EDITORIAL 1359 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from

Temporal lobe and good prognosis of FMTLE have ...... since been described by others investi- gating idiopathic TLE.18–21

Genetics of temporal lobe epilepsy FMTLE, hippocampal sclerosis, and febrile L Vadlamudi, I E Scheffer, S F Berkovic The initial descriptions of ADPEAF and more common syndrome of FMTLE led ...... to the idea of a clinicoradiological Our traditional understanding is that TLE is an acquired condition, distinction between these benign TLE syndromes, without preceding febrile but only now are we beginning to understand the extent of genetic seizures or hippocampal sclerosis, and involvement patients with severe ‘‘sporadic’’ TLE with hippocampal sclerosis and fre- quently preceding febrile seizures. n the second half of the 19th century, MRI, and no association with febrile Subsequently, it has become apparent John Hughlings Jackson proposed the seizures (table 1). that the relationship between FMTLE concept of partial epilepsy, including Debate as to whether the families I syndromes, hippocampal sclerosis, and ‘‘uncinate seizures’’, based on clinico- with somewhat differing clinical fea- febrile seizures is far more complex. pathological observations from patients tures were due to the same gene was with structural lesions and further sup- settled when Kalachikov et al11 identified ported by pioneering brain surgery.12 mutations in the leucine rich, glioma FMTLE often associated with With the discovery of EEG in the early inactivated 1 (LGI1) gene in five hippocampal sclerosis 20th century, the concepts of temporal families with ADPEAF and mutations Heterogeneity of FMTLE was shown lobe epilepsy (TLE) were further eluci- in this gene were also found in families when multiple TLE families with more dated. Gibbs et al3 described widespread with prominent visual or dysphasic severe syndromes were described with slow activity during ‘‘psychomotor features. LGI1 mutations are not found onset in the first to third decades of life, frequent hippocampal sclerosis, and a attacks’’; they proposed a diffuse under- in all families with ADPEAF, suggesting variable association with febrile seizures lying cerebral disturbance, which was genetic heterogeneity.12 13 Specificity of (table 1).22 23 Inheritance in some not in line with Jackson’s observations. LGI1 to ADPEAF has been confirmed by families is autosomal dominant, but Jasper and Kershman4 then described the absence of mutations in different mapping studies are yet to be reported. focal temporal sharp waves in patients TLE phenotypes (unpublished data, These new data add to the puzzle of they diagnosed with ‘‘temporal lobe Berkovic et al).

the aetiology of hippocampal sclerosis. copyright. seizures’’. By the middle of the 20th LGI1 was first described in glial There remains debate as to whether century, the term TLE was widely tumours where it may be deleted or hippocampal sclerosis is the conse- utilised and much of the subsequent rearranged, but glial tumours do not quence of an early childhood injury understanding of this disorder was occur with increased frequency in (such as prolonged febrile seizures and based on pre-surgical studies of intract- ADPEAF. It has been suggested