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Objective:Essential tremor (ET) is one of the most prevalent movement disorders. Because ET is so common, individuals with other neurological disorders may also have ET. There is evidence, however, that the co-occurrence of ET with Parkinson’s disease (PD) and/or dystonia is not merely a chance co-occurrence. We have observed combinations of these three movement disorders within individuals and across individuals within families containing multiple individuals with ET. This observation has a number of implications. Our objective is to present four ET families in whom motor phenomenology was heterogeneous, and discuss the implications of this finding.Methods:ET cases and their relatives were enrolled in the Family Study of Essential Tremor (2015 – present). Phenotyping was performed by a senior movement disorders neurologist based on neurological examination.Results:We present four families, including 14 affected individuals, among whom assigned diagnoses were ET, PD, ET + PD, and ET + dystonia. In those with ET and another movement disorder, the predominant and earliest phenotype was ET.Conclusion:There are assortments of these three involuntary motor disorders, ET, dystonia and PD, both within individuals and in different individuals within ET families. This observation has mechanistic implications. Furthermore, we believe the concept of the “mixed motor disorder” should enter into and inform the clinical dialogue. In assigning diagnoses, clinicians are swayed by family history information, and they should be prepared a mix of different motor disorders to manifest within particular families.

Background: Assessment of the penetrance of disease-causing mutations is extremely important for developing clinical applications of gene discovery, such as genetic testing and counseling. Mutations in the leucine-rich, glioma inactivated 1 gene ( LGI1 ) have been identified in about 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), but estimates of LGI1 mutation penetrance have ranged widely, from 50 to 85%. The current study aimed to provide a more precise estimate of LGI1 mutation penetrance. Methods: We analyzed data from all 24 previously published ADPEAF families with mutations in LGI1 . To estimate penetrance, we used the information from the published pedigree figures to determine the proportion of obligate carriers who were affected. We assessed whether penetrance was associated with the total number of affected individuals in each family, or mutation type (truncating or missense) or location within the gene. We also compared penetrance in males and females, and among different generations within the families. Results: Overall penetrance was 67% (95% CI 55–77%), and did not vary according to mutation type or location within the gene. Penetrance was greater in families with more affected individuals, but this trend was not significant. Penetrance did not differ by gender but increased with advancing generation, probably because of limited information about early generations. Conclusions: Our results suggest that about two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals.

Objective: To evaluate the frequency of glucocerebrosidase ( GBA ) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study. Methods: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO Results: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p p 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) ( p GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, Rec NciI , and a novel mutation, P175P. Conclusions: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset. GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.

To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD).We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in theor =50 age at onset (AAO) category.The LRRK2 G2019S mutation was present in 28 cases with PD (5.6%) and two controls (0.6%) (chi(2) = 13.25; p0.01; odds ratio 9.18, 95% CI: 2.17 to 38.8). The mutations L1114L, I1122V, R1441C, and Y1699C were not identified. The frequency of the LRRK2 G2019S mutation was 4.9% in 245 cases with AAOor =50 years vs 6.2% in 259 cases with AAO50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p0.01). Age-specific penetrance to age 80 was 24% and was similar in Jewish and non-Jewish cases.The G2019S mutation is a risk factor in both early- and late-onset Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

Objectives: To develop standardized definitions for classification of partial seizure symptoms for use in genetic research on the epilepsies, and evaluate inter-rater reliability of classifications based on these definitions. Methods: The authors developed the Partial Seizure Symptom Definitions (PSSD), which include standardized definitions of 41 partial seizure symptoms within the sensory, autonomic, aphasic, psychic, and motor categories. Based on these definitions, two epileptologists independently classified partial seizures in 75 individuals from 34 families selected because one person had ictal auditory symptoms or aphasia. The data used for classification consisted of standardized diagnostic interviews with subjects and family informants, and medical records obtained from treating neurologists. Agreement was assessed by kappa. Results: Agreement between the two neurologists using the PSSD was “substantial” or “almost perfect” for most symptom categories. Conclusions: Use of standardized definitions for classification of partial seizure symptoms such as those in the Partial Seizure Symptom Definitions should improve reliability and accuracy in future genetic studies of the epilepsies.

