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Epilepsia, 38(6):738-740, 1997 Lippincott-Raven Publishers, Philadelphia 0 International League Against Epilepsy

Letters to the Editor

To the Editor: We wish to compliment Drs. Oldani et al. (1) for

their paper, “Autosomal Dominant Nocturnal Fron- tal Lobe Epilepsy (ADNFLE).” However, several points require clarification.

Oldani et al. subdivided paroxysmal nocturnal episodes using our 1993 classification scheme (2) to char- acterize the full phenotypic expression of the nocturnal frontal epilepsy attacks. This classification was developed by us after careful evaluation of many video-EEG recordings of nocturnal seizures, and we believe that it is useful for both diagnostic and scien- tific purposes. We noted that minor episodes accrue over minimal, and major over minor episodes, seem- ingly indicating spread of epileptic activity to larger areas of the brain. The other characteristic empha- sized in our report (2) is the periodic repetition of the nocturnal episoses, every 20-60 s, during NRem sleep. These two features seem to be characteristic of NFLE and allow interesting speculations about its pathogenesis and relation to sleep (the orbitofrontal areas are involved in sleep mechanisms) (3). We stress these aspects of our study because since 1981 we have been deeply involved in the evaluation of paroxysmal nocturnal attacks, which we clearly rec- ognized as being an epileptic syndrome since 1990 (4). In subsequent years, we described the full clinical spectrum in detail, encompassing paroxysmal arousals (PA) (5), nocturnal paroxysmal dystonia (NPD) (6), and episodic nocturnal wandering (ENW) (7). In 1992 we wrote: “PAS, short-lasting NPD and ENWs probably represent a spectrum of peculiar sleep- related epileptic seizures” (6).

Scheffer et al. (8) were first to indentify ADNFLE and described the genetic mutation responsible for the disease (9,lO). However, in most of our cases of NFLE, whether sporadic or familial, the mutation is absent, implying heterogeneity of the syndrome (11). Moreover, our NFLE group (95 cases) is certainly not homogeneous clinically. Age at onset, seizure semiology, and response to antiepileptic drug treat- ment have varied widely. Many of our patients display pharmacoresistence, and seizures often persist into adulthood, not features of benign epilepsy, as Oldani et al. imply. We believe that NFLE is not equivalent to ADNFLE, and that several nosological categories are present; some are genetic but others are not. Each case must therefore be studied in depth,

usually requiring repeated polysomnography, and close relatives should also be studied before a diagnosis of ADNFLE is reached. A final point worth con- sideration is how to validate a diagnosis of epilepsy in patients whose ictal EEGs do not display paroxysmal features. NFLE constitutes a diagnostic challenge, even when the attacks are directly monitored, and in some cases it may be impossible to reach a definite diagnosis. These difficulties must be borne in mind to avoid trivializing every sleep-related paroxysmal episode as FLE.

Giuseppe Plazzi Pasquale Montagna

Paolo Tinuper Angelina Cerullo Federica Provini

Elio Lugaresi Institute of Clinical Neurology

University of Bologna, Bologna, Italy

REFERENCES

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Oldani A, Zucconi M, Ferini-Strambi L, Bizzozero D, Smirne S. Autosomal dominant nocturnal frontal lobe epilepsy: electroclinical picture. Epilepsia 1996;37:964-76. Sforza E, Montagna P, Rinaldi R, et al. Paroxysmal periodic motor attacks during sleep: clinical and polygraphic features. Electroencephalogr Clin Neurophysiol 1993;86:161-6. Sterman MB, Clemente CD. Forebrain inhibitory mechanisms: sleep patterns induced by basal forebrain stimulation in the behaving cat. Exp Neurol 1962;6:103-17. Tinuper P, Cerullo A, Cirignotta F, Cortelli P, Lugaresi E, Montagna P. Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures. Epilepsia 1990;31:549-56. Montagna P, Sforza E, Tinuper P, Cirignotta F, Lugaresi E. Paroxysmal arousals during sleep. Neurology 199040:1063-6. Montagna P. Nocturnal paroxysmal dystonia and nocturnal wandering. Neurology 1992;42(suppl 6):61-7. Plazzi G, Tinuper P, Montagna P, Provini F, Lugaresi E. Epi- leptic nocturnal wanderings. Sleep 1995;18:749-56. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder. Lancet 1994;343:515-7. Phillips HA, Scheffer IE, Berkovic SF, Hollway GE, Suther- land GR, Mulley JC. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nature Genet 1995;10:117-8. Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor a 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet 1995;11:201-3. Mochi M, Provini F, Plazzi G, et al. Genetic heterogeneity in autosomal dominant nocturnal frontal lobe epilepsy. 1997 (in press).

