Table 11.5 Hematological tests that can be helpful in determining the cause of epilepsy Investigation Condition being tested for Clinical epilepsy presentation Full blood count, differential Various disorders Abnormalities are associated with a variety of conditions which can result in epilepsy, and should prompt an extensive search, both for primary conditions and also for conditions in which abnormalities are secondary consequences of other disorders Acanthocytes Neuroacanthocytosis Progressive myoclonic epilepsy, other neurological signs B12 and folate de \201 ciency and alcoholism Seizures are an occasional feature of B12 or folate de \201 ciency, and are common in alco holism Macrocytosis Sickle-cell Sickle-cell disease and sickle cell trait Seizures can result from cerebrovascular consequences White cell count and differential Various hematological, immunological, infective disorders Seizures can be a symptom in a variety of disorders of white-cell production and also lymph omas Vacuolated lymphocytes Lysosomal storage disorders including the neuronal ceroid lipofuscinoses and the sphingolip idoses The neuronal lipofuscinoses can present as progressive myoclonic epilepsy, seizures are les s common features of lysosomal disorders Platelet abnormalities and other abnormalities of the clotting cascade Various disorders Seizures can be a symptom in a variety of hematological and clotting disorders, leading to haemorrhagic stroke or sinus thrombosis. Autoimmune thrombocytopenia. Vitamin K de \201 ci ency in neonates Table 11.6 Tests of the cerebrospinal \202 uid that can be helpful in determining the cau se of epilepsy Investigation Alpha-aminoadipic semialdehyde ( -AASA) Conditions being tested for Clinical epilepsy presentation Pyridoxine de \201 cient seizures Neonatal seizures and refractory seizures in childhood Serine and glycine Disorders of serine biosynthesis Neonatal seizures and encephalopathies Glucose GLUT-1 de \201 ciency Epilepsy, myoclonus, regression, behavioral and movement disorders Lactate Mitochondrial disorders (various types) Acute encephalopathy with seizures, myoclonic seizures, other neurological signs 5-methyl-tetrahydrofolate (5-MTHF) Cerebral folate de \201 ciency states (e.g. 5-MTHF reductase de \201 ciency) Epilepsy, regression, and other neurological signs Pyridoxal 5 \200 -phosphate (PLP) Pyridox(am)ine phosphate oxidase (PNPO) de \201 ciency Neonatal seizures CSF creatine can be used diagnostically, but now is replaced by largely MRS and the estimat ion of GAA and creatine in urine. CHAPTER 11 biochemical, hematological, histological, immunological, and genetic investigati on 131 Table 11.7 Histological tests which can be helpful in identifying the cause of epilepsy Tissue Conditions being tested for Comments Brain Otherwise undiagnosed structural or degenerative disorders of brain: examples include cereb ral tumors, infective lesions, in \202 ammatory lesions, cerebral malformations, mitochond rial and other genetic disorders, SSPE where CSF is negative, Rasmussen \200\231s encephali tis, Creutzfeldt \200\223Jakob disease, primary cerebral or granulomatous disorders Neurological features in which epilepsy is often a prominent feature. Bone marrow Niemann \200\223Pick type C, malignancies, and marrow aplasia In Niemann-Pick type C, the marrow characteristically shows sea-blue histiocytes and foamy cells Conjunctiva Mucoliposis IV Multilaminate bodies \200\224 but this test is now rarely used Hair Menkes disease Epilepsy is a feature associated with other neurological features Liver (including copper assay) Wilson disease Epilepsy is an occasional symptom associated with other features Liver (including respiratory chain analysis and electron microscopy) Mitochondrial disease Hepatic failure can be a presenting feature, and epilepsy can be present