that ),24 a consequence of able cases. Traditionally, TLE has been LGI1 has a role in neuronal migration or ongoing seizures,25 or an early develop- considered to be an acquired disorder 11 cortical organisation. Given that the mental lesion.26 Genetic factors have secondary to lesions such as hippo- majority of LGI1 mutations cause pro- been implicated since Falconer’s pio- campal sclerosis, tumours, trauma, tein truncation, loss of function is the neering studies and these large families vascular malformations, and neuronal 11 14 likely underlying mechanism. All with hippocampal pathology suggests a migration disorders.5 prior genes that have been discovered major genetic component to its aetiol- Falconer et al, however, studied the for idiopathic have been asso- ogy, at least in certain cases. http://jnnp.bmj.com/ aetiology of TLE in 110 refractory cases ciated with ion channels.15 This discov- and demonstrated 95% of cases had ery suggests new neurobiological FMTLE often associated with underlying cerebral pathology, but also mechanisms for familial epilepsies. astutely stated, ‘‘these lesions, however febrile seizures Two large families and some smaller may develop on a soil already predis- FAMILIAL MESIAL TEMPORAL kindred’s have been described with posed to convulsions’’.6 In the past 20 LOBE EPILEPSY many individuals with both TLE and years, what is becoming more evident is In 1994, we described familial mesial febrile seizures. The TLE syndrome this evolving key role of genetics in TLE. on September 30, 2021 by guest. Protected temporal lobe epilepsy (FMTLE) as a begins in the first to second decades of benign syndrome with onset in the life, there are no temporal lobe or AUTOSOMAL DOMINANT second to fifth decades of life, no hippocampal abnormalities on MRI PARTIAL EPILEPSY WITH temporal lobe or hippocampal abnorm- and the course is benign (table 1).27–29 AUDITORY FEATURES alities on MRI, and no association with Digenic inheritance was suggested for In 1995, Ottman et al described partial febrile seizures (table 1).16 17 The nature the French family, one locus with epilepsy with auditory features linked to of the aura, with prominent psychic and significant linkage at chromosomes chromosome 10q7 and later termed the autonomic features, suggested mesial 18qter and one with supportive linkage syndrome autosomal dominant partial temporal origin. The commonest symp- at 1q25–q31.28 Linkage was not found in epilepsy with auditory features tom was intense de´ja` vu; in some cases the Belgian family to known candidate (ADPEAF).8 Similar families mapping epilepsy had not been diagnosed and the loci.27 to the same region were described with intense de´ja` vu was regarded as ‘‘nor- prominent visual features or sensory mal’’. Inheritance is consistent with Febrile seizures often associated dysphasia, all suggesting a lateral tem- autosomal with reduced with mesial TLE poral origin.910 ADPEAF is a benign penetrance, but no very large pedigrees It is more common to find families where syndrome with onset in the first to third have been reported and the disorder is there are multiple individuals with feb- decades of life, no abnormalities on yet to be mapped. The clinical features rile seizures and a few with TLE. A large

