Parasomnias versus epilepsy: common grounds and a need to change the approach to the problem

Epilepsy in Resource Poor
Generalised seizures with focal signs: secondary gener- Countries—Suggestion of an Adjusted
alised seizures with a focal start or clear unilateral seizures Classification
but without major brain damage. There may be devel-opmental delay, subtle signs of brain damage and/or fo- According to the WHO 50 million people suffer from cal neurology. Causes are often due to progressive en- epilepsy; 80% of them live in resource poor countries cephalopathies. All age groups can be affected.
(WHO, 2001). In these settings, classification of seizures Complex partial seizures: as defined by the ILAE in view of adequate treatment has been difficult due to lack of diagnostic tools such as electroencephalograms (EEG) Simple partial seizures: as defined by the ILAE (ILAE and imaging. Drawing from a vast working experience of many years in neurology in developing countries, theauthors developed a classification system for seizures suit- 3) Other types of seizures:
able for local circumstances. Considering clinical, diag- Two different seizure types: the patient has more than nostic, prognostic and therapeutic needs, we adjusted the one type of seizure. Possible combinations are simple par- International Classification of Epileptic Seizures (ICES) tial or complex partial seizures with any of the generalised and opted for a simple-structured, easy-to-understand seizures of group 2 or generalised seizures of group 1 and classification of epileptic seizures which is still in accor- dance with the ICES and in fact shares many similarities Unclassified epileptic seizures: include all those with the ILAE version of guidelines for epidemiologic seizures that cannot be classified because of incomplete studies on epilepsy (ILAE 1981, ILAE 1993). EEG and neuroimaging are normally not available in developing The first diagnostic group was termed “generalised countries, thus the diagnosis is based on clinical symp- types of seizures” and split according to the age of on- tomatology alone. We suggest the following classification: set. They present as classical primary generalised seizures.
The subdivision into those that start within a specific age 1) Generalised types of seizures:
range (6–25 years; Fr¨oscher et al., 2003) and those with a Generalised seizures within a specific age range: pri- similar clinical presentation, but which lie outside that mary generalised seizures that start within a specific age age range was deemed important as both groups need group (mainly between 6 and 25 years). There is no obvi- a different approach. The idiopathic epilepsies encom- ous cause for the seizures, brain damage is absent. There pass distinct seizure types and a common neurobiological may however be a positive family history, suggesting a and genetic background has been suggested (Reutens and possible genetic background. Seizures of this group may Berkovic, 1995; Fr¨oscher et al., 2003; Wolf, 2005). Pa- also be termed idiopathic generalised epilepsies.
tients with primary generalised seizures outside that spe- Generalised seizures outside a specific age range: pri- cific age range may still be idiopathic in nature. However, mary generalised seizures that lie outside the specific age in early childhood and adulthood brain affection mainly range of most of the idiopathic generalised epilepsies, but due to perinatal damage and cerebral infections, respec- have no focal start and no clinical signs of brain damage.
tively, may be more frequent in a resource poor setting.
There may be a cause which cannot be diagnosed with the These patients should undergo EEG examination and cere- currently available ancillary means, thus these seizures bral imaging and thus need to be sought out carefully.
We further differentiated between “generalised seizures with diffuse brain damage” and “generalised seizures with 2) Partial types of seizures:
focal signs” but without obvious brain damage. Clinically Generalised seizures with diffuse brain damage: clini- both seizure types appear as generalised seizures, but be- cally seizures start in a generalised way, however, diffuse long into the ILAE group of secondary generalised and brain damage is obvious, which is the major difference thus partial seizures as cerebral structural lesion is obvi- when compared to group 1. Causes are mainly due to ous from clinical examination (ILAE 1981). Based on our static encephalopathies. All age groups can be affected, experience, we found the inclusion of mental retardation but there tends to be a shift to the younger ages.
into the classification of paramount importance in order to identify patients at risk of refractory seizures and those of Engel J Jr. (1998) Classifications of the International League Against defaulting their follow-up appointments (Iloeje and Ejike- Epilepsy: time for reappraisal. Epilepsia 39:1014–1017.
Fr¨oscher W, Vassella F, Hufnagel A. (2004) Die Epilepsien. Schattauer, Orji, 1993). We are pleased to see that this important issue has already been taken up by the WHO. A functional im- Iloeje SO, Ejike-Orji I. (1993) Compliance by cerebral palsy patients pairment score is currently being developed with the op- attending a child neurology service, in a developing country: a pre-liminary study. West African Journal of Medicine 12:1–5.
tional inclusion into the revised form of the ICES (Engel, Reutens DC, Berkovic SF. (1995) Idiopathic generalized epilepsy of ado- 1998). In a resource poor setting, we deemed it important lescence: are the syndromes clinically distinct? Neurology 45:1469– to separate the two groups of focal seizures, because of ma- Wolf P. (2005) Historical aspects of idiopathic generalized epilepsies.
jor clinical implications. The first group, mainly consisting of children with mental retardation, deserves special atten- World Health Organisation. The world health report 2001: Epilepsy.
tion with regards to treatment. Antiepileptic drugs which are sedating such as phenobarbitone may further ham-per development of these children and thus appear to be Hormone Replacement Therapy in Women
inappropriate. Also, early physiotherapy to prevent func- with Epilepsy
tional impairment seems appropriate. Further diagnostic tests are rarely needed as the origin and the extent of the Changes in reproductive hormone levels may influ- cerebral sequelae is known and the condition is not pro- ence seizure activity (Scharfman and MacLusky, 2006).
gressive. Diagnostic and therapeutic reasoning, however, A previous survey suggested that hormone replacement seems to be quite different in patients who show focal signs therapy (HRT) may adversely affect seizure control in without diffuse affection of the brain, although cognitive women with epilepsy (Harden et al., 1999). Although this impairment may be present. Often the clinical course is trial was terminated prematurely, resulting in greatly re- progressive and the patient was previously healthy. Here duced statistical power, the results provide evidence that further diagnostic steps are essential in order to identify intake of estrogen/medroxyprogesterone acetate HRT in the underlying, potentially treatable cause, of the epilepsy.
postmenopausal women with epilepsy is associated with EEG and, if possible, computed tomography should be some worsening in seizure control. A more recent study by Harden and colleagues (Harden et al., 2006) confirms In summary, we suggest an ILAE adjusted classifica- the results of their previous survey (Harden et al., 1999), tion of seizures for the purpose of primarily clinical work and raises a number of interesting points for discussion: in developing countries based on history taking and clin-ical examination only. The ICES forms the basis of our • Although HRT was widely used at the time the trial classification. However, we adapted this framework to lo- was initiated, intriguing ethical issues exist in con- cal circumstances in view of diagnostic and therapeutic ducting a placebo-controlled study to test the hypoth- esis that active treatment could cause seizure aggra- vation. One may argue, however, that based on evi- dence available at the time, HRT might have been a safe option in the enrolled population.