Muscle (including respiratory chain enzyme analysis) Mitochondrial disease Epilepsy amongst other neurological features. Also, progressive myoclonic epilepsy Liver biopsy Glycogen storage diseases, SLE, and other systemic diseases Neurological features can include epilepsy Skin Lafora body disease, SLE, neuro \201 bromatosis, and other systemic diseases A cause of progressive myoclonic epilepsy Fibroblasts \200\224 for assay of enzymes Many enzymes (including: methylmalonic CoA mutase and methionine synthetase, methylcobalami n and adenosylcobamain synthesis) Table 11.8 Immunological tests which can be helpful in identifying the cause of epilepsy Test Conditions being tested for Comments Antiadenylate kinase 5 antibodies Limbic encephalitis Reported very rarely Antiglycine receptor antibodies Limbic encephalitis Reported very rarely Antinuclear antibodies (ANA), aniphospholipid antibodies (aPL), LA (lupus anticoagulant), a ntiglutamate receptor antibodies, anti-NR2 antibodies, anti-N-methyl-D-aspartate (NMDA) ant ibodies Systemic lupus erythematosus and antiphospholipid syndrome (and other collagen vascular dis eases) Lupus not infrequently presents as epilepsy Anti- NMDA antibodies Acute encephalopathy and limbic encephalitis (often associated with ovarian teratoma) Presents with characteristic form of status epilepticus Anti- Saccharomyces cerevisiae antibodies Crohn \200\231s disease Seizures rare in Crohn \200\231s disease IgA antibodies to endomysium, gliadin and reticulin Coeliac disease Highly sensitive and speci \201 c (but can be negative in cases on dietary treatment) Oligoclonal bands in CSF (unmatched in serum) Various auto-immune and infective and para-infective disorders, multiple sclerosis Oligoclonal bands (unmatched in serum) imply immunological cause but not speci \201 c Oligoclonal bands in CSF Rasmussen \200\231s encephalitis Positive in only some cases Protoplasmic staining antineutrophil cytoplasmic antibodies (p-ANCA) Ulcerative colitis Epilepsy rare in ulcerative colitis Thyroid peroxidase antibodies (TPO) Hashimoto encephalitis (steroid responsive encephalopathy associated with auto-immune thyro iditis; STREAT) Seizures and status are common presentations of Hashimoto \200\231s encephalitis Voltage-gated potassium channel antibodies (VGKC) Limbic encephalitis Intracellular antibodies (e.g. anti-Hu, anti-Ma-2, etc) Limbic encephalitis, especially paraneoplastic Antibodies against glutamic acid decarboxylase (anti-GAD antibodies) Stiff person syndrome, and other neurological syndromes Other antineuronal antibodies oxford textbook of epilepsy and epileptic seizures 132 Table 11.9 Pure epilepsies \200\224 genetic abnormalities Table 11.10 Cortical dysplasia \200\224 gene mutations Syndrome Commonly involved genes Type of cortical dysplasia Genes carrying mutations Generalized epilepsy with febrile seizures plus (GEFS + ) SCN1A, SCN1B, GABRG2 Agyria \200\223pachygyria, band spectrum and lissencephaly (various types) LIS1, DCX, ARX, RELN, TUBA1A, POMT1, POMT2, FKRP, FKTN Severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome) SCN1A, GABRG2 Periventricular nodular heterotopia FLNA Periventricular nodular heterotopia with other associations FMR1, ARFGEF2, LRP2, KIAA1803, ASXL2 Benign familial neonatal seizures (BFNS) KCNQ2, KNCQ3 Benign familial neonatal-infantile seizures (BFNIS) SCN2A Polymicrogyria (various types) SRPX2, TBR2, PAX6, TUBB2B, GPRS6, RAB3GAP1, KIAA1279, COL19A1 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) CHRNA4, CHRNB2, CHRNA2 Schizencephaly EMX2 Autosomal dominant temporal lobe epilepsy LGI1 Tuberous sclerosis Agenesis of the corpus callosum ARX, ZEB2, 1q44 deletions , Note: other pure epilepsy genes include: KCNA1, GABRA1, EFCH1, PCDH19, ATP1A2 . in Table 11. 