www.jnnp.com 1360 EDITORIAL J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from

Table 1 Familial temporal lobe epilepsy (TLE) subtypes

TLE in broader partial epilepsy syndromes Familial mesial (FM) TLE syndromes* syndrome

FMTLE no HS no FMTLE often HS FMTLE with FS Syndrome ADPEAF7–11 FS16–20 +/2FS22 23 usually no HS27 28 FPEVF32 33 PEPS34

Typical age of onset 8 years to 4th decade 10 years to 4th 1 year to 3rd 1 year to 2nd 1 year to 4th decade 2 years to 2nd decade decade decade decade Characteristic features Auditory, sensory aura Psychic, autonomic Seizures with different Multiple types aura focal origin in family in the same individual members EEG Rare temporal discharges Rare temporal Frequent temporal Occasional Occasional temporal Frequent peri-central discharges discharges temporal discharges spikes discharges MRI Normal Normal HS Normal Normal Normal Outcome Generally benign Generally benign Often refractory Variable Variable Generally benign Linkage 10q – 18qt,1q (?) 22q,2q (?)4p Genes LGI1 – – – – –

*These divisions are preliminary and they are probably overlapping mesial TLE syndromes. Range of onset ages reflects the majority of reported cases. Some ‘‘outliers’’ may begin earlier or later, but most family members fall within the stated ranges. ADPEAF, autosomal dominant partial epilepsy with auditory features; HS, hippocampal sclerosis; FS, febrile seizures; FPEVF, familial partial epilepsy with variable foci; PEPS, partial epilepsy with pericentral spikes. study of such families demonstrated a analysis, a robust technique depending evidence from animal studies suggest strong association between prolonged on large families. Many patients with the brain’s ability to repair damage is febrile seizures and hippocampal sclero- TLE do not have such a strong family impaired by its presence, hence may sis.30 Another family has been described history, yet genetic factors are likely to result in an epileptogenic focus.42 43 It with generalised epilepsy with febrile be involved to some extent. Such sus- was found that the presence of APOE e4 seizures plus, with a few family members ceptibility genes have been studied by allele may shorten latency between with TLE.31 The proband had TLE with association studies. Association studies initial injury and seizure onset in hippocampal sclerosis. All affected family involve large numbers of sporadic cases TLE,42 however associations between members had a sodium channel muta- to determine if there is significant APOE polymorphism and TLE were not tion (SCN1A). association of epilepsy with a particular found in other studies.44 45 polymorphism within a gene. Polymorphisms of the GABA (B) copyright. Identifying susceptibility genes TLE AS PART OF DOMINANT receptor 1 gene, which encodes the remains challenging, as there is no PARTIAL EPILEPSY SYNDROMES major inhibitory neurotransmitter in single locus of large effect, but rather Other familial partial epilepsies have the CNS, have been studied and an multiple loci probably exist.35 recently been described that include association between the G1465A poly- Determination of such genes by associa- seizures arising from the temporal lobe morphism and increased susceptibility tion studies has many methodological 46 as part of their spectrum of clinical to TLE was recently described. To date, problems and replication of the initial manifestations. this is the only published study of this observation is often negative. Familial partial epilepsy with variable association. Methodological issues include power of foci (FPEVF) was first described by our We are only beginning to understand the study, false positives and differing group (in an Australian family) with the genetics of TLE. Our traditional ethnic background. Currently four poly- onset in the first to third decades of life, understanding was that it was an http://jnnp.bmj.com/ morphisms have been suggested as heterogeneous seizures types including acquired condition, but only now are susceptibility genes for TLE. TLE within the same family, and with- we beginning to understand the extent There has been a reported increased out associated MRI abnormalities or of genetic contribution to this condition. risk of TLE in those with a family history febrile seizures (table 1).32 There was a In the future we need to continue to of seizures with polymorphisms of the suggestion of linkage to chromosome find large families to perform linkage prodynorphin gene, which encodes 2q. In 1999 a more definite linkage at analysis in order to determine further dynorphin (anticonvulsant peptide), a chromosome 22q11–q12 was found in candidate genes as well as continue the strong candidate for a seizure suppres- two large French–Canadian families search for susceptibility genes through on September 30, 2021 by guest. Protected sor gene,36 which has not been repro- with similar clinical features.33 association studies. duced by other investigators.37 Partial epilepsy with pericental spikes Polymorphisms of interleukin-1b (IL- J Neurol Neurosurg Psychiatry (PEPS) was described in a single 1b), IL-1a, and IL-1 receptor antagonist 2003;74:1359–1361 Brazilian family as a generally benign genes have been studied, which encode syndrome with onset in the first to ...... proinflammatory cytokines that modu- second decades of life, partial seizures late neurotoxic neurotransmitters. Author’s affiliation including TLE, characteristic pericentral L Vadlamudi, I E Scheffer, S F Berkovic, Functional polymorphisms in the IL-1b spikes on EEG, without associated MRI Epilepsy Research Institute, University of gene associated with TLE and hippo- abnormalities or febrile seizures Melbourne, Australia campal sclerosis have been described,38 (table 1).34 Linkage was demonstrated but not reproduced by others.39 40 Competing interests: none declared to chromosome 4p15.34 Polymorphisms of IL-1 receptor antago- nist have been described in susceptibil- Correspondence to: Professor S Berkovic, SUSCEPTIBILITY GENES ity to febrile convulsions,41 but not Epilepsy Research Institute, University of found by other investigators.38 Melbourne, Austin Health, First Floor, The syndromes described above appear Neurosciences Building, Banksia Street, to segregate major autosomal dominant Apolipoprotein E (APOE) e4 allele, Heidelberg West, VIC 3081, Australia; genes; these are studied by linkage promotes deposition of b-amyloid, and [email protected]

www.jnnp.com EDITORIAL COMMENTARIES 1361 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from

