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Hippocampal Sclerosis and the Syndrome of Medial Temporal Lobe

Hippocampal Sclerosis and the Syndrome of Medial Temporal Lobe

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Hippocampal sclerosis and the syndrome of medial Craig Watson Medial due to is the most common epileptic syndrome and, if medically refractory, is a progressive disorder. Advances over the past decade allow this clinicopathological syndrome to be diagnosed in vivo. Many patients with hippocampal sclerosis become refractory to antiepileptic medications and are at risk of progressive hippocampal damage, cognitive deterioration and other disabling manifestations of refractory epilepsy. Fortunately, if hippocampal sclerosis is CONTENTS detected early and treated surgically, most patients with this syndrome can be rendered -free, thus sparing them from further progression and disability. Etiology & pathogenesis Expert Rev. Neurotherapeutics 3(6), 821–828 (2003) Clinical features Diagnostic evaluation The International Classification of , linked to specific chromosomes [7–26]. The Epileptic Syndromes and Related Seizure Dis- subject of this review is MTLE associated Treatment & outcome orders recognizes five symptomatic localiza- with HS. Medically refractory medial tion-related (i.e., focal, partial) epilepsies, one temporal lobe epilepsy of which is temporal lobe epilepsy (TLE) [1]. Epidemiology Expert opinion Most would subclassify TLE TLE is the most common epileptic syndrome Five-year view into two or three main syndromes with further [3]. HS is the most common neuropathologic subdivisions as shown in BOX 1 [2]. finding in patients with medically refractory Key issues The syndrome of medial temporal lobe epi- TLE and occurs in 60 to 75% of patients References lepsy (MTLE) is characterized by treated surgically for medically refractory TLE Affiliation originating in or primarily involving medial [27–29]. Therefore, MTLE associated with HS temporal lobe structures, such as the hippoc- is the single most frequent epileptic syndrome ampus, and [3]. HS is characterized by neuronal cell loss [3]. The vast majority of patients with MTLE and gliosis involving hippocampal sectors have hippocampal sclerosis (HS), although CA1 and CA3/CA4 with relative sparing of lesions adjacent to or involving medial tempo- CA2, the and , ral lobe structures can also produce seizures although in severe cases pathologic findings identical to those seen in patients with HS. may be widespread (FIGURE 1) [27,29,30]. The syndrome of lateral temporal lobe epi- Department of , lepsy (LTLE), which is characterized by sei- Etiology & pathogenesis Wayne State University School of , 8D-University Health zures originating in the temporal lobe neocor- Despite intensive investigation for over a cen- Center, 4201 St. Antoine, Detroit, tex, is more difficult to define, perhaps due to tury, the precise cause of HS remains elusive. MI, 48201, USA the reciprocal connections between medial Three main hypotheses concerning the etiol- Tel.: +1 313 745 8640 temporal lobe structures and the lateral tem- ogy and pathogenesis of HS have been Fax: +1 313 993 0643 poral [2,4–6]. Recently, several famil- advanced [12,31,32]. The first theory is that a [email protected] ial temporal lobe epilepsy (FTLE) syndromes prolonged febrile or other initial KEYWORDS: have been described, including benign and precipitating injury (IPI), such as , anterior temporal lobectomy, hippocampal sclerosis, medial refractory syndromes and a heterogeneous , head trauma or birth injury, dam- temporal lobe epilepsy, medically group of syndromes with a variety of genetic ages the during a vulnerable refractory epilepsy, PET scanning, volumetric MRI and clinical features, some of which have been period of time in development. The damaged

www.future-drugs.com © Future Drugs Ltd. All rights reserved. ISSN 1473-7175 821 Watson hippocampus then matures into an epileptogenic lesion (i.e., factors to develop this clinical and pathological entity. One HS) over time and the patient develops habitual seizures char- suspects that more factors contributing to the pathogenesis of acteristic of MTLE. This view is supported by the fact that HS will be discovered in the future. approximately 50 to 70% of patients with refractory HS have a history of prolonged febrile or other IPIs in early Clinical features childhood; although, as has been highlighted, this association is Clinical presentation & course not universal [12,31]. As previously mentioned, there is often a latent interval The second theory over the etiology of HS concerns early between an IPI, such as a prolonged febrile convulsion and disordered development. This view holds that HS is a develop- the onset of