140 windows, 23 withdrawal, 150 word recognition, 42 working memory, 43, 61 X xenon, 110, 114 Y yield, 151 young adults, 12, 16 Z zinc, 47 ... al., 20 06a ,20 07b), and infants after perinatal asphyxia (Jiang et al., 20 01 ,20 04 ,20 06b) We have also studied the two clinical problems using MLS BAER (Jiang, 20 08 ,20 10; Jiang et al., 20 00 ,20 03 ,20 09b,c;... al., 20 01 ,20 02, 2006; Eysholdt and Schreiner, 19 82; Jirsa, 20 01; Jiang, 20 08; Jiang et al., 20 00; Lasky, 1997; Lasky et al., 1998; Lina-Granada et al., 1994; Musiek and Lee, 1997; Musiek et al., 20 07;... Semin Fetal Neonatal Med 20 10;15 :28 7- 92 Eysholdt U, Schreiner C Maximum length sequences - a fast method for measuring brainstem evoked responses Audiology 19 82; 21 :24 2-50 Glass HC, Ferriero DM