REFERENCES 17 Berkovic SF, McIntosh A, Howell A, et al. Familial 33 Xiong L, Labuda M, Li D-S, et al. Mapping of a temporal lobe epilepsy: a common disorder gene determining familial partial epilepsy with 1 Horsley V. Brain-surgery. BMJ 1886;ii:670–5. identified in twins. 1996;40:227–35. variable foci to chromosome 22q11–q12. 2 Jackson H. On a particular variety of epilepsy 18 Aguglia U, Gambardella A, Le Piane E, et al. Am J Hum Genet 1999;65(6):1698–1710. (‘‘intellectual aura’’), one case with symptoms of Mild non-lesional temporal lobe epilepsy a 34 Kinton L, Johnson MR, Smith SJ, et al. Partial organic brain disease. Brain 1888;11:179–207. common, unrecognized disorder with onset in epilepsy with pericentral spikes: a new familial 3 Gibbs FA, Gibbs EL, Lennox WG. Epilepsy: a adulthood. Can J Neurol Sci 1998;25(4):282–6. epilepsy syndrome with evidence for linkage to paroxysmal cerebral dysrhythmia. Brain 19 Regesta G, Tanganelli P. Temporal lobe epilepsy chromosome 4p15. Ann Neurol 1937;60(4):377–88. of adult age of possible idiopathic nature. Seizure 2002;51(6):740–9. 4 Jasper H, Kershman J. Electroencephalographic 2002;11(2):131–5. 35 Botstein D, Risch N. Discovering genotypes classification of the epilepsies. Archives of 20 Gambardella A, Messina D, Le Piane E, et al. underlying human phenotypes: past successes for and Psychiatry 1941;45:903–43. Familial temporal lobe epilepsy Autosomal mendelian disease, future approaches for 5 Bruton CJ. The neuropathology of temporal lobe dominant inheritance in a large pedigree from complex disease. Nat Genet Supplement epilepsy. Oxford: Oxford University Press, 1988. Southern Italy. Epilepsy Res 2000;38:127–32. 2003;33:228–237. 21 Brewster Smith W, So N, Thompson K. Familial 6 Falconer MA, Serafetinides EA, Corsellis JAN. 36 Stogmann E, Zimprich A, Baumgartner C, et al. temporal lobe epilepsy. Epilepsia 1996;37(Suppl. Etiology and pathogenesis of temporal lobe A functional polymorphism in the prodynorphin 5):34. epilepsy. Arch Neurol 1964;10:233–48. gene promotor is associated with temporal 22 Cendes F, Lopes-Cendes I, Andermann E, et al. 7 Ottman R, Risch N, Hauser WA, et al. lobe epilepsy. Ann Neurol 2002;51:260–3. Familial temporal lobe epilepsy: a clinically Localization of a gene for partial epilepsy to heterogeneous syndrome. Neurology 37 Tilgen N, Rebstock J, Horvath S, et al. chromosome 10q. Nat Genet 1995;10:56–60. 1998;50:554–7. Prodynorphin gene promoter polymorphism and 8 Winawer M, Ottman R, Hauser WA, et al. 23 Kobayashi E, Lopes-Cendes I, Guerreiro CAM, et temporal lobe epilepsy. Ann Neurol Autosomal dominant partial epilepsy with al. Seizure outcome and hippocampal atrophy in 2003;53(2):280–2. auditory features: defining the phenotype. familial mesial temporal lobe epilepsy. Neurology 38 Kanemoto K, Kawasaki J, Miyamoto T, et al. Neurology 2000;54:2173–6. 2001;56:166–72. Interleukin (IL) 1b, IL-1a, and IL-1 receptor 9 Poza JJ, Saenz A, Martinez-Gil A, et al. 24 Mathern GW, Babb TL, Vickrey BG, et al. The antagonist gene polymorphisms in patients with Autosomal dominant lateral temporal epilepsy: clinical-pathogenic mechanisms of hippocampal temporal lobe epilepsy. Ann Neurol clinical and genetic study of a large Basque neuron loss and surgical outcomes in temporal 2000;47(5):571–4. pedigree linked to chromosome 10q. Ann Neurol lobe epilepsy. Brain 1995;118:105–18. 39 Buono RJ, Ferraro TN, O’Connor MJ, et al. Lack 1999;42(2):182–8. 