10 , but a few of these are relatively routinely tested as the diagnosis is us ually made by neuroimaging or neuropathology. Syndromes with chromosomal disorders Epilepsy is sometimes a feature of chromosomal disorde rs which can be detected by karyotyping. All are invariably associated with learning disabi lity (usually severe) and other clinical features. The most commonly identi \201 able are shown in Table 11. 12 . Genetic and prenatal testing are widely available. Where mosaicism is common, Progressive myoclonic epilepsies This is a syndrome which is often susceptible to genetic t esting. The common causes and the genetic and laboratory tests are sum- marized in Table 11 . 11 . Table 11.11 The progressive myoclonic epilepsies (PMEs) Disease Age at onset Suggestive clinical features Suggestive laboratory features Genetics Gene Unverricht \200\223Lundborg disease 8 \200\22313 years Myoclonus, mild dementia and ataxia None identi \201 ed AR EPM1 Lafora body disease 10 \200\22318 years Severe myoclonus, occipital seizures, inexorable dementia, Lafora bodies Lafora bodies in axillary skin biopsies AR EPM2A EPM2B Myoclonus epilepsy and ragged red \201 bres (MERRF) Variable Deafness, optic atrophy, myopathy, myoclonus Muscle biopsy showing ragged red \201 bres and histochemical changes. Also, increased lev el of pyruvate and lactate (blood and CSF) Mitochondrial tRNAlys Sialidoses Type I 8 \200\22320 years Severe myoclonus, tonic \200\223clonic seizures, ataxia, cherry-red spot, visual failure Elevated urinary sialyloligosacch- arides, de \201 ciency of neuroaminidase in leucocytes and cultured skin \201 broblasts AR NEU Type II 10 \200\22330 years Severe myoclonus, ataxia, cherry-red spot, visual failure, dysmorphic features, hearing los s Elevated urinary sialyloligosaccharides, de \201 ciency of neuroaminidase and b-galactosid ase in leucocytes and cultured skin \201 broblasts AR PPGB Neuronal ceroid lipofuscinoses CLN2 2.4 \200\2234 years Myoclonic, tonic \200\223clonic, atonic or atypical absence seizures, psychomotor delay and ataxia, visual failure Curvilinear, rectilinear or \201 ngerprint lipidic inclusions in skin biopsy at electron microscopy AR TPP1 CNL3 5 \200\22310 years Myoclonus and tonic \200\223clonic seizures, macular degeneration, optic atrophy, dementia AR CLN3 CNL4 15 \200\22350 years Generalized seizures, myoclonic jerks, extrapyramidal symptoms AR/AD \200\223 Dentato-rubro- pallido-luysian atrophy (DRPLA) Variable Seizures, myoclonus, ataxia, chorea, dementia None identi \201 ed AD ATN1 (CAG repeat disorder) NB These are the more common causes of this rare syndrome. A similar clinical picture of ca n also be due to other conditions, although often with other features present. Conditions w hich have been reported include: biotin-responsive progressive myoclonus; infantile and oth er variants of neuronal ceroid lipofuscinosis; coeliac disease; Gaucher disease; GM2 gangli osidosis (juvenile type); hexosaminidase de \201 ciency; Huntington disease; Hallervorden \200\223Spatz disease; neuroserpin inclusion body disease; juvenile neuroaxonal dystrophy; Menkes disease. Adapted from: Shorvon S. Handbook of Epilepsy Treatment . Oxford: Wiley-Bla ckwell Publishing, 2010 CHAPTER 11 biochemical, hematological, histological, immunological, and genetic investigati on 133 Table 11.12 Some chromosomal disorders causing epilepsy Table 11.13 Other single-gene disorders causing epilepsy Condition Angelman syndrome a Gene Down syndrome (trisomy 21) UBE3A (due to deletions in 15q11 \200\223q13 region) Fragile X syndrome (loss of function mutation of FMR1 gene) Wolf \200\223Hirschhorn syndrome (deletion of 4p) Lysosomal storage or transportation disorders Various Inc dup(15) syndrome (inverted duplicated chromosome 15) Ring chromosome 20 Neuroacanthocytosis VPS13A Organic acid, amino acid and peroxisomal disorders Various Porphyria