• Because an adverse influence on seizure control was confirmed, the question arises, what HRT component was responsible for the effect? The bulk of the evi- dence points to estrogens, which can have a facilitat- ing effect on seizure activity (Logothetis et al., 1959; Logothetis and Harner, 1960; Hom and Buterbaugh, 1986; McEwen, 2002), although evidence on this is not univocal (Scharfman and MacLusky, 2006).
Whether medroxyprogesterone acetate contributed toseizure deterioration is unknown.
• The authors elected to test the HRT preparation most widely prescribed in the United States. How- REFERENCES
ever, it might have been preferable in this popula-tion to combine estrogens with natural progesterone.
Commission on Classification and Terminology of the International League Against Epilepsy (ILAE). (1981) Proposal of revised clini- Natural progesterone is converted to neuroactive cal and electroencephalographic classification of epileptic seizures.
metabolites, such as allopregnanolone, which have anticonvulsant activity in animal models by acting Commission on Epidemiology and Prognosis of the International League Against Epilepsy (ILAE). (1993) Guidelines for epidemiologic stud- as positive allosteric modulators at the GABAA re- ies on epilepsy. Epilepsia 34:592–596.
ceptor (Kokate et al., 1994; Herzog, 1995; Reddy, 2001; Lonsdale and Burnham, 2003; Scharfman and Herzog AG. (1995) Progesterone therapy in women with complex partial MacLusky, 2006). Preliminary evidence suggests a and secondary generalized seizures. Neurology 45:1660–1662.
Herzog AG. (1999) Progesterone therapy in women with epilepsy: a positive effect of progesterone in catamenial epilepsy 3-year follow-up. Neurology 52:1917–1918.
(Herzog, 1995, 1999). Whether use of natural pro- Hom AC, Buterbaugh GG. (1986) Estrogen alters the acquisition of gesterone instead of MPA would be a safer option seizures kindled by repeated amygdala stimulation or pentylenetetra-zol administration in ovariectomized female rats. Epilepsia 27:103– Kokate TG, Svensson BE, Rogawski MA. (1994) Anticonvulsant activity From a practical point of view, the relevance of this of neurosteroids: correlation with gamma-aminobutyric acid-evoked study has been reduced by the drastic decline in the use chloride current potentiation. Journal of Pharmacology and Experi-mental Therapeutics 270:1223–1229.
of HRT in postmenopausal women, after publication of Logothetis J, Harner R, Morrell F, Torres F. (1959) The role of estrogens the WHI results (Rossouw et al., 2002). Today, HRT is no in catamenial exacerbation of epilepsy. Neurology 9:352–360.
longer recommended as preventive treatment in asymp- Logothetis J, Harner R. (1960) Electrocortical activation by estrogens.
Archives of Neurology 3:290–297.
tomatic women, because the increased risks of breast can- Lonsdale D, Burnham WM. (2003) The anticonvulsant effects of pro- cer, coronary heart disease, stroke, and pulmonary em- gesterone and 5alpha-dihydroprogesterone on amygdala-kindled bolism clearly outweigh any benefits.
seizures in rats. Epilepsia 44:1494–1499.
McEwen B. (2002) Estrogen actions throughout the brain. Recent The authors are correct in pointing out that their results Progress in Hormone Research 57:357–384.
should not be interpreted as contraindicating the use of Reddy DS, Kim HY, Rogawski MA. (2001) Neurosteroid withdrawal HRT for short-term control of postmenopausal symptoms model of perimenstrual catamenial epilepsy. Epilepsia 42:328–336.
Reimers A, Helde G, Brodtkorb E. (2005) Ethinyl estradiol, not progesto- in women with epilepsy. Their results do suggest, however, gens, reduces lamotrigine serum concentrations. Epilepsia 46:1414– that the HRT regimen tested may not be the optimal one Rossouw JE, Anderson GL, Prentice RL, La Croix AZ, Kooperberg C, Stefanik ML, Jackson RD, Beresford SA, Howard BV, Johnson An interesting ancillary observation was that serum KC, Kotchen JM, Ockene J; Writing Group for the Women’s Health lamotrigine (LTG) levels decreased after initiation of HRT Initiative Investigators. (2002) Risks and benefits of estrogen plus in both women who were treated with this drug. Although progestin in healthy postmenopausal women: principal results fromthe Women’s Health Initiative Randomized Controlled Trial. JAMA exclusion of these women from the analysis did not alter the results, these findings confirm previous reports that Sabers A, Ohman I, Christensen J, Tomson T. (2003) Oral contraceptives serum LTG levels can be reduced to a clinically significant reduce lamotrigine plasma levels. Neurology 61:570–571.
Scharfman HE, MacLusky NJ. (2006) The influence of gonadal hor- extent by estrogen-containing preparations, including oral mones on neuronal excitability, seizures, and epilepsy in the female.
contraceptives (Sabers, 2003; Reimers et al., 2005; Sidhu Sidhu J, Job S, Singh S, Philipson R. (2006) The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamot- Careful clinical observation and, if possible, monitor- rigine and a combined oral contraceptive in healthy female subjects.
ing of serum LTG levels are recommended whenever British Journal of Clinical Pharmacology 61:191–199.
estrogen-containing preparations are started or discontin-ued in women taking LTG.