25 Kalviainen R, Salmenpera T, Partanen K, et al. of association between an interleukin 1 beta (IL– 10 Brodtkorb E, Gu W, Nakken KO, et al. Familial Recurrent seizures may cause hippocampal 1b) gene variation and refractory temporal lobe temporal lobe epilepsy with aphasic seizures and damage in temporal lobe epilepsy. Neurology epilepsy. Epilepsia 2001;42(6):782–4. linkage to chromosome 10q22–q24. Epilepsia 1998;50:1377–82. 40 Heils A, Haug K, Kunz WS, et al. Interleukin-1b 2002;43(3):228–35. 26 Fernandez G, Effenberger O, Vinz B, et al. gene polymorphism and susceptibility to temporal 11 Kalachikov S, Evgrafov O, Ross B, et al. Hippocampal malformation as a cause of familial lobe epilepsy with hippocampal sclerosis. Ann Mutations in LGI1 cause autosomal-dominant febrile convulsions and subsequent hippocampal Neurol 2000;48(6):948–50. partial epilepsy with auditory features. Nat Genet sclerosis. Neurology 1998;50:909–17. 41 Tsai F-J, Hsieh Y-Y, Chang C-C, et al. 2002;30(3):335–41. 27 Depondt C, Van Paesschen W, Matthijs G, et al. Polymorphisms for interleukin 1b exon 5 and 12 Morante-Redolat JM, Gorostidi-Pagola A, Familial temporal lobe epilepsy with febrile interleukin 1 receptor antagonist in Taiwanese Piquer-Sirerol, et al. Mutations in the LGI1/ seizures. Neurology 2002;58:1429–33. children with febrile convulsions. Arch Pediatr Epitempin gene on 10q24 cause autosomal 28 Baulac S, Picard F, Herman A, et al. Evidence for Adolesc Med 2002;156:545–8. dominant lateral temporal epilepsy. Hum Mol digenic inheritance in a family with both febrile 42 Briellmann RS, Torn-Broers Y, Busuttil BE, et al. Genet 2002;11(9):1119–28. convulsions and temporal lobe epilepsy APOE e4 genotype is associated with an earlier 13 Bissulli F, Tinuper P, Marini C, et al. Partial implicating chromosomes 18qter and 1q25–q31. onset of chronic temporal lobe epilepsy. copyright. epilepsy with prominent auditory symptoms not Ann Neurol 2001;49:786–92. Neurology 2000;55:435–7. linked to chromosome 10q. Epileptic Disorders 29 Ward N, Evanson J, Cockerell OC. Idiopathic 43 Poirier J. Apolipoprotein E in animal models of 2002;3:183–7. familial temporal lobe epilepsy with febrile CNS injury and in Alzheimer’s disease. Trends 14 Pizzuti A, Flex E, Di Bonaventura C, et al. convulsions. Seizure 2002;11(1):16–19. Neurosci 1994;17:525–30. 30 Maher J, McLachlan RS. Febrile convulsions. Is Epilepsy with auditory features: a LGI1 gene 44 Bluemcke I, Brockhaus A, Scheiwe C, et al. The seizure duration the most important predictor of mutation suggests a loss-of-function mechanism. temporal lobe epilepsy? Brain apolipoprotein E epsilon 4 allele is not associated Ann Neurol 2003;53:396–9. 1995;118:1521–28. with early onset temporal lobe epilepsy. 15 Kullmann DM. Genetics of epilepsy. J Neurol 31 Abou-Khalil B, Ge Q, Desai R, et al. Partial and Neuroreport 1997;8:1235–37. Neurosurg Psychiatry 2002;73(Suppl with febrile seizures plus 45 Gambardella A, Aguglia U, Cittadella R, et al. II):ii32–ii35. and a novel SCN1A mutation. Neurology Apolipoprotein E polymorphisms and the risk of 16 Berkovic SF, Howell A, Hopper JL. Familial 2001;57(12):2265–72. nonlesional temporal lobe epilepsy. Epilepsia temporal lobe epilepsy: a new syndrome with 32 Scheffer IE, Phillips HA, O’Brien CE, et al. 1999;40(12):1804–07. adolescent/adult onset and a benign course. In: Familial partial epilepsy with variable foci: a new 46 Gambardella A, Manna I, Labate A, et al.