habitual seizures typical of MTLE. Although mental lesion and is present before birth. In this scenario, the the onset of habitual seizures typically begins towards the prolonged febrile convulsion is regarded as a consequence of end of the first decade of life, the latent interval can be quite the developmentally abnormal hippocampus rather than the long in some instances. Initially, seizures may respond well cause of hippocampal damage [33,34]. This view is supported by to antiepileptic medications and the patients do well for a the high incidence of other developmental lesions found in the number of years. However, as time passes many patients temporal lobes of patients with HS [35–38]. become refractory to antiepileptic medications and ulti- Recently, the possibility of a genetic contribution to the eti- mately develop a progressive course in terms of seizure fre- ology and pathogenesis of HS has emerged. Although it has quency, neuropsychological outcome and progression of long been recognized that febrile seizures tend to run in fami- hippocampal atrophy. lies, HS has not been considered to have strong genetic underpinnings, a concept supported by identical twin studies Clinical seizure characteristics [12,39,40]. Although initial studies describing FTLE suggested The clinical manifestations of seizures originating in medial that this was a benign disorder with no evidence of hippocam- temporal lobe structures have been studied intensely in the past pal abnormalities, subsequent studies have shown that some 10–15 years utilizing data obtained from video EEG monitor- FTLE patients do have HS [7,8,10,11]. Other studies have ing. From these studies, several features characteristic of medial shown genetic abnormalities in some patients with HS [13–15]. temporal lobe seizures have emerged. The common seizure From this evidence, it appears likely that the causes of HS are types associated with MTLE are simple partial seizures (SPS) multiple and multifactorial [12]. While in some patients a sin- characterized by retention of consciousness and therefore often gle cause or event may lead to the development of HS, other termed an , complex partial seizures (CPS) characterized by patients may require a sequence of events involving multiple an impairment of awareness and responsiveness and secondarily generalized tonic–clonic seizures. SPS or auras are very common in HS and may occur in as Box 1. Classification of temporal lobe epilepsy. many as 90% of patients. They can occur in isolation, but often serve as a warning or first manifestation of a CPS. In A. Medial temporal lobe epilepsy: seizures originating in or patients with HS, the most common aura is a rising epigastric primarily involving medial temporal lobe structures sensation often described as nausea, butterflies or a queasy (i.e., hippocampus and amygdala) feeling in the epigastrium, which rises into the chest (often 1. Hippocampal sclerosis termed an abdominal aura). The second most common SPS (~ 70% of patients with refractory temporal lobe epilepsy) in MTLE is the unprovoked feeling of . It is not unusual 2. Lesional medial temporal lobe epilepsy for fear and an abdominal aura to be present simultaneously in an individual patient [41]. Other less common auras B. Lateral (neocortical) temporal lobe epilepsy: seizures described by patients with HS include , jamais vu, originating elsewhere in the temporal lobe (i.e., in the temporal lobe neocortex) tachycardia and palpitations, olfactory and gustatory halluci- nations, as well as feelings of . In general, 1. Nonlesional lateral temporal lobe epilepsy the mentioned SPS or auras are helpful in localizing seizure (~10% of patients with temporal lobe epilepsy) onset to medial temporal lobe structures but are less helpful in 2. Lesional lateral temporal lobe epilepsy lateralizing the side of seizure onset [42]. C. Familial temporal lobe epilepsy The typical complex partial seizure in MTLE begins with an arrest of motor activity and development of a blank stare with 1. Benign familial temproal lobe epilepsy impaired awareness and responsiveness. The seizure may not (some patients with hippocampal sclerosis) progress beyond this state but more often semipurposeful, 2. Refractory familial temproal lobe epilepsy involuntary, automatic motor behaviors (automatisms) (most patients with hippocampal sclerosis) develop. The most common type of seen in 3. Familial temproal lobe epilepsy with various genetic and MTLE is an oral–alimentary automatism consisting of lip clinical features smacking, chewing, swallowing, lip licking and/or tooth grind- ing activity. Other types of more complex automatic behavior