Response to Hussain and Perucca
We agree with the letter of Dr. Hussain, indicating that ∗Department of Neurology and Internal Medicine the use of hormone replacement therapy (HRT) in post- menopausal women with epilepsy is an important and complex issue. It merits much more attention in light of the recent demonstration that HRT leads to significant health Department of Internal Medicine and Therapeutics We also agree that HRT may be problematic because the commonly prescribed forms of HRT do not utilize thenatural ovarian steroids, estradiol, and progesterone. Forexample, Premarin, an estrogen preparation that is widely REFERENCES
used for HRT, is a complex combination of equine steroids, Belelli D, Lambert JJ. (2005) Neurosteroids: endogenous regulators only some of which are actually estrogenic. As Dr. Hussain of the GABA (A) receptor. Nature Reviews Neuroscience 6:565– indicates, medroxyprogesterone acetate, which is often used as the progestin component of HRT, is also problem- Harden CL, Herzog AG, Nikolov BG, Koppel BS, Christos PJ, Fowler K, Labar DR, Hauser WA. (2006) Hormone replacement therapy atic. Medroxyprogesterone is a synthetic progestin that in women with epilepsy: a randomized, double-blind, placebo- acts not only on progesterone receptors but also is a glu- controlled study. Epilepsia 47:1447–1451.
cocorticoid receptor agonist (Ishida et al., 2002; Cirizza Harden CL, Pulver MC, Ravdin L, Jacobs AR. (1999) The effect of menopause and perimenopause on the course of epilepsy. Epilepsia et al., 2006), suggesting that its administration will not induce the same effects as progesterone.
As Dr. Hussain pointed out, a potentially useful strat- REFERENCES
egy is one that would more closely simulate the normal Ciriza I, Carrrero P, Frye CA, Garcia-Segura LM. (2006) Reduced physiology of the female. One reason for this is that syn- metabolites mediate neuroprotective effects of progesterone in the thetic analogs may not exert all of the actions of natu- adult rat hippocampus. The synthetic progestin medroxyproges- ral steroid hormones. This is particularly true for pro- terone acetate (Provera) is not neuroprotective. Journal of Neuro-biology 66:916–928.
gesterone because natural progesterone is metabolized Harden CL, Pulver MC, Ravdin L, Jacobs AR. (1999) The effect of to a neurosteroid (allopregnanolone), but synthetic pro- menopause and perimenopause on the course of epilepsy. Epilepsia gestins such as medroxyprogesterone acetate are not.
Herzog AG. (1986) Progesterone therapy in women with complex partial Metabolism to allopregnanolone is potentially important and secondary generalized seizures. Neurology 45:1660–1662.
in epilepsy because allopregnanolone has anticonvulsant Herzog AG. (1999) Progesterone therapy in women with epilepsy: a effects (Rhodes et al., 2004). Therefore, natural proges- 3-year follow up. Neurology 52:1917–1918.
Ishida Y, Ishida Y, Heersche JN. (2002) Pharmacologic doses of medrox- terone would be likely to have greater anticonvulsant ef- yprogesterone may cause bone loss through glucocorticoid activity: fects than synthetic progestins, and this indeed appears to an hypothesis. Osteoporosis International 13:601–605.
be the case (Herzog, 1999). Another reason is that hor- Maki PM. (2006) Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience 138:1027–1030.
mones may exert different effects if they are administered Rhodes ME, Harney JP, Frye CA. (2004). Gonadal, adrenal, and neu- in a way that mimics normal secretion but not in other roactive steroids’ role in ictal activity. Brain Research 1000:8–18.
ways. For example, it may be important to develop a HRT Scharfman HE, MacLusky NJ. (2006) The influence of gonadal hor- mones on neuronal excitability, seizures, and epilepsy in the female.
regimen that involves cyclical rather than continual hor- mone administration, given that ovarian secretion of go-nadal hormones is not constant. Indeed, chronic exposure Psychiatric Disorders in Juvenile Myoclonic Epilepsy
to gonadal hormones often leads to a loss of effect. Chronicexposure to estradiol, for example, leads to changes in the levels of steroid receptors, and loss of efficacy can re- We read with interest the article of Trinka et al. (2006) sult (for further discussion, see Scharfman and MacLusky, about the presence of psychiatric disorders in juvenile my- 2006). Again, the simulation of normal physiology may oclonic epilepsy (JME). JME is a stable condition and is be especially important in epilepsy because administra- not associated with mental or neurologic deterioration.
tion of progesterone for a period of time that matches the However, like other idiopathic epilepsies, JME may be duration of the luteal phase appears to provide improved fortuitously associated with brain abnormalities and/or seizure control in women with epilepsy (Herzog, 1986).
mental retardation (Gelisse et al., 2000; Gelisse et al., There is an additional factor that should be emphasized: 2001). Janz and Christian (1957), in their description of HRT is administered to women with epilepsy who are impulsive petit mal, noted that some patients had an “at- distinct physiologically and pharmacologically from the tractive but immature” personality that resulted in some woman of reproductive age, because the women are older, difficulties of social adjustment, abnormal lifestyle, and have had a longer history of seizures, and have experi- low compliance: such findings rely on clinical experience enced menopause. Age influences seizure susceptibility, but are rarely quantified. In our series of 170 consecutive and it also changes pharmacodynamics, so it is likely it JME patients referred to two departments of epileptology will influence the effects of HRT. A long history of re- (Marseilles and Nice) between 1981 and 1998 (Gelisse current seizures may also influence the efficacy of HRT et al., 2001), 26.5% had a lifetime history of some form because of progressive changes to neurons, glia, or the of psychiatric disorder, versus 47% in the study of Trinka vasculature, which are all potential targets of hormone et al. Personality disorders were the most frequent finding action. Menopause clearly influences seizures in women and were detected in 14% (vs. 23% for Trinka et al.). A with epilepsy (Harden et al., 1999), and the latency from borderline personality, responsible for social maladjust- menopause to treatment can be an important variable. For ment, represented the most frequent personality disorder example, the length of time between menopause and the in our study (6.5%), whereas no specific personality dis- onset of HRT seems to be an important determinant of orders were found in the study of Trinka et al.
age-related dementia (Maki, 2006). Therefore, one must Our study was retrospective, whereas the study of not only consider HRT per se, but also the changes in the Trinka et al. is prospective and could explain in part the CNS of the women with epilepsy that are due to chronic difference, but our population was larger. Both studies seizures, age, and the loss of ovarian function.