Wolf P, ed. Epileptic seizures and syndromes. partial epilepsy syndrome with suggestion of GABA(B) receptor 1 polymorphism (G1465A) is http://jnnp.bmj.com/ London: John Libbey & Company Ltd, linkage to chromosome 2. Ann Neurol associated with temporal lobe epilepsy. 1994:257–63. 1998;44(6):890–9. Neurology 2003;60:560–3.

Chronic fatigue syndrome n the paper by Lane et al(see pp 1382– on September 30, 2021 by guest. Protected ...... 1386)1 an association was found Ibetween abnormal exercise lactate response and enterovirus sequences in Enteroviruses in chronic fatigue the muscle of some patients with (CFS). The syndrome: ‘‘now you see them, now paper rekindles the old saga of entero- viruses, muscle , and you don’t’’ fatigue. CFS remains an elusive entity. When M C Dalakas all known factors causing fatigue are excluded, a number of patients have ...... organic disease. Because some CFS patients have impaired muscle energy Can enteroviruses infect human muscle and cause persistent metabolism,2 the cause of fatigue may infection that affects only the metabolic machinery of the cells not be ‘‘in their head’’ but ‘‘in their without muscle destruction? muscle’’. Now, Lane et al propose that

www.jnnp.com 1362 EDITORIAL COMMENTARIES J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from such metabolic impairment is more mutate, become less lytic or infective persistence alters the metabolic machin- common in patients with enteroviral and under certain conditions, may ery of the cell; and show that such sequences in the muscle. The paper produce interferon or other cell media- abnormalities cause clinical symptoma- raises a fundamental question: can tors that upregulate transcription of tology. This is a laborious, but worth- enteroviruses infect human muscle and cytokine genes through activation of while effort that may prove rewarding cause persistent infection that affects nuclear factor kappa B (NFkB). The for the millions of CFS patients because only the metabolic machinery of the induced nitric oxide synthase and cyto- anti-enteroviral agents are now avail- cells without muscle destruction? If so, kines, such as tumour necrosis factor able (pleconaril) or in the offing. The is this clinically relevant to CFS alpha or interleukin 1, may either authors may be on the right target but patients? cause a slow muscle fibre injury or there are no shortcuts in pursuing it. Although coxsackieviruses in mice deprive the cells of their luxury func- cause acute myositis, there is no con- tions, resulting in indolent metabolic J Neurol Neurosurg Psychiatry vincing evidence that they also infect dysfunction.34 2003;74:1361–1362 3 human muscle. Cases of epidemic Accordingly, the findings of Lane et al ...... pleurodynia, myoglobinuria, or myocar- are theoretically relevant to CFS even Author’s affiliation ditis attributed to coxsackieviruses, though a causal relationship between M C Dalakas, Neuromuscular Diseases Section, remain unsubstantiated. The evidence viral persistence and reduced muscle National Institute of Neurological Disorders and is even weaker for chronic diseases, endurance was not demonstrated. In the , National Institutes of Health, Bethesda, such as CFS or inflammatory myopa- past, such findings have turned out to Building 10, Room 4N248, 10 Center Dr. MSC thies.3 Unfortunately, the application of be epiphenomena because enteroviruses 1382, MD 20892-1382, USA modern molecular virology techniques are ubiquitous in humans and technical Correspondence to: Dr M C Dalakas; have not cleared the field; instead, they flaws inherently connected to contam- [email protected] keep the controversy alive. Furthermore, ination in laboratories working with data on viral persistence emerging from these viruses are inevitable. Lane et al REFERENCES the mouse model and tissue cultures, have performed a careful study and 1 Lane RJM, Soteriou BA, Zhang H, et al. fuel the scientific interest. After an acute their findings deserve attention because, Enterovirus related metabolic myopathy: a post- enteroviral infection, mice develop a if proved to be specific, they will provide viral fatigue syndrome. J Neurol Neurosurg Psychiatry 2003; 74:1382–6. chronic, T cell dependent, myositis; viral the first indirect indication of a viral 2 McCully KK, Natelson BH, Iotti S, et al. Reduced RNA is detectable in the muscle but related fatigue in a subset of CFS oxidative muscle metabolism in chronic fatigue declines over a 12 month period, as the patients. syndrome. Muscle Nerve 1996;19:621–5. inflammation resolves. Non-dividing CFS is a common problem and any 3 Dalakas MC. Viral related muscle disease. In:

Engel AG, ed. Myology. New York: McGraw Hill, copyright. cells, such as myofibres, if survived the clues regarding its cause are welcome. 2003 (in press). acute cytopathic damage, regenerate The authors need, however, to demon- 4 Pelletier I, Duncan G, Pavio N, et al. Molecular mechanisms of poliovirus persistence: key role of and may harbour viral RNA, trapped in strate enterovirus within the muscle capsid determinants during the establishment 34 the cytoplasm. These viral material fibres by in situ PCR; prove that viral phase. Cell Mol Life Sci 1998;54:1385–1402.