Objective: To examine the genetic relationships among epilepsies with different seizure types—myoclonic, absence, and generalized tonic-clonic—within the idiopathic generalized epilepsies (IGEs).Background: Careful phenotype definition in the epilepsies may allow division into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups.Methods: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent sample of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed.Results: The proportion of families concordant for myoclonic vs absence seizures was greater than expected by chance in the Australian families. In addition, GTCs clustered in families with IGEs to a degree greater than expected by chance.Conclusions: These results provide additional evidence for distinct genetic effects on myoclonic vs absence seizures in an independent set of families and suggest that there is a genetic influence on the occurrence of generalized tonic-clonic seizures within the idiopathic generalized epilepsies.

Objective—To examine the relationship between genotype and phenotype in idiopathic generalized epilepsies (IGEs) using a novel approach that focuses on seizure type rather than syndrome. Methods—The authors evaluated whether the genetic effects on myoclonic seizures differ from the genetic effects on absence seizures. For this purpose, they studied 34 families containing 2 or more members with IGEs and assessed whether the number of families concordant for seizure type exceeded that expected by chance. The authors performed a similar analysis to examine the genetic contributions to juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and childhood absence epilepsy (CAE). Results—The observed number of families concordant for seizure type (myoclonic, absence, or both) was greater than expected (20 vs 7.51; p < 0.0001). The observed number of families concordant for syndrome was greater than expected when JME was compared with absence epilepsies (JAE +CAE) (17 vs 11.9; p < 0.012) but not when JAE was compared with CAE (8 vs 6.82; p = 0.516). Conclusions—These results provide evidence for distinct genetic effects on absence and myoclonic seizures, suggesting that examining the two seizure types separately would be useful in linkage studies of idiopathic generalized epilepsies. The approach presented here can also be used to discover other clinical features that could direct division of epilepsies into groups likely to share susceptibility genes. Despite progress in identifying the monogenic causes of some relatively rare forms of epilepsy, most epilepsy remains unexplained by genes discovered so far, and the relationship between genes and syndromes or seizure types is not clear. This is particularly true for the complex epilepsies, which have multiple genetic (and perhaps nongenetic) influences. Do genes dictate the specific clinical features of epilepsy rather than simply raising risk for epilepsy overall? If there are such phenotype-specific genes, then what clinical features do they dictate? Answering these questions could elucidate the function of epilepsy genes before gene discovery through molecular studies and guide rational subdivision of epilepsy syndromes for genetic analysis. The idiopathic generalized epilepsies (IGEs) have posed a particularly difficult problem. Gene discoveries reported to date in the IGEs appear to explain only a small subset of the families

Background: Previously, the authors found that risk of spontaneous abortion was increased in the pregnancies of women with epilepsy compared with their same-sex siblings, which could have implications for risk of epilepsy in their offspring. An association between a history of spontaneous abortion in the mother and risk of epilepsy in her live-born offspring may arise through selective loss of fetuses with a genetic susceptibility to epilepsy or through intrauterine environmental factors that may predispose the mother to a spontaneous abortion and to epilepsy in her live-born children. Method: The authors examined the relation of a history of spontaneous abortion to the risk of idiopathic or cryptogenic epilepsy in 791 live-born offspring of 385 women with cryptogenic localization-related epilepsy (probands) ascertained from voluntary organizations. A semistructured telephone interview with probands and additional family informants, supplemented by medical record review, was used to obtain information on seizures and other risk factors in probands and relatives. Results: Live-born offspring of women with a history of spontaneous abortion were four or five times as likely to develop epilepsy as were children of women without (12.8% versus 4.7%; rate ratio = 4.6, 95% CI: 2.3–9.0). Cumulative incidence of epilepsy was 21.9% in offspring of women with a history of spontaneous abortion and a family history of epilepsy, compared with 4.7% in offspring of women with neither risk factor. Conclusions: These results suggest that a history of spontaneous abortion is associated with increased risk of epilepsy in live-born offspring and may be a marker for genetic susceptibility for epilepsy in the mother.

Article abstract The authors previously reported linkage to chromosome 10q22-24 for autosomal dominant partial epilepsy with auditory features. This study describes seizure semiology in the original linkage family in further detail. Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin. Auditory hallucinations, the most striking clinical feature, are useful for identifying new families with this synome.