include patients with long follow-ups. To have a realis-tic evaluation of the real significance and of the actualprevalence of psychiatric disorders in JME, it would, how- Helen E. Scharfman and Neil J. MacLusky ever, be interesting to have controls in the general popu- lation, in other forms of epilepsy, and in other chronic neurologic disorders like migraine. Our overall impres- sion is that JME, which is indeed associated with some degree of psychological and social dysfunction, remains, for future research, we think that there is a need to change all things said, a comparatively benign disorder. The clin- the approach to the problem and would like to highlight ician should be prepared for some specific problems in the management of JME patients, but these should not be First, a reliable diagnostic instrument or standard cri- teria for the diagnosis of NFLS and of parasomnias(Vignatelli et al., 2005) is still lacking. The historical and clinico-polysomnographic features proposed by some re- search groups, which may differentiate NFLS from para- somnias, have not been systematically assessed (Derry et al., 2006b). Interictal and ictal EEG findings are nor- ∗Explorations Neurologiques et Epileptologie mal or nonspecific in a third of NFLS patients (Provini et al., 1999), and even though ictal video-recording re- mains the gold standard, it is expensive and risks failing ∗Department of Neurology, CHU Pasteur, Nice, France Second, we reported the frequent coexistence in patients with NFLE and in their relatives of different types of para- §Center Saint Paul-H. Gastaut, Marseilles, France somnias and discussed whether this was a true finding or abias error (Provini et al., 1999; Bisulli et al., 2005). In ouropinion, the cooccurrence of NFLS with parasomnias may REFERENCES
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Gelisse P, Genton P, Samuelian JC, Thomas P, Bureau M. (2001) Trou- ual, parasomnias in infancy could be replaced by NFLS bles psychiatriques dans l’´epilepsie myoclonique juv´enile. [Psychi- later in life, suggesting a common pathophysiological sub- atric disorders in juvenile myoclonic epilepsy]. Revue Neurologique strate, possibly an impaired arousal mechanism common Janz D, Christian W. (1957) Impulsive petit-mal. Deutsche Zeitschrift to NFLE and parasomnias (Tinuper and Lugaresi, 2002; f¨ur Nervenheilkunde 176:346–386. (English translation by Gen- ton P. (1994). In: Malafosse A, Genton P, Hirsch E, Marescaux C, NFLE is a complex disease with both genetic and envi- Broglin D, Bernasconi M (Eds) Idiopathic Generalized Epilepsies.
John Libbey, London, pp. 229–251.
ronmental risk factors. Case–control studies of the relative Trinka E, Kienpointner G, Unterberger I, Luef G, Bauer G, Doering LB, risk factors, and genetic studies of both sporadic and fa- Doering S. (2006) Psychiatric comorbidity in juvenile myoclonic milial cases are needed not only to clarify the puzzle of the epilepsy. Epilepsia 47:2086–2091.
sporadic cases but also to cast some light on any patho-genetic mechanisms shared by NFLE and arousal disor- Parasomnias Versus Epilepsy:
ders. Prospective longitudinal studies in familial NFLE Common Grounds and a Need to
Change the Approach to the Problem
The final and possibly most exciting point concerns the semeiological features of both disorders, when they We read with interest the paper by Derry et al. (2006) are scrutinized on video-polysomnographic recordings of and we congratulate the authors on their admirable ef- the attacks. In many patients, the ictal motor sequences fort. After an exhaustive review of the literature, in partic- contain clear-cut “epileptic” features like dystonic postur- ular of the data reported in our series of patients with ing, choreic, or ballic movements mixed, however, with nocturnal frontal lobe epilepsy (NFLE) (Provini et al., more “parasomnic” behaviors like repetitive rocking or 1999), and based on the International Classification of rolling, deambulation, and even pseudoperiodic patterns Sleep Disorders (ICSD-2), the authors indicate the pos- (Tinuper et al., 1990; Nobili et al., 2005; Bisulli et al., sible elements of diagnostic differentiation between noc- 2005). Periodism, the attacks coinciding with K-complex turnal frontal lobe seizures (NFLS) and other paroxysmal bursts and/or recalling the typical CAP recurrence (Parrino sleep events. While, some of the criteria considered by et al., 2006), has been reported both in nocturnal epilep- several authors as characteristic of NFLS could be obso- tic (Sforza et al., 1993; Tinuper et al., 1993) and para- lete since apparently “typical” NFLS have been shown, somnic episodes. In such a perspective, we suggest that by stereo-EEG study, to arise in the temporal area or the the “classical” semeiological dichotomy between epilep- insula (Nobili et al., 2004), we suggest that the approach tic and nonepileptic attacks should be reappraised on the to differential diagnosis requires a widely different angle basis of new exploratory concept and bias-free investi- of view. Indeed, looking back at more than 20 years’ ex- gations. This could ultimately pave the way to a more perience in the field, and in order to give useful insights comprehensive interpretation of the clinical phenomena.
frontal lobe epilepsy (NFLE) have seizure onset in the frontal lobes (Nobili et al., 2004). It is notoriously difficult to localize the precise epileptic focus in individuals with frontal lobe epilepsy due to the large surface area, high degree of connectivity, and rapid seizure propagation in this region. The term “NFLE” is usually used to describe Epilepsy Centre and Centre of Sleep Medicine a clinical presentation, rather than indicating a precise Department of Neurological Sciences epileptic focus, and we have used it in this manner in this University of Bologna, Bologna, Italy Secondly, the authors highlight issues in the diagnostic criteria for parasomnias and NFLE. Our own instrument, REFERENCES
The Frontal Lobe Epilepsy and Parasomnias (FLEP) scale Bisulli F, Naldi I, Vignatelli L, Ferrioli S, Plazzi G, Vetrugno R, Mon- (Derry et al., 2006b), was shown to be very reliable in tagna P, Tinuper P. (2005) Paroxysmal motor phenomena during distinguishing the disorders in a sample of 62 subjects; sleep: study of the frequency of parasomnias in patients with noctur- we look forward to other groups independently validating nal frontal lobe epilepsy and their relatives. Epilepsia 46(suppl. 6):284.
this scale. We agree that video EEG monitoring is still Derry CP, Davey M, Johns M, Kron K, Glencross D, Marini G, Shef- needed in some individuals, and indeed even this may not fer IE, Berkovic SE. (2006a). Distinguishing sleep disorders from be diagnostic but, in the majority of cases, a careful history seizures: diagnosing bumps in the night. Archives of Neurology63:705–709.
should distinguish between the conditions.