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can develop, including picking, scratch- Normal hippocampus Hippocampal sclerosis ing, squeezing and fumbling with objects CV/LFB stain GFAP stain in the patients’ environment. Other less common automatisms in MTLE include vocalization, spitting, wandering and other more elaborate motor behaviors. In addition to these common auto- matic behaviors, a sequence of clinical manifestations with lateralizing features has been described in MTLE [3]. These signs include, nonforceful head turning towards the side of seizure onset early in the CPS, tonic or dystonic posturing of the contralateral upper and/or lower Figure 1. Coronal sections through the body of the hippocampus. Left panel: Normal limbs, ipsilateral upper limb automatisms hippocampus stained with CV. Middle panel: Hippocampus with marked HS stained with CV/LFB. Right and forced contralateral head and eye panel: Hippocampus with marked HS stained with GFAP antigen to detect astrocytes (gliosis). deviation late in the seizure, often at the CV: Crystal violet; GFAP: Glial fibrillary acidic protein; HS: Hippocampal sclerosis; LFB: Luxol fast blue. beginning of a secondarily generalized tonic–clonic phase of the seizure. Other manifestations of lat- modalities eralizing value include ictal vomiting, which can be seen in The advent of a variety of high-resolution imaging modalities nondominant or right medial temporal lobe seizures, unilat- in the past 20 years has had a significant impact on the diag- eral eye blinking, which is usually ipsilateral to the side of sei- nosis and management of patients with MTLE due to HS. zure onset and speech arrest or in CPS originating Anatomical or structural imaging with high-resolution mag- from the dominant temporal lobe. Postictal aphasia also relia- netic resonance imaging (MRI) modalities can readily detect bly lateralizes seizure onset to the dominant temporal lobe. hippocampal sclerosis in patients with MTLE. Functional Postictal anterograde or retrograde has also been imaging techniques, such as positron emission tomography reported in medial temporal lobe seizures in patients with HS, (PET) and single photon emission computed tomography but has a less lateralizing value than many of the signs and (SPECT) are also valuable in the preoperative evaluation of symptoms previously mentioned. patients with medically refractory MTLE due to HS [45]. The two principal MRI findings in HS are hippocampal atro- Diagnostic evaluation phy and MRI signal changes indicative of increased tissue-free Neurological examination water [46–49]. A routine MRI scan can easily miss these findings, In patients with HS, the neurologic examination is usually normal, but HS is readily detected presurgically by using high-resolution although a mild-to-moderate memory deficit may be demonstra- MRI-based hippocampal volume measurement to document ble. More often, patients report difficulty with memory that often the hippocampal atrophy associated with the neuronal cell loss increases with the duration of their seizure disorder. in HS and other appropriate sequences (T2-weighted and fluid attenuated inversion recovery [FLAIR] images) to detect the increased signal associated with gliosis [49–52]. The typical interictal electroencephalography (EEG) findings The success of qualitative, visual analysis of MRI in detecting in MTLE are unilateral or are independent bilateral spikes, hippocampal sclerosis has varied widely in reported studies. The spike and wave complexes, sharp waves and slow waves seen best results have been obtained using a combination of MRI cri- best with basal derivations, such as sphenoidal, anterior tem- teria, such as increased signal intensity on T2-weighted or FLAIR poral or zygomatic electrodes. Prolonged video EEG monitor- images, decreased signal intensity on T1-weighted images, dis- ing may be necessary to demonstrate these interictal abnor- ruption of internal hippocampal architecture and hippocampal malities, since routine EEG’s in patients with HS are often atrophy [45,53]. When these criteria are applied to thin (3–5 mm), normal or nonspecific. coronal MR images, HS can be detected in 70 to 85% of cases. During video EEG monitoring, the typical ictal EEG pattern To increase the sensitivity and specificity of MR imaging in the begins with variable suppression of the background activity, fol- detection of HS, a variety of quantitative MRI techniques have lowed by higher amplitude 5 to 7 Hz rhythmic sharp waves been employed [46,49–51,54–60]. The most productive of these is the seen maximally in one sphenoidal electrode [3,33,43]. This activ- use of MRI-based volumetric measurements of the hippocampus ity may be seen at, or before, the clinical onset of the seizure or to detect the volume loss characteristic of HS [46,49–51,54]. In utiliz- may appear within 30 s of a nonlocalizing ictal EEG onset [44]. ing this technique, HS can be detected in approximately 95% of Invasive intracranial depth or subdural electrodes are rarely cases. Several studies have demonstrated a close correlation required in the presurgical evaluation of patients with HS due between histologically determined cell loss and atrophy, as deter- to recent advances in neuroimaging modalities. mined with hippocampal volume measurements [49,61–64]. The