Objective: We describe all Juvenile Parkinson9s Disease (JPD) probands who were recruited through the CORE-PD study. Background JPD is exceptionally rare, seldom reported, and defined as disease age at onset (AAO) Design/Methods: Eleven hundred and three individuals with early-onset PD (defined as AAO SNCA , PRKN , PINK1 , DJ1 , LRRK2 and GBA . Results: Twenty probands (1.8%) reported AAO PRKN carriers, two were PRKN heterozygotes, two carried heterozygous GBA mutations (one L444P and one N370S) and one carried the LRRK2 G2019S mutation. Only four (20%) reported a family history of PD in a first degree relative, all of whom carried PRKN mutations (two compound heterozygotes and two heterozygotes). Of these four probands, two had a family history of JPD in siblings (one heterozygote with AAO=16 and one compound heterozygote with AAO=12), each with a similar genotype to proband. None of the 66 PRKN mutation carriers with disease onset>20 had a sibling with JPD. Conclusions: JPD is extremely rare among EOPD. While identifiable genetic risk factors are common, first degree family history of PD is present in a minority. Supported by: Funded by NIH NS36630, UL1 RR024156 (K.S.M.), NS050487, NS060113 (L.N.C.), the Parkinson9s Disease Foundation (K.S.M., S.F., and L.N.C.), P50 NS039764 (W.K.S) and NS36960 (H.P). RNA is a Brookdale Foundation Leadership in Aging Fellow. Disclosure: Dr. Alcalay has nothing to disclose. Dr. Rosado has nothing to disclose. Dr. Mejia-Santana has nothing to disclose. Dr. Orbe-Reilly has nothing to disclose. Dr. Caccappolo has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Ruiz has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Verbitsky has nothing to disclose. Dr. Kisselev has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Comella has received personal compensation for activities with Ipsen, Merz Pharma, Allergan, Inc., and NuPathe. Dr. Comella has received research support from Ipsen, Merz Pharma, Allergan, Inc., the National Institutes of Health, and the Dystonia Study Group. Dr. Colcher has nothing to disclose. Dr. Jennings has received personal compensation for activities with Lundbeck Research USA as a speaker. Dr. Nance has received research support from Medivation, Santhera, Juvantia, Neurosearch Sweden, Pfizer Inc, Neuraltus, Impax, and Schwarz Biosciences. Dr. Bressman has received license fee payments from Beth Israel/Mount Sinai/Athena. Dr. Scott has nothing to disclose. Dr. Tanner has received personal compensation for activities with Impax Pharmaceuticals, Allergan, Inc. & Genentech, Inc. as a consultant. Dr. Tanner has received research support from Michael J. Fox Foundation, Department of Defense, Parkinson9s Disease Foundation, Parkinson9s Institute, Unity Walk and Brin Foundation. Dr. Andrews has nothing to disclose. Dr. Waters has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Intec Pharma, Merz Pharma, Oxford Biomedica, RJG Foundation, IMPAX Pharmaceuticals, and Lundbeck as a consultant. Dr. Fahn has received personal compensation in an editorial capacity for Elsevier and Springer. Dr. Cote has nothing to disclose. Dr. Frucht has received personal compensation for activities with UCB Pharma. Dr. Ford has received personal compensation for activities with Novartis and Medtronic, Inc. Dr. Rezak has received personal compensation for activities with Medtronic, Teva, Novartis, Allergan, Smih-Klein, Boehringer-Ingleheim, and UBC as a speaker. Dr. Novak has nothing to disclose. Dr. Friedman has received personal compensation for activities with Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Genzyme Corporation, Adix, Roche Diagnostics Corporation. Dr. Friedman has received research support from Teva Neuroscience, Merck & Co., Inc., EMD Serono, Schering-Plough Corporation, National Institutes of Health, Michael J. Fox Foundation, GE Healthcare and Acadia. Dr. Pfeiffer has received personal compensation for activities with UCB Pharmaceuticals, Teva Neurosciences, Novartis, Glaxo-Smith-Kline, and Boehringer Ingelheim.Dr. Pfeiffer has received personal compensation in an editorial capacity for Parkinsonism and Related Disorders.Dr. Pfeiffer has received (royalty or license fee or contractual rights) payments from Butterworth Heinemann, Elsevier, CRC Press, Taylor & Francis, and Humana Press.Dr. Pfeiffer has received research support from Boehringer Ingelheim, UCB Pharmaceuticals, and Schwarz Biosciences. Dr. Marsh has received research support from Eli Lilly & Company, Forest Pharmaceuticals, Acadia, Ovation, and National Institutes of Health. Dr. Hiner has received personal compensation for activities with Teva Neuroscience. Dr. Siderowf has received personal compensation for activities with Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. Dr. Siderowf has received research support from the NINDS, the Department of Health of the Commonwealth of Pennsylvania, and Avid Radiopharmaceuticals. Dr. Payami has nothing to disclose. Dr. Molho has received personal compensation for activities with Allergan, Teva, Merz, Ipsen, and Boehringer Ingelheim. Dr. Molho has received research support from Teva, Allergan, Merz, IPsen, Parkinson9s Study Group, and Huntington9s Study Group. Dr. Nutt has received personal compensation for activities with XenPort, Impax Laboratories, Neurogen, Synosia, Neuroderm, Merck, Lily/Medtronic, Elan Pharmaceuticals, Lundbeck, Merz Pharmaceuticals, Synagile, and the National Parkinson Foundation. Dr. Nutt has received research support from Merck. Dr. Factor has received personal compensation for activities with Merz and Ipsen as a consultant. Dr. Factor has received personal compensation in an editorial capacity for Current Neurology and Neuroscience. Dr. Factor has received research support from Ceregene, Teva Neuroscience, Ipsen, and EMD Serono. Dr. Ottman has received personal compensation for activities with Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Clark has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the NIH, Michael J. Fox Parkinson Disease Foundation, CHDI, and the Huntington9s Disease Society of America.