Derry CP, Duncan JS, Berkovic SF. (2006b) Paroxysmal motor disorders Third, the issue of a possible genetic relationship be- of sleep: the clinical spectrum and differentiation from epilepsy.
tween these disorders, as first suggested by the Bologna Nobili L, Cossu M, Mai R, Tassi L, Cardinale F, Castana L, Citterio group, is indeed tantalizing. We have also been impressed A,Sartori I, Lo Russo G, Francione S. (2004) Sleep-related hy- by the apparent association of parasomnias in some NFLE perkinetic seizures of temporal lobe origin. Neurology 10;62:482– cases and families, but a methodologically rigorous eval- Nobili L, Sartori I, Terzaghi M, Tassi L, Mai R, Francione S, Cossu M, uation to exclude biased ascertainment has yet to be per- Cardinale F, Castana L, Lo Russo G. (2005). Intracerebral record- ings of minor motor events, paroxysmal arousals and major seizures Finally, we agree that systematic semiological analy- in nocturnal frontal lobe epilepsy. Neurological Sciences 26(suppl.
3):s215–s219.
ses using video-polysomnography of these phenomena are Tinuper P, Cerullo A, Cirignotta F, Cortelli P, Lugaresi E, Montagna P.
needed and may indeed lead to novel insights into their (1990). Nocturnal paroxysmal dystonia with short-lasting attacks: underlying biology and possible pathophysiological rela- three cases with evidence for an epileptic frontal lobe origin ofseizures. Epilepsia 31:549–556.
Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. (1999).
Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 122:1017–1031.
Tinuper P, Lugaresi E. (2002) The concept of paroxysmal nocturnal dys- tonia. In Bazil CW, Malow BA, Sammaritano MR (Eds.) Sleep and epilepsy: the clinical spectrum. Elsevier Science BV Amsterdam, ∗Epilepsy Research Centre and Department of Medicine (Neurology), University of Tinuper P, Provini F, Bisulli F, Vignatelli L, Plazzi G, Vetrugno R, Mon- tagna P, Lugaresi E. (2007) Movement disorders in sleep: guide- lines for differentiating parasomnias and epileptic seizures. Sleep †Department of Clinical and Experimental Response to Tinuper et al.
To the Editors:We would like to thank Dr. Tinuper and colleagues for their comments and interest in our recent review article(Derry et al., 2006a). The authors point out that there REFERENCES
may be a more complex relationship between epilepticand nonepileptic sleep disorders than a simple dichotomy, Derry CP, Duncan JS, Berkovic SF. (2006a) Paroxysmal motor disorders and that common underlying mechanisms may be at play of sleep: the clinical spectrum and differentiation from epilepsy.
Epilepsia. 47:1775–1791.
Derry CP, Davey M, Johns M, Kron K, Glencross D, Marini C, Sheffer IE, Although we would agree with many of the points Berkovic SF. (2006b) Distinguishing sleep disorders from seizures: made, there are some comments to which we would diagnosing bumps in the night. Archives of Neurology 63: 705—709.
Nobili L, Cossu M, Mai R, Tassi L, Cardinale F, Castana L, Citterio A, like to respond. Firstly, we acknowledge the fact that Sartori I, Lo Russo G, Francione S. (2004) Sleep-related hyperkinetic not all seizures with the clinical phenotype of nocturnal seizures of temporal lobe origin. Neurology 10(62):482–485.
Nonconvulsive Status Epilepticus versus Triphasic
ical practice: (a) both TWs of toxic-metabolic origin and Encephalopathy
generalized epileptiform discharges may be suppressedwith intravenous benzodiazepines; (b) an immediate clin- ical improvement can be difficult to evaluate in a patient, Kaplan and Birbeck (2006) have studied the difficulty particularly elderly subjects, under the hypnotic effects of for interpreting the presence of triphasic waveforms in benzodiazepines; (c) the absence of a clinical improve- the electroencephalogram (EEG) from confused subjects ment after intravenous benzodiazepines is not always def- on treatment with lithium. Most of considerations men- inite sign of encephalopathy because a delayed or slow tioned in their article may be also applied to all those sit- normalization of the mental state may occur in NCSE, uations in which an EEG exhibits triphasic waves (TWs) and (d) both encephalopathy and NCSE may coexist (as in patients referred by altered mental status on treatment mentioned by Kaplan and Birbeck), above all in patients with other potentially neurotoxic drugs. Whether these with pluripathology (Fern´andez-Torre, 2006).
situations should be considered as toxic encephalopathy A high level of suspicion, broad metabolic screening, or drug-induced nonconvulsive status epilepticus (NCSE) and a precise knowledge of all drugs associated with is a controversial matter that does not appear to have a episodes of NCSE can be helpful in the differential diagno- sis (Fern´andez-Torre, 2004). In cases of possible NCSE, a TWs frequently adopt an appearance of blunt spike- therapeutic trial of medications can be useful, despite the waves. This epileptiform aspect, and its occurrence in pa- persistence of the metabolic derangements (Fern´andez- tients with delirium, is the clue of our problem. Thus, continuous, rhythmic, diffuse TWs may resemble an elec- In conclusion, a general consensus is necessary to es- troencephalographic substrate of generalized NCSE. On tablish strict clinical and electroencephalographic criteria clinical practice, the presence of TWs in an obtunded for diagnosing NCSE, especially, in patients taking neu- patient with hepatic or renal failure is an electroen- rotoxic drugs. In the meantime, further investigations as cephalographic feature rather suggestive of metabolic en- that recently published by Kaplan and Birbeck (2006) are cephalopathy. However, the diagnosis is more challenging when triphasic waveforms occur in a subject with pluri-pathology (e.g., mild hepatic or renal insufficiency, sepsis,preexisting dementia), taking also potentially neurotoxic drugs such as lithium, baclofen, ifosfamide, cefepime, cef- Department of Clinical Neurophysiology, tazidime, and others. This difficulty of interpretation oc- University Hospital “Marqu´es de Valdecilla,” curs even in expert epileptic settings. Treiman and Walker (2006) mentioned in a recent review that sometimes itcan be extremely difficult to differentiate between hepaticcoma without status epilepticus and hepatic coma compli-cated by NCSE. An extraordinary illustration (see figure REFERENCES
8.7) of this issue is that included by Thomas et al. (2006) intheir chapter about absence status in which a false diagno- Boulander J-M, Deacon C, L´ecuyer D, Gosselin S, Reiher J. (2006) sis of generalized NCSE was detected in a young woman Triphasic waves versus nonconvulsive status epilepticus: EEG dis-tinction. Canadian Journal of Neurological Science 33:175–180.
with idiopathic generalized epilepsy suffering from acute Fern´andez-Torre JL. (2004) Overuse of the term nonconvulsive status epilepticus. Clinical EEG and Neuroscience 35(letter):V.