ALAD, ALAS2, CPOX, FECH, HMBS, PPOX, UROD, or UROS . for instance in Ring chromosome 20 Syndrome, at least 100 mitoses may need to be examined b efore excluding the condition. Pyridoxine-dependent epilepsy ALDH7A1, PNPO Neurocutaneous syndromes There are two common neurocutaneous syndromes, causing epi- lepsy, with a known genetic basis \200\224 tuberous sclerosis and neuro \201 - bromatosis type 1. Approximately 85 % of patients with tuberose sclerosis can be found to have a mutation i n either the TSC1 or TSC2 genes. Molecular genetic testing for diagnostic con \201 rmation and prenatal testing of the TSC1 and TSC2 genes is available but complicated by the large size of the two genes, the large number of disease-causing mutations, and the high rate of somatic mosaicism (10 \200\22325 % ). Other screening tests include: clinical examination, dermatological examination and examination with Wood \200\231s light, biopsy, ophthalmologi cal examination, renal ultrasound, and other imaging. Mutations in the NF1 gene is the caus e of neuro \201 broma- tosis type 1. Genetic linkage has been found in other much rarer ne urocutaneous syndromes including: hypomelanosis of Ito, incontinentia pigment, nevus sebace ous syndrome, and Parry \200\223 Romberg syndrome. Rett syndrome MECP2. CDKL5 Urea cycle disorders CPS1, OTC. ASS1, ASL, ARG1, NAGS Wilson disease ATP7B MMACHC, MMADHC, MTRR, LMBRD1, MTR, SLC46A1, FTCD, MTHFR, GRT Inherited disorders of cobalamin and folate metabolism b a In about 80 % of cases defects are present in the chromosome 15q11 \200\223q13 region, an d involve a deletion, maternal disomy, imprinting defect or rarely translocation. This regi on contains a cluster of GABA receptor subunit genes. Iatrogenic mutations in the UBE3A gen e are found in about 10 % of cases. Diagnostic genetic testing is available. About 80 % of cases can be identi \201 ed via the methylation test, and mutation testing of the UBE3A ge ne can be used in cases where the methylation test is negative. b Two inherited disorders of folate and seven inherited disorders of cobalamin de \201 cie ncy are recognized. Seizures can occur in any of these, although are generally more promi- nent in the folate de \201 ciency states. result in the failure to metabolize nitrogen from the breakdown of protein. Severe de \201 ciency results in infantile death, but milder or partial de \201 ciency can present at an y age. Typical symptoms include a loss of appetite, vomiting, lethargy, seizures, disorders of sleep, behavioral change, delusions, hallucinations and psychosis. The EEG shows an enc ephalopathic pattern. Diagnosis is made by the \201 nding of a high plasma ammonia ( > 15 0 mol/L), with normal plasma sugar and anion gap, in the presence of a chronic or suba- c ute encephalopathy. Measurements of plasma amino acids analy- sis (citrulline, arginine, al anine, asparagine, glutamine) and urinary orotic acid can distinguish between the speci \201 c disorders, The de \201 nitive diagnosis is by molecular genetic analysis Other single-gene disorders resulting in epilepsy There are over 120 single gene disorders which result in epilepsy, and in which the gene has been identi \201 ed. Some of the more common disorders, for which genetic testing is available, are listed in Table 11. 