Essential sclerosis) undergoing bilateral deep ...... brain stimulation; no tremor had returned in any of the 13 patients with essential tremor. The greater efficacy of Multicentre European study of thalamic bilateral thalamic deep brain stimula- http://jnnp.bmj.com/ tion for essential tremor is highlighted stimulation in essential tremor by Deuschl et al in their review.5 They comment that a bilateral procedure may J P R Dick have additional benefit for tremor of mid-line structures.5 ...... In this study,1 37 essential tremor patients managed with bilateral thala- Bilateral thalamic continues to show well on September 30, 2021 by guest. Protected mic deep brain stimulation were maintained benefit in patients who have severe essential tremor reviewed after one and six years. While after seven years with little increase in stimulation parameters there was a non-significant trend towards increased tremor after six years, n their paper, Sydow et al (see this comparison of bilateral Vim stimulation an excellent functional improvement issue pp 1387–1391)1 have shown with unilateral thalamotomy suggested was still maintained when comparing Isustained long term efficacy of high that deep brain stimulation was more both activities of daily living and tremor frequency deep brain stimulation of the effective and certainly associated with scores, ON and OFF stimulation. This (Vim) for the management of fewer side effects.4 In the latter study trend would, of course, be consistent severe essential tremor. This observation the outcome was slightly better for with the natural history of essential is of interest as certain authors had essential tremor patients (using either tremor. The observed increase in stimu- commented that its benefit may wane procedure) than for patients with lator output during the six year period with time.2 Parkinson’s disease or . largely arose in the first year (2.0 to A multicentre European trial had At 6 months some tremor had recurred 2.3 V). The authors speculate that the initially demonstrated the efficacy of in 7 of 34 patients (3 Parkinson’s subsequent increase (2.3 to 2.6 V) was a thalamic deep brain stimulation (largely disease, 4 multiple sclerosis) undergoing reflection of disease progression, unilateral) in the management of unilateral thalamotomy and in 3 of 34 although acknowledge that it may have essential tremor3 and a subsequent (1 Parkinson’s disease, 2 multiple reflected an element of tolerance.

www.jnnp.com EDITORIAL COMMENTARIES 1363 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1362 on 20 October 2003. Downloaded from

They quote only one other study ability of long term deep brain stimula- Competing interests: JPRD was sponsored by with a follow up period of equivalent tion, the marginal superiority of Medtronic to attend a two day workshop length.6 In that study, 19 essential stimulation over thalamotomy would organised by the European Continuing Medical Training Group, on deep brain stimu- tremor patients were followed for six have been lost, especially considering lation in Keil, Germany, January 2003 to seven years after unilateral thalamic the cost and the more intense follow up deep brain stimulation. The benefits regime required for deep brain stimula- REFERENCES for postural and action tremor were tion. However, these two long term 1 Sydow O, Thobois S, Alesch F, et al. Multicentre well maintained over 6.5 years (SD studies show well maintained sympto- European study of thalamic stimulation in essential 0.3) although, again, some slippage matic benefit over six to seven years, tremor: a six year follow up. J Neurol Neurosurg of effect was seen, for example for and any trend for recurrent tremor was Psychaitry 2003;74:1387–91. 2 Benabid AL, Pollak P, Hoffman D, et al. Chronic action tremor of the legs. The stimulator scarcely detectable by statistics and may high frequency stimulation in Parkinson’s disease. output increased from 2.0 V (SD 0.7), reflect the natural progression of the In: Koller WC, Paulson GW, eds. Therapy of initially to 2.4 V (SD 0.9) after two disease. Parkinson’s disease, 2nd edn. New York: Marcel years, and was 2.3 V (SD 1.0) after six Dekker, 1994:381–482. J Neurol Neurosurg Psychiatry 3 Limousin P, Speelman JD, Gielen F, et al. to seven years. 2003;74:1362–1363 Multicentre European study of thalamic These and other studies have shown stimulation in parkinsonian and essential tremor...... J Neuro Neurosurg Psychiatry 1999;66:289–96. that unilateral deep brain stimulation is 4 Schuurman PR, Bosch DA, Bossuyt PMM, et al. A as effective as unilateral thalamotomy Author’s affiliation comparison of continuous thalamic stimulation in the management of severe essential J P R Dick, Department of Neurology, Greater and thalamotomy for suppression of severe Manchester Neuroscience Centre, Hope tremor. New Engl J Med 2000;342:461–8. tremor and it may be that bilateral deep 5 Deuschl G, Wenzelburger R, Raethjen J. Tremor: brain stimulation is better than unilat- Hospital, Stott Lane, Salford M6 8HD, UK a review. Curr Opin Neurol 2000;13:437–43. eral deep brain stimulation, particularly 6 Rehncrona S, Johnels B, Widner H, et al. Long- Term (6–7 years) efficacy of thalamic DBS for for those with a generalised tremor Correspondence to: DR J P R Dick; tremor: double blind assessments. Mov Dis syndrome. Had there been poor dur- [email protected] 2003;18:171–5. copyright.

Want full text but don't have

a subscription? http://jnnp.bmj.com/

Pay per view on September 30, 2021 by guest. Protected For just $8 you can purchase the full text of individual articles using our secure online ordering service. You will have access to the full text of the relevant article for 48 hours during which time you may download and print the pdf file for personal use. www.jnnp.com

www.jnnp.com