From an electroencephalographic viewpoint, the mor- Fern´andez-Torre JL, Mart´ınez-Mart´ınez M, Gonz´alez-Rato J, Maestro I, Alonso I, Rodrigo E, Horcajada JP. (2005) Cephalosporin-induced phology and topography of the triphasic complexes, dis- nonconvulsive status epilepticus: clinical and electroencephalo- tribution of the electrical field, predominance of the neg- graphic features. Epilepsia 46:1550–1552.
ative or positive phases, and response to stimulation may Fern´andez-Torre JL. (2006) Triphasic waves versus nonconvulsive sta- tus epilepticus: EEG distinction. Canadian Journal of Neurological be helpful in distinguishing TWs from generalized NCSE (Mart´ınez-Rodr´ıguez et al., 2001; Boulander et al., 2006).
Kaplan PW, Birbeck G. (2006) Lithium-induced confusional states: non- However, even taking in mind all these criteria, electro- convulsive status epilepticus or triphasic encephalopathy? Epilepsia47:2071–20074.
physiologic distinction may be difficult in severely ill pa- Mart´ınez-Rodr´ıguez JE, Barriga FJ, Santamar´ıa J, Iranzo A, Pareja JA, Revilla M, de la Rosa CR. (2001) Nonconvulsive status epilepticus I completely agree with Kaplan and Birbeck (2006) associated with cephalosporins in patients with renal failure. Amer-ican Journal of Medicine 111:115–119.
on that both clinical resolution of the confusional state Thomas P, Zifkin B, Andermann F. (2006) Absence status. In Waster- and electroencephalographic abolition of the epileptiform lain CG, Treiman DM (Eds) Status epilepticus: mechanisms and discharges after the administration of intravenous benzo- management. The MIT press, Cambridge, pp. 109–112.
Treiman DM, Walker MC. (2006) Treatment of seizure emergencies: diazepines is the method of choice to diagnosis NCSE.
convulsive and non-convulsive status epilepticus. Epilepsy Research However, this approach has some limitations on the clin- Response to Fern´andez-Torre
REFERENCES
Fagan KJ, Lee SI. (1990) Prolonged confusion following convulsions We wish to thank Dr. Fernandez-Torre for his thought- due to generalized non-convulsive status epilepticus. Neurology40:1689–1694.
ful comments on the difficulties of distinguishing tripha- Hirsch LJ, Brenner RP, Drislane FW, So E, Kaplan PW, Jordan KG, sic waves (TWs) from some cases of NCSE with blunted Herman ST, LaRoche SM, Young B, Bleck TP, Scheuer ML, Emer- sharp-slow wave morphologies. As we have noted else- son RG. (2005) The ACNS subcommittee on researchn terminologyfor continuous EEG monitoring: proposed standardized terminology where, the diagnostic challenge is further complicated by for rhythmic and periodic EEG patterns encountered in critically ill the multiple risk factors (such as metabolic dysfunction, patients. J Clin Neurophysiol 22:128–135.
dementia, intercurrent infection, medication burden and Kaplan PW. (1996a) Nonconvulsive status epilepticus in the emergency room. Epilepsia 37:643–650.
cerebral atrophy) that may underlie either encephalopa- Kaplan PW. (1996b) Nonconvulsive status epilepticus. Seminars in Neu- thy or NCSE (as well as both occurring together)[Kaplan 1996b]. As Dr. Fernandez-Torre comments, illustrations Kaplan PW. (2005a) Clinical features, diagnosis and prognosis of non- convulsive status epilepticus. The Neurologist 11:348–361.
provided in publications may be incorrect or at least am- Kaplan PW. (2005b) Pitfalls of EEG interpretation of repetitive dis- biguous. This is the situation for some cases of confusional charges. Epileptic Disord 7:261–265.
states due to tiagabine, interpreted by EEG as showing Kaplan PW, Birbeck G. (2007) Lithium-induced confusional states: non- convulsive status epilepticus or triphasic encephalopathy? Epilepsia NCSE, whilst suggesting, rather, an encephalopathy. We note that BZP challenges are only helpful in diagnosing Young GB, Jordan KG, Doig GS. (1996) An assessment of nonconvulsive NCSE when there is both an EEG and clinical regression of seizures in the intensive care unit using continuous EEG monitoring:an investigation of variables associated with mortality. Neurology abnormality [Kaplan, 2005a; Kaplan and Birbeck, 2007], and are struck by the often delayed clinical regressionover several days [Fagan and Lee, 1990; Kaplan, 1996a].
Developing EEG criteria in isolation may not be possiblefor NCSE, and other contextual clues, such as absence of A Possible Role of the Thalamus in Some Cases of
a known epileptic encephalopathy, or response to BZPs, Sudden Unexpected Death in Epilepsy
As Dr. Fernandez-Torre notes, a general consensus is Sudden Unexpected Death in Epilepsy (SUDEP) is the necessary to establish strict clinical and EEG criteria for most important direct epilepsy-related cause of death in people with chronic epilepsy. Its physiopathology is still Working criteria for NCSE have been put forward unknown; however, the most commonly suggested poten- by several authors [Young et al., 1996; Kaplan, 2005b; tial mechanisms involve cardiac or respiratory abnormal- Hirsch et al., 2005]. To resolve and refine the EEG criteria ities. As the anatomical substrate of epileptic activity in for NCSE, the nomenclature for periodic discharges and the CNS shows a direct relationship with cardiovascular triphasic waves should be replaced by standardized de- alterations, this may suggests that patients with epilepsy scriptors (Hirsch et al., 2005). A synopsis and modification associated with focal CNS lesions may be at particular of EEG diagnostic criteria for NCSE are being developed risk of SUDEP (Tomson et al., 2005).