Objective: To compare the cognitive performance carriers and non-carriers of parkin mutations with long disease duration. Background We and others have reported that early-onset Parkinson disease (EOPD) individuals who are parkin mutation carriers have similar neuropsychological performance to non-carriers; however, it is unknown whether the risk for cognitive impairment among carriers and non-carriers remains similar as the disease advances. Design/Methods: We recruited 1103 individuals through the CORE-PD study through 16 centers, of which 155 probands underwent detailed neuropsychological testing. Carriers of LRRK2 and GBA mutation were excluded. Participants were divided by disease duration (range 1-47 years) median split. Neuropsychological performance among participants with longer duration (>14years) was examined. Neuropsychological domains included psychomotor speed, attention, memory, visuospatial function, and executive function. Domain scores were compared for parkin heterozygotes (n=9), compound heterozygotes/homozygotes combined (n=17) and non-carriers (n=22). Linear regression models were applied to assess the association between parkin mutation status (independent variable) and domain scores (dependent), adjusted for age, education and age at onset (AAO). Models were repeated to compare: 1.) homozygotes/compound heterozygotes to non-carriers excluding heterozygotes, and 2.) all mutation carriers to non-carriers. Results: Parkin mutation status was associated with younger age (heterozyogtes=53.4years, homozygotes/compound heterozygotes=53.3years, non-carriers=61.4years, p=0.012) and younger AAO (heterozygotes=30.4, homozygotes/compound heterozygotes=27.4, non-carrier=40.2 p parkin homozygotes/compound heterozygotes mutation status was associated with better performance after adjustment for age, AAO and education for memory (p=0.029) and attention (p=0.004). When all parkin carriers were compared with non-carriers the differences were noted in the executive domain (p=0.013) as well as memory and attention. Conclusions: EOPD individuals with long disease duration who are parkin mutation carriers perform better on tests of memory, attention and executive functioning than non-carriers. Supported by: NS36630, ULI RR024156 (Karen Marder). Disclosure: Dr. Caccappolo has nothing to disclose. Dr. Alcalay has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the NIH, Michael J. Fox Parkinson Disease Foundation, CHDI, and the Huntington9s Disease Society of America. Dr. Tang has nothing to disclose. Dr. Rosado has nothing to disclose. Dr. Mejia-Santana has nothing to disclose. Dr. Ruiz has nothing to disclose. Dr. Orbe-Reilly has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Verbitsky has nothing to disclose. Dr. Kisselev has nothing to disclose. Dr. Louis has nothing to disclose. Dr. Colcher has nothing to disclose. Dr. Comella has received personal compensation for activities with Ipsen, Merz Pharma, Allergan, Inc., and NuPathe. Dr. Comella has received research support from Ipsen, Merz Pharma, Allergan, Inc., the National Institutes of Health, and the Dystonia Study Group. Dr. Siderowf has received personal compensation for activities with Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. Dr. Siderowf has received research support from the NINDS, the Department of Health of the Commonwealth of Pennsylvania, and Avid Radiopharmaceuticals. Dr. Jennings has received personal compensation for activities with Lundbeck Research USA as a speaker. Dr. Nance has received research support from Medivation, Santhera, Juvantia, Neurosearch Sweden, Pfizer Inc, Neuraltus, Impax, and Schwarz Biosciences. Dr. Bressman has received license fee payments from Beth Israel/Mount Sinai/Athena. Dr. Scott has nothing to disclose. Dr. Tanner has received personal compensation for activities with Impax Pharmaceuticals, Allergan, Inc. & Genentech, Inc. as a consultant. Dr. Tanner has received research support from Michael J. Fox Foundation, Department of Defense, Parkinson9s Disease Foundation, Parkinson9s Institute, Unity Walk and Brin Foundation. Dr. Mickel has nothing to disclose. Dr. Waters has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Intec Pharma, Merz Pharma, Oxford Biomedica, RJG Foundation, IMPAX Pharmaceuticals, and Lundbeck as a consultant. Dr. Fahn has received personal compensation in an editorial capacity for Elsevier and Springer. Dr. Cote has nothing to disclose. Dr. Frucht has received personal compensation for activities with UCB Pharma. Dr. Ford has received personal compensation for activities with Novartis and Medtronic, Inc. Dr. Rezak has received personal compensation for activities with Medtronic, Teva, Novartis, Allergan, Smih-Klein, Boehringer-Ingleheim, and UBC as a speaker. Dr. Friedman has received personal compensation for activities with Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Genzyme Corporation, Adix, Roche Diagnostics Corporation. Dr. Friedman has received research support from Teva Neuroscience, Merck & Co., Inc., EMD Serono, Schering-Plough Corporation, National Institutes of Health, Michael J. Fox Foundation, GE Healthcare and Acadia. Dr. Marsh has nothing to disclose. Dr. Hiner has received personal compensation for activities with Teva Neuroscience. Dr. Payami has nothing to disclose. Dr. Molho has received personal compensation for activities with Allergan, Teva, Merz, Ipsen, and Boehringer Ingelheim. Dr. Molho has received research support from Teva, Allergan, Merz, IPsen, Parkinson9s Study Group, and Huntington9s Study Group. Dr. Ottman has received personal compensation for activities with Ortho-McNeil Janssen Scientific Affairs, LLC. Dr. Clark has nothing to disclose.