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LETTERS TO THE EDITOR 739

To the Editor: I read with interest the paper by Oldani et al. (1).

As the authors are experienced hypnologists, I hope their work will help eliminate the terminological am- biguities that have confused the topic.

In 1981, the School of Sleep Medicine in Bologna coined the term “nocturnal (hypnogenic) paroxysmal dystonia (NPD)” to describe sleep-related short- lasting attacks that were believed to reflect a “paroxysmal disturbance of the dynamic balance between the cortex and the basal ganglia” during sleep (2). Since then, two groups of investigators have described independently and in parallel what are clearly identical clinical phenomena.

Sleep-related attacks characterized by sudden awakening, grasping, grunting, thrashing, and other hyperkinetic activity with tonic stiffening, bimanual and bipedal automatisms, sitting up, and wandering were considered an unusual parasomnia by most hypnologists (3), whereas epileptologists regarded them as epileptic seizures of probable frontal lobe origin (4). The usual absence of typical interictal and even ictal EEG epileptiform activity was regarded by hypnologists as evidence of a nonepileptic origin for the attacks, and by epileptologists as reflecting a deep location (orbito-mesial) for the epileptogenic brain region. These two streams of thought converged when, at the beginning of the 1990s, the Bologna group admitted an epileptic origin for such sleep- related attacks (5). That would have been the logical time to abandon the term NPD as misleading and erroneous: an epileptic seizure should be defined by a term that overtly or implicitly recognizes an epileptogenic origin. Unfortunately, the term NPD has been maintained and two further terms, paroxysmal arousals (PA) and episodic nocturnal wanderings (ENW) were employed to describe, respectively, the start and development of these seizures (6). Such terms have added even more confusion. Moreover, the fragmentation of a single clinical phenomenon into three “types” of spells-PA, NPD, and ENW-is semiologically appreciable but physiologi- cally and clinically meaningless.

The artificial subdivision was perpetuated by emerging genetic data. In 1994, Sheffer et al. (7) reported autosomal dominant inheritance for these nocturnal epileptic seizures. A year later, Plazzi et al. (8) suggested a similar mode of inheritance for ENW. It should be obvious that part of a seizure, as well as the whole seizure, will have identical inheritance.

I am most appreciative that Oldani et al. (1) cor- rectly define the syndrome as “autosomal dominant nocturnal frontal lobe epilepsy,” but allow the epileptic seizures to be subdivided clinically into “mini-

mal,” “minor,” “major,” and “prolonged” attacks, which avoids the use of ambiguous terms. Errare human est, sed diabolicum perseverare. PA, NPD, and ENW should be eliminated from medical termi- nology once and for all because they arose from a diagnostic error.

Giovanni Ambrosetto Institute of Clinical Neurology

University of Bologna Bologna, Italy

REFERENCES

1. Oldani A, Zucconi M, Ferini-Strambi L, Bizzozero D, Smirne A. Autosomal dominant frontal lobe epilepsy: electroclinical picture. Epilepsia 1996;37:964-76.

2. Lugaresi E, Cirignotta F. Hypnogenic paroxysmal dystonia: epileptic seizures or a new syndrome? Sleep 1981;4:129-38.

3. Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial seizures of frontal lobe origin. Ann Neu- rol 1985;18497-504.

4. Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry 1986;49:375-80.

5. Tinuper P, Cerullo A, Cirignotta F, et al. Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizure. Epilepsia 199031549-56.

6. Montagna P. Nocturnal paroxysmal dystonia and nocturnal wanderings. Neurology 1992;42(Suppl 6):61-7.

7. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal lobe epilepsy misdiagnosed as sleep disorder. Lan- cet 1994;343:515-7.