for the First London Colloquium on Status Epilepticus, Currently, experimental and clinical data support an im- taking place in April. This may generate working criteria portant role for thalamic nuclei in the behavioural manifes- for future prospective studies that may include intensive tations, initiation and propagation of seizures (Norden and care patients with NCSE, TWs or PEDs, so as to resolve, Blumenfeld, 2002). Whilst TLE is the most common form or at least clarify the impications and features of these of partial epilepsy, and hippocampal atrophy and sclero- sis are the most frequent abnormalities associated withTLE, brain structural changes in patients with TLE arenot confined solely to the hippocampus. Indeed, a recent study demonstrated thalamic atrophy in patients with TLE, Department of Neurology, Johns Hopkins which was more prominent in the thalamic nuclei that have strong connections with the limbic system (Bonilha et al., 2005). Furthermore, using the pilocarpine model of temporal lobe of epilepsy, our group has also reported an important role of the posterior thalamus in the cerebral cir- cuits of rats with epilepsy. In the first study investigating the interictal cerebral metabolic rate by 14–2DG autora- Michigan State University, East Lansing, Michigan diography in chronic pilocarpine-induced rats (Scorza et al., 1998), the most relevant finding was a consistent rise of cerebral metabolic rate in the lateral posterior thalamic nuclei (LP), suggesting that it may be involved in the cere- bral circuitry controlling epileptic activity during interictal Epilepsy Institute of the Netherlands, SEIN intervals. A second study evaluated the contribution of LP Achterweg 5, 2103 SW Heemstede, the Netherlands to spontaneous recurrent seizure activity induced by pilo- ‡Departamento de Neurologia. Universidade carpine (Scorza et al., 2002). It was shown that bilateral LP lesion by ibotenic acid in rats with epilepsy resulted in an increase of seizure frequency, suggesting that LP is one of the most important thalamic nuclei involved in Universidade Federal de S˜ao Paulo/Escola Paulista the inhibition of spreading mechanisms. Moreover, subtle thalamic structural abnormalities may also present in pa- tients with generalized idiopathic epilepsies as suggestedby MRI volumetric and voxel-based morphometry studies(Betting et al., 2006a,b).
In view of the above findings, we porpose the hypoth- REFERENCES
esis that SUDEP, at least in some cases, is related to theoccurrence of thalamic dysfunction or anatomic change.
Betting LE, Mory SB, Li LM, Lopes-Cendes I, Guerreiro MM, Guerreiro In 1979, Boyko and colleagues showed that bilateral CA, Cendes F. (2006a) Voxel-based morphometry in patients withidiopathic generalized epilepsies. Neuroimage 32:498–502.
injections of kainic acid into the thalamus, mainly in the Betting LE, Mory SB, Lopes-Cendes I, Li LM, Guerreiro MM, Guerreiro LP, produced myocardial necrosis in adult rats, suggest- CA, Cendes F. (2006b) MRI volumetry shows increased anterior ing that this specific thalamic nucleus has a direct relation- thalamic volumes in patients with absence seizures. Epilepsy Behav8:575–580.
ship with cardiovascular alterations. More recently, Scorza Bonilha L, Rorden C, Castellano G, Cendes F, Li LM. (2005) Voxel- (unpublished data) evaluated the heart rate, in vivo (ECG) based morphometry of the thalamus in patients with refractory medial and isolated ex vivo preparation (Langendorf preparation) temporal lobe epilepsy. Neuroimage 25:1016–1021.
Boyko WJ, Galabru CK, McGeer EG, McGeer PL. (1979) Thalamic of rats with epilepsy before and after bilateral LP lesion.
injections of kainic acid produce myocardial necrosis. Life Sci 25:87– The results showed differences in the mean heart rate in vivo, but surprisingly, no differences in heart rate could Norden AD, Blumenfeld H. (2002) The role of subcortical structures in human epilepsy. Epilepsy Behav 3:219–231.
be observed in the isolated ex vivo situation. These ob- Scorza FA, Sanabria ERG, Calderazzo L, Cavalheiro EA. (1998) Glucose servations suggest some form of thalamic modulation of utilization during interictal intervals in an epilepsy model induced heart functioning, and are consistent with the hypothesis by pilocarpine: a qualitative study. Epilepsia 39:1041–1045.
Scorza FA, Arida RM, Priel M, Calderazzo L, Cavalheiro EA. (2002) that SUDEP may result from cardiac arrest as a result of The contribution of the lateral posterior and anteroventral thalamic nuclei on spontaneous recurrent seizures in the pilocarpine model of A clear relationship between thalamic dysfunction, car- epilepsy. Arq Neuropsiquiatr 60:572–575.
Tomson T, Walczak T, Sillanpaa M, Sander JW. (2005) Sudden un- diac arrest, and SUDEP remains to be demonstrated. In expected death in epilepsy: a review of incidence and risk factors.
the meantime, clinical focus on cardiovascular function in patients with epilepsy — taking a detailed cardiovascularhistory, looking for cardiovascular co-morbidity and riskfactors, and assessing cardiac finding (electrocardiogramand echocardiogram) — should be developed as they may have a role in the prevention of SUDEP.
The June issue of Epilepsia will focus on studies rel- evant to pediatric epilepsies. We are happy to feature a set of papers on Panayiotopoulos Syndrome, includ- ing an historical commentary from Dr. Panayiotopoulos, a critical review from Dr. Koutroumanidis, and a spe- cial report on “autonomic status epilepticus” from a dis- tinguished international group of clinical investigators.
∗Disciplina de Neurologia Experimental Full-length research papers deal with such diverse topics Universidade Federal de S˜ao Paulo/Escola as first seizure, levetiracetam use in infants and young Paulista de Medicina (UNIFESP/EPM) children, behavioral and psychiatric relationships to pe- diatric epilepsy, and phenotypic variation in genetically- †Department of Clinical and Experimental Epilepsy determine epilepsies in infants and children. The June is- sue also presents a “Proposal of an algorithm for diagnosis and treatment of neonatal seizures in developing coun- and Neurosurgery, Queen Square, London These articles have been posted on the Epilepsia EUREPA Distance Education Programs 2007/2008
Blackwell-Synergy website prior to publication in aprint issue of Epilepsia. They can be accessed at EUREPA’s schedule of educational programs for 2007- http://www.blackwell-synergy.com/loi/epi.