An autosomal dominant form of human temporal lobe epilepsy (TLE) has been mapped to a region of chromosome 10q that contains the intronless alpha(2A)-adrenergic receptor (alpha(2A)AR) gene. Because mutation of the alpha(2A)AR gene in the mouse fosters epileptogenesis, we developed methods for analysis of the alpha(2A)AR coding region applicable to any pathophysiologic state in which the alpha(2A)AR could be implicated in the disease mechanism. This study rules out mutations in the alpha(2A)AR coding region as causal for this form of autosomal dominant TLE.

We investigated comorbidity of migraine and epilepsy by using information from structured telephone interviews with 1,948 adult probands with epilepsy and 1,411 of their parents and siblings. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. Cumulative incidence of migraine to age 40 was 24% in probands with epilepsy, 23% in relatives with epilepsy, and 12% in relatives without epilepsy. Using Cox proportional hazards analysis to control for years at risk and gender, the rate ratio for migraine was 2.4 (95% CI, 2.02 to 2.89) among probands and 2.4 (1.58 to 3.79) among relatives with epilepsy in comparison with relatives without epilepsy. Migraine risk was highest in probands with epilepsy due to head trauma, but it was significantly higher in every subgroup of probands than in unaffected relatives when probands were stratified by seizure type, age at onset, etiology of epilepsy, and history of epilepsy in first-degree relatives. Age-specific incidence of migraine among probands was increased to a greater extent after onset of epilepsy than before, but it was also significantly increased more than 5 years before onset and 1 to 5 years before onset. These results indicate that migraine and epilepsy are strongly associated, independent of seizure type, etiology, age at onset, or family history of epilepsy.