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to support memory can be demonstrated when injection of Box 2. Manifestations of refractory epilepsy. amobarbital into the contralateral internal carotid artery results in a memory deficit. Many epilepsy centers are presently investi- Intractable seizures gating the feasibility of replacing the Wada test with a noninva- sive modality, the functional MRI (fMRI). To date, paradigms Excessive drug burden using fMRI to demonstrate language laterality have proven Neurobiochemical plasticity changes more robust than those to detect memory function. Cognitive deterioration Treatment & outcome Psychosocial dysfunction Current treatment options for patients with MTLE due to HS Dependent behavior include antiepileptic drugs (AEDs), epilepsy in the form of temporal lobectomy and Restricted lifestyle (VNS). Most epileptologists begin medical treatment for HS Unsatisfactory quality of life with either or and seizure control Increased mortality may be established for a number of years [75,76]. However, since most studies concerning AED efficacy do not separate patients Source: Brodie and Kwan. Neurology 58(Suppl. 5), S2–S8 (2002). with HS from those with other forms of partial epilepsy, little information is available concerning the long-term outcome of presence of unilateral HS, as determined by volumetric MRI and HS patients treated with either established or newer AEDs. seizure control after anterior temporal lobectomy have also been Two recent studies investigating the relationship between the demonstrated [65]. cause of epilepsy and response to AED shed some light PET scanning with 18F-fluorodeoxy-glucose (FDG-PET) in on this issue. Semah and colleagues found that only 10% of their MTLE identifies areas of decreased glucose utilization (hypome- patients with HS were rendered seizure-free by AED therapy [77]. tabolism) involving the medial and lateral temporal cortices In a similarly designed study, Stephen and colleagues reported [66–68]. In addition, this area of hypometabolism may involve the that 42% of their patients with HS were seizure-free on AED ipsilateral thalamus and the frontal or parietal cortical areas ipsi- therapy [78]. The main difference between these two studies was lateral to the epileptogenic temporal lobe [66–68]. Therefore, a that 70% of the patients treated by Stephen and colleagues were rather wide area of hypometabolism can be present on FDG-PET newly diagnosed and untreated when first seen, while only 8% of scans in HS. PET studies using the benzodiazepine receptor those treated by Semah and colleagues were untreated. Therefore, antagonist Flumazenil (Anexate®, Hoffman-La Roche Inc., NY, the patients of Semah and colleagues were in a more refractory USA) (FMZ-PET) have shown that patients with partial epilepsy, group when entered into their study. These two studies, there- including MTLE, have significantly reduced binding in the epi- fore, reflect the typical clinical course that patients with HS often leptogenic focus and that the FMZ-PET abnormality is much follow (i.e., initial control of seizures by AEDs, ultimately giving more restricted than the FDG-PET area of hypometabolism way to medical intractability). [67–71]. Therefore, FMZ-PET appears to be a much more specific Surgical treatment of MTLE due to HS, on the other hand, tracer for HS than FDG-PET [67,71]. is a much more efficacious therapy. Recent studies indicate that Interictal SPECT scanning may show unilateral temporal 80 to 90% of patients with this condition can be rendered sei- hypoperfusion in MTLE, but the yield is much lower than zure-free with anterior temporal lobectomy [79]. A recent rand- interictal FDG- or FMZ-PET. However, when the SPECT omized controlled trial of surgical versus medical treatment for tracer is injected during a seizure (ictal SPECT scanning), a TLE showed clear superiority of surgical therapy [80]. Anterior characteristic pattern of hyperperfusion of the involved tempo- temporal lobectomy is generally safe and efficacious with the ral lobe is seen. Therefore, ictal SPECT scanning is much more most significant adverse outcome being a 5 to 10% incidence sensitive in the detection of HS than is interictal SPECT [72–74]. of diminished verbal memory function. The third treatment modality available at this time