13 . Almo st all are associated with intellectual impair- ment and often with other neurological feat ures. DNA analysis can be carried out for all these conditions, although alternative meth- ods of diagnosis (clinical and biochemical) are more commonly employed in many cases. Some illustrative examples of single-gene disorders of metabolism These examples are given here to illustrate the complexity of single- gene disorders which can cause epilepsy. These conditions are all rare, often have a family history, present usually in infancy or childh ood and are associated with a constellation of neurological and non-neurological features. There diagnostic evaluation should be conducted in specialized pediatric units with experti se in clini- cal biochemistry, neuropathology, and neurogenetics. Peroxisomal disorders The peroxisome is an organelle present in almost all nucleated cells. It is responsible for the metabolism of fatty acids and phos- pholipids amongst other meta bolic processes. Seizures are common in some of these conditions, but are invariably associ ated with other prominent and severe neurological features (the range of symptoms depend on the speci \201 c defect). There are 17 peroxiso- mal disorders, which have been categoriz ed into four diagnostic groups. Those in which epilepsy is a particularly prominent symp- t om are Zellweger syndrome, the adrenoleucodystrophies, and glutaric aciduria type III. Urea cycle disorders There are six inherited urea cycle defects, in which de \201 ciency c an produce seizures: N-acetyl glutamate synthetase (NAGS; a cofactor), carbamoylphosphate s ynthetase I de \201 ciency (CPS1 de \201 ciency), ornithine transcarbamylase de \201 cie ncy (OTC de \201 ciency), citrulinemia type 1 (ASS1 de \201 ciency), argininosuccinic aci duria (ASL de \201 ciency), arginase de \201 ciency (hyperargininaemia; ARG de \201 cien cy). Defects 1. Peroxisome biogenesis disorders (PBDs) \200\224 these include: cere- bro-hepatic-renal (Zellweger) syndrome (ZS, ZWS1), neonatal adrenoleucodystrophy (NALD), and infantile Refsum disease (IRD). In these disorders the process of peroxisomal assembly is oxford textbook of epilepsy and epileptic seizures 134 performed via skeletal radiography to look for evidence of dysostosis multiplex, abdominal ultrasonography to identify hepatosplenom- egaly, and echocardiography to evaluate for card iac involvement. Ophthalmologic examination may reveal corneal clouding or cherry-red spot. A peripheral blood smear may reveal white blood cell vacuoles (granular, \201 ngerprint lipid whorls, zebra bodies, or autophagic vacuoles). Urine can be screened for elevated exc retion of oligosaccharides (oligosaccharidoses) and glycosaminoglycans (mucopolysaccharidos es). Blood chitotriosidase (an enzymatic marker of macrophage activation) may be elevated. Assay of enzy- matic activity in peripheral white blood cells provides a de \201 nitive di agnosis. Con \201 rmatory DNA mutation analysis can helpful. disrupted and all peroxisomal function is absent or de \201 cient. In all these, plasma co ncentrations of VLCFAs (very long chain fatty acids) are elevated. Other biochemical abnorm alities (including erythrocyte plasmalogen, plasma bile-acid interme- diates, pristanic aci d, and phytanic acid) can be detected in blood and or urine and con \201 rmed in cultured \201 broblasts. 2. Rhizomelic chondrodysplasia punctata (RCDP; three types). In these cases, plasmalogen le vel in erythrocytes is the diagnostic test, con \201 rmed by enzyme analysis and DNA analy sis. 3. All types of X-linked adrenoleucodystrophy (X-ALD). These are most common peroxisomal di sorder and the diagnostic screen- ing test is elevated VLCFAs followed by molecular analysi s. Probably the most common of these diseases causing epilepsy is Neimann \200\223Pick Type C, and the diagnosis is con \201 rmed by bone marrow biopsy which shows lipid-laden histiocy tes, the biochemi- cal demonstration of impaired cholesterol esteri \201 cation and posi- tive \201 lipin staining in cultured \201 broblasts. 