8. Plazzi G, Tinuper P, Montagna P, Provini F, Lugaresi E. Epilep- tic nocturnal wanderings. Sleep 1995;18:749-56.

REPLY

To the Editor: We thank Drs. Plazzi et al. and Prof. Ambrosetto

for their comments. The contribution of the Institute of Clinical Neurology, University of Bologna to the field of sleep research, especially concerning the evaluation of paroxysmal nocturnal attacks, is unques- tionable. Indeed, our studies can sometimes be viewed simply as extensions of their observations.

Since the first description of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) by Schef- fer et al. in 1994 (l), the number of patients identified as having this syndrome has increased rapidly. Never- theless, the responsible genetic mutation, described by Steinlein et al. in 1995 (2) has not been found invariably. Indeed, in most of our cases of ADNFLE, the mutation is absent, confirming a genetic heterogeneity 3).

Some of the clinical characteristics of our 38 patients with ADNFLE, such as daytime and night- time symptoms, age-dependent degree of severity, seizure semiology, and response to antiepileptic drugs (AEDs) are fairly consistent. Moreover, we did not observe significant differences between familial and

Epilepsia, Vol. 38, No. 6, 1997

740 LETTERS TO THE EDITOR

sporadic cases (43 patients) (4). About 5% of our patients had neuroradiological abnormalities, which may suggest a symptomatic form of the disease. The electroclinical picture and the response to AEDs of these “symptomatic” cases need to be further studied. The response to AEDs ranged from 73.3% (familial form) to 87.5% (sporadic form). However, in nocturnal forms of epilepsy, it is particularly difficult to establish pharmacoresistence on the basis of the clinical assessment alone, and video-polysomnographic monitoring is needed. In most cases, daytime symptoms are readily controlled by AEDs, as are the prolonged and major nocturnal attacks.

We agree that there are probably several nosologic categories of nocturnal frontal lobe epilepsy (NFLE) (familial and sporadic; idiopathic, symptomatic and, possibly, cryptogenetic forms). On the other hand, to continue describing cases of nocturnal epilepsy using different names may well contribute to misun- derstandings, as pointed out by Prof. Ambrosetto. We believe that the criteria for ADNFLE include an idiopathic origin (unequivocal genetic influence, absence of specific etiology, normal neurological and neuropsychological development, relatively benign course, and usually a good response to AEDs. De- spite persistence of seizures into adulthood, we would consider it to be a benign form of epilepsy, as have other investigators (5) .

Diagnosis may be difficult. All our patients (81 among a sample of 94 = 86.2%) received a definite diagnosis only at the end of a complete evaluation, including video-polysomnographic monitoring (often repeated). In the remaining 13 cases, all of whom had repeated nocturnal motor or behavioral episodes, we were unable to make a definite diagnosis. The bound-

aries between atypical nocturnal seizures and some parasomnias are still vague (4,6).

The systematic use of nocturnal video-polysomnography has greatly improved our ability to make a firm diagnosis in patients with repeated abnormal nocturnal phenomena. Nevertheless, as in every field of medicine, it may be impossible to reach a definite diagnostic conclusion in some cases.

Alessandro Oldani Marco Zucconi

Luigi Ferini-Strambi Daniele Bizzozero

Salvatore Smirne Sleep Disorders Center University of Milano

School of Medicine Istituto ScientiJico H San Raffaele

Milan, Italy

REFERENCES

1.

2.

3.

4.

5.

6.

Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal lobe epilepsy misdiagnosed as sleep disorder. Lan- cet 1994;343:515-7. Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor a 4 subunit is associated with autosomal dominant frontal lobe epilepsy. Na- ture Genet 1995;11:201-3. Oldani A, Zucconi M, Asselta R, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome, 1997 (in press). Zucconi M, Oldani A, Ferini-Strambi L, Smirne S. Nocturnal paroxysmal arousals with motor behaviors during sleep: frontal lobe epilepsy or parasomnia? J Clin Neurophysiol 1997 (in press).

Roger J, Bureau M, Dravet C, Deifuss FE, Perret A, Wolf P. Epileptic syndromes in infancy, childhood and adolescence, 2nd ed. London: John Libbey, 1992. Plazzi G, Tinuper P, Montagna P, Provini F, Lugaresi E. Epilep- tic nocturnal wanderings. Sleep 1995;18:749-56.

Epilepsia, Vol. 38, No. 6, 1997

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