for Neuropsychological evaluation patients with HS is VNS. However, to date, no studies have Neuropsychological testing in patients with HS often demon- been performed testing the efficacy of VNS therapy in patients strates a material-specific memory deficit, in which patients with MTLE due to HS. with left-sided HS demonstrate a verbal memory deficit whereas those with right-sided HS may, in some cases, display Medically refractory medial temporal lobe epilepsy a nonverbal or visual– deficit. Neuropsycho- Recent studies raise concerns that certain forms of partial epi- logical evaluation during the intracarotid amobarbital (Wada) lepsy, including MTLE due to HS, may be associated with test demonstrates hemispheric dominance for language func- progressive damage to medial temporal lobe structures [81–92]. tion, as well as the ability of the temporal lobe contralateral to These studies, employing a variety of experimental and clinical the epileptogenic side to support memory function. During methods, suggest that continuing seizures over time may result the Wada test, the reduced ability of the sclerotic hippocampus in progressive changes in hippocampal structure and function,

824 Expert Rev. Neurotherapeutics 3(6), (2003) Hippocampal sclerosis and MTLE

including a decline in neuropsychological functioning [91]. identification, and definitive therapy of medically refractory These studies found a longer duration of epilepsy, and an ear- HS in order to avoid the disabling manifestations of medically lier age at onset or both, to be related to diminished hippoc- refractory epilepsy. ampal volumes, reduced N-acetyl aspartate/creatine, prolonged The field of genetics will explode using microarray techniques T2 relaxation times or increased severity of HS on pathologi- to discover genetic involvement with pathogenesis and therapy, cal evaluation [82–88,91]. Using a longitudinal study design, the as well as the discovery of genes that directly contribute to the author recently showed that patients with intractable unilat- condition of HS. Genetic analysis will further aid in addressing eral MTLE and HS showed a progressive volume loss in the the issues of FTLE versus sporadic HS and determine what hippocampus ipsilateral to the side of seizure onset [92]. overlaps are present and where the entities remain separate. A recent study by Kwan and Brodie demonstrated that Current surgical therapy is evolving toward restricting the nec- patients with medically refractory epilepsy can be identified essary volume of resection in hippocampal sclerosis. However, to early on, utilizing a systematic and aggressive approach to med- date, the clear superiority of selective amygdalohippocampec- ical treatment [93]. They and others, suggest that patients with tomy over the traditional anterior temporal lobectomy has not refractory epilepsy should be managed aggressively and referred been established. Other , such as gamma knife treat- to comprehensive epilepsy centers for consideration of alterna- ment and deep stimulation are under study and may also tive treatments in order to prevent the disabling manifestations play a role in the management of this intractable condition. of chronic intractable epilepsy (BOX 2) [80,91–94]. Many patients The pharmaceutical industry will undoubtedly utilize the knowl- with HS display these manifestations. edge gained through genetic research, as well as other molecular biology studies, to develop more targeted AEDs. This will allow Expert opinion drugs to attack the basic mechanisms involved in the pathogenesis MTLE due to HS represents a well-defined epileptic syndrome of HS and in its evolution toward medical intractability [95]. with known histopathology, clinical seizure semiology, clinical Much work is underway to understand how interventions course, EEG and neuroimaging findings, response to medical can be antiepileptogenic (i.e., block the development of epi- and surgical therapy, and prognosis for the development of lepsy) as well as antiepileptic (i.e., simply blocking and control- medically refractory epilepsy. Its pathogenesis and etiology are ling seizures) [95]. This is an especially important line of incompletely understood, but many features are emerging. research in a condition, such as HS, which has now been shown The best approach to this condition at this time is to aggres- to be a progressive condition. sively pursue a definitive diagnosis in patients who appear to fit All of these factors will allow the earlier identification and its clinical profile. This can easily be achieved with high-resolu- definitive treatment of conditions, such as HS. By intervening in tion MRI scanning and other studies. Once the diagnosis is this process early, one would hope that the disabling