2008 will again include a course on “Genetics of Epilepsy”(deadline for application July 30, 2007) and on “EEG in Adachi et al., “Duration of postictal psychotic episodes the diagnosis and management of epilepsy” (deadline for Ayyildiz et al., “The effects of ascorbic acid on application May 30, 2007). In addition, two new courses penicillin-induced epileptiform activity in rats” will be offered, with their initiation at the 27th Interna- Boon, et al., “Deep brain stimulation in patients with tional Epilepsy Congress on July 7, 2007 in Singapore.
The new courses are: “Neuroimaging” (deadline for ap- Capablo et al., “Neurologic improvement in a type 3 plication April 30, 2007) and “Clinical Pharmacology Gaucher disease patient treated with imiglucerase / miglu- and Pharmacotherapy” (deadline for application April 30, Carrington et al, “Effect of focal low-frequency stimu- For detailed information and application procedures, lation on amygdala-kindled afterdischarge thresholds and please go to http://www.epilepsy-academy.org or contact seizure profiles in fast- and slow-kindling rat strains” the EUREPA Secretariat at office@epilepsy-academy.org.
Chien, et al., “An interaction study between the new antiepileptic and CNS drug carisbamate (RWJ-333369) 2nd Eilat International Educational Course on
Pharmacological Treatment of Epilepsy
Cunnington, et al., “Effect of dose on the frequency of Princess Hotel, Eilat, Israel, September 2–9, 2007.
major birth defects following fetal exposure to lamotrigine The Course (conducted in English) will include ses- monotherapy in an international observational study” sions on Pharmacology of AEDs, Pharmacokinetics and Feichtinger, et al., “Automatic and remote controlled TDM, Drug Interactions, Assessing Efficacy and Safety, ictal SPECT injection for seizure focus localization by Optimizing Medical Management. There will also be sev- use of a commercial contrast agent application pump” eral tutorial sessions, training workshops, case studies, and Hamiwka, et al., “Diagnostic inaccuracy in children re- ferred with ‘first seizure’: Role for a first seizure clinic” The Course will be held under the auspices of the ILAE Herlenius, et al., “SCN2A mutations and benign famil- Commission on European Affairs (CEA) and the Euro- ial neonatal-infantile seizures: The phenotypic spectrum” pean Epilepsy Academy (EUREPA). It is designed for Lin et al., “Facial paresis in patients with mesial tem- junior scientists (45 years and younger). Suitable candi- poral sclerosis: Clinical and quantitative MRI-based evi- dates accepted to the course will receive a bursary towards Kalamangalam, et al., “Neuroimaging and neurophysi- Course Organizers: Meir Bialer, Israel, Chairperson; ology of periodic lateralized epileptiform discharges: Ob- Ana Dimova, Macedonia; Alla Guekht, Russia; Svein I. Johannessen, Norway; Anne-Mari Kantanen, Finland; Osorio et al., “High frequency thalamic stimulation for Cigdem Ozkara, Turkey; Emilio Perucca, Italy; Torbj¨orn Tomson, Sweden; Federico Vigevano, Italy.
Salih et al., “A hypothesis for how non-REM sleep For details, see http://www.eilat-aeds.com, under Forth- might promote seizures in partial epilepsies: A transcra- coming Conferences, or contact the Secretariat: Target Conferences Ltd, PO Box 29041, Tel Aviv 61290, Israel, Sherman, et al., “ADHD, neurological correlates and Tel: +972 3 5175150, Fax: +972 3 5175155, e-mail: eilat- health-related quality of life in severe pediatric epilepsy” Striano, et al., “Brain MRI findings in severe myoclonic epilepsy in infancy and genotype–phenotype correlations” Milken Family/American Epilepsy Society Early
Tomson et al., “Pharmacokinetics of levetiracetam dur- Career Physician Scientists Award
ing pregnancy, delivery, in the neonatal period, and lacta- The Milken Family Foundation and the American Epilepsy Society announce the opening of the Early Career Wyckhuys, et al., “High frequency deep brain stimula- Physician Scientists awards to investigators from around tion in the hippocampus modifies seizure characteristics the world. This award is designed to assist physician- scientists embarking on early academic careers devoted Zaccara, et al., “Idiosyncratic adverse reactions to to epilepsy research. Preference is given to innovative studies leading to new treatments or other novel trans- lational research. $50,000 USD is awarded for a 12- Topic: Clinical and Therapeutic Approaches to Child- month period beginning in January 2008. Applications are due by Friday September 14, 2007. Eligibility re- This course is primarily targeted to neuropediatri- quirements and application information are available by cians, neurophysiologists and neuropsychiatrists inter- email (ctubby@aesnet.org) or at http://www.aesnet.org/ ested in the pathophysiology, diagnosis and manage- Visitors/Research/sponsoredgrants/early˙career.cfm ment of epilepsies of childhood, and in research pro-grams implementing in childhood epilepsy. The course 6th International Course on Epilepsy
will be limited to 50 participants. For more information, Venice International University, San Servolo, Venice, go to http://www.ilae-epilepsy.org, http://www.epilepsy- academy.org, or http://www.epilearn.eu.
August 2007
1st Migrating Course on Epilepsy
Baltic Sea Summer School on Epilepsy
June 2007
September 2007
Seventeenth Meeting of the European Neurological
2nd Eilat International Educational Course: Phar-
Society (ENS)
macological Treatment of Epilepsy
http://www.eilat-aeds. com/eilatedu2/index.asp July 2007
October 2007
27th International Epilepsy Congress
Idiopathic Generalized Epilepsy (IGE): Develop-
mental Aspects, Bridging Basic Science and Clinical
Research
3–6 October
6th International Course on Epilepsy: Clinical and
Therapeutic Approaches to Childhood Epilepsy
23 July–3 AugustVenice, Italyemail: epilepsysummercourse@univiu.org

Source: http://old.pediatria.unipd.it/form/materiale_sonno/tinuper2007.pdf