manifesta- established, aggressive medical therapy should ensue with new tions of refractory epilepsy will be avoided and our patients will and established antiepileptic medications, as recently described return to productive and fulfilling lives. by Brodie and Kwan [94]. If medications fail, the patient should be referred to a com- Key issues prehensive epilepsy center for early consideration of alternative therapy, especially anterior temporal lobectomy. This therapy should be entertained early in the course of the disorder in • Medial temporal lobe epilepsy (MTLE) due to hippocampal order to halt seizures, prevent progression and forestall the sclerosis (HS) represents a well-defined epileptic syndrome manifestations of medically refractory epilepsy. with known histopathology, clinical seizure semiology, clinical At this time, there is ample evidence that surgery is significantly course, electroencephalography and neuroimaging findings, more effective than AED therapy in controlling seizures in patients response to medical and surgical therapy, and prognosis for with intractable MTLE due to HS and that timely evaluation for the development of medically refractory epilepsy. It is the temporal lobectomy is preferable to prolonged attempts at medical single most frequent epileptic syndrome. management [80]. Patients with MTLE due to HS suffer progres- • Patients with MTLE due to HS suffer progressive hippocampal sive hippocampal damage and neuropsychological decline and damage and neuropsychological decline. should be managed aggressively [91,92,94]. • HS can be detected readily with high-resolution magnetic resonance imaging scanning and other studies. Five-year view • Once the diagnosis is established, aggressive medical therapy Over the next 5 years, one would expect significant advances should ensue with new and established in the diagnosis, understanding and treatment of patients with antiepileptic medications. MTLE due to HS. These advances should come in the five • If medications fail, surgical therapy should be entertained areas mentioned, although many other areas may also emerge. early in the course of the disorder in order to halt seizures, I envision these five areas of advancement to include the fields prevent progression and forestall the manifestations of of genetics, alternative surgical therapy, targeted antiepileptic medically refractory epilepsy. drugs, antiepileptogenic interventions and improved early

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73 Ho SS, Berkovic SF, McKay WJ, Kalnins •• To date, the first randomized controlled 89 Jackson GD, Chambers BR, Berkovic SF. RM, Bladin PF. Temporal lobe epilepsy trial comparing the efficacy and safety of Hippocampal sclerosis: development in adult subtypes: differential patterns of cerebral surgical versus medical therapy in patients life. Dev. Neurosci. 21, 207–214 (1999). perfusion on ictal SPECT. Epilepsia 37, with refractory temporal lobe epilepsy 90 Briellmann RS, Newton MR, Wellard M, 788–795 (1996). (TLE) due to any cause (i.e., not all Jackson GD. Hippocampal sclerosis 74 O’Brien TJ, Therefore, EL, Mullan BP patients had HS). Landmark study in the following brief generalized seizures in et al. Subtraction ictal SPECT understanding of the appropriate adulthood. Neurology 57, 315–317 (2001). management of medically refractory TLE. coregistered to MRI improves clinical 91 Fuerst D, Shah J, Kupsky WJ et al. usefulness of SPECT in localizing the 81 Sutula TP, Hermann B. 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Neurology 43, logical and systematic management of It also compares the response rate of 2117–2124 (1993). patients with epilepsy. patients with HS with those of groups of 87 Kalviainen R, Salmenpera T, Partanen K 95 Brodie MJ, Leach JP. Success or failure with patients with other causes of their seizures. et al. Recurrent seizures may cause antiepileptic drug therapy: beyond 79 Wieser HG, Williamson PD. Ictal hippocampal damage in temporal lobe empiricism? Neurology 60, 162–163 (2003). semiology. In: Surgical Treatment of the epilepsy. Neurology 50, 1377–1382 Epilepsies. Engel J (Ed.). Raven Press, NY, (1998). Affiliation USA, 161–172 (1993). 88 O’Brien TJ, Therefore, EL, Meyer FB et al. •Craig Watson, MD, PhD, Director, 80 Wiebe S, Blume WT, Girvin JP, Eliasziw Progressive hippocampal atrophy in chronic Comprehensive Epilepsy Program, Department of M. A randomized, controlled trial of intractable temporal lobe epilepsy. Ann Neurology, Wayne State University School of Medicine,Detroit, MI 48201, USA, surgery for temporal-lobe epilepsy. N. Engl. Neurol. 45, 526–529 (1999). J. Med. 345, 311–318 (2001). Tel.: +1 313 745 8640, Fax: +1 313 993 0643, [email protected]

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