4. Refsum, AMACR (alpha-methylacyl-CoA racemase), hyper- oxaluria type I, glutaric aciduria type III, mevalonate kinase de \201 ciency, acatalasaemia. These conditions are heterogen ous. In Refsum disease, an elevated serum level of phytanic acid is reli- able in diagnosis . Liver biopsy is needed in hyperoxaluria type I for enzymatic assay. In glutaric aciduria type III, there is persist- ent elevation of glutaric acid excretion. In mevalonate kinase de \201 ciency there is increased urinary excretion of mevalonic acid. In AMACR increased levels of pristanic acid can be detected and con \201 rmed by enzymatic and molecular assa ys. Acknowledgements This work was undertaken at UCLH/UCL who received a propor- tion of fundin g from the Department of Health \200\231s NIHR Biomedical Research Centers funding scheme. Further reading The following are general sources for, and provide further details of, the Lysosomal storage disorders More than 50 lysosomal storage disorders exist. These include: the glycogen storage diseases, the mucopolysaccharidoses, the mucoli- pidoses, the oligosac charidoses (including sialidosis), lipidoses (including Niemann \200\223Pick disease types C and D, and NCL), sphin- golipidoses (including: Niemann \200\223Pick disease types A and B, Gaucher, Krabbe, Fabry, GM1 and GM2 gangliosidosis, metachro- matic leucodystrophy galac tosialidosis) and lysosomal transportation diseases. The conditions are characterized by pr ogressive neuro- logical disorders with symptoms which include epilepsy, develop- mental de lay, hypotonia, epilepsy (complex partial or myoclonic), peripheral neuropathy, intellectua l disability, ataxia, and/or spas- ticity. There are also dysmorphic features, bony abnorma lities, organomegaly, cardiac and ophthalmic signs. Screening can be investigations listed in this chapter: Human Metabolome Database: http:// www.hmdb.ca King MD , Stephenson JBP . A handbook of neu rological investigation in children . Oxford : Wiley-Blackwell , 2009 . Metabolic and genetic disease information center: http://www.metagene.de/ program/s.prg?id=1943 OMIM, Online Mendelian Inheritance in Man : http:// www.ncbi.nlm.nih. gov/omim Shorvon SD . Handbook of the treatment of epilepsy (3rd edn) . Oxford : Wiley-Blackwell Publishing , 2010 . Shorvon SD , Guerrini R , Andermann F . The Causes of Epilepsy: Common and uncommon causes in adults and children . Cambridge : Cambridge University Press , 2011 . CHAPTER 12 Non-Pharmacological Therapy of Epilepsy Peter Wolf , Katia Lin , and Marina Nikanorova Generalized tonic \200\223clonic seizures (GTCSs) may start with pro- dromes (8), a series of minor seizure-like absences or myoclonic seizures, or auras of variable length. Interven tion may be possible during the prodromal phase to prevent the convulsive seizures. Epilepsy may be de \201 ned conceptually as \200\230an enduring predisposi- tion to gener ate seizures \200\231 requiring \200\230the occurrence of at least one epileptic seizure \200\231 (1) or operationally as \200\230a condition characterized by recurrent unprovoked seizures \200\231 (2). Both de \201 nitions imply an indication for treatment but not for a speci \201 c type of treatment. Pharmacotherapy, if possible with one antiepileptic dru g (AED) in monotherapy, is considered the standard treatment for the major- ity of the affe cted persons. The method of continuous administra- tion of AEDs is closely related to the v iew that epileptic seizures are spontaneous and unpredictable. This may be correct in most cases but other possibilities exist and allow different approaches address- ing the prevent ion or arrest of individual seizure events by various means. In an important group of patients, seizures are habitually and reproducibly precipitated by speci \201 c sensory or cognitive stimuli, which is termed re \202 ex epilepsy (9). The most common and best- known variety is photosensitivity (10). It is less well known that th e same triggers can also inhibit seizures (11). Prevention and inhibi- tion of re \202 ex seizures is another possible non-pharmacological approach to the treatment of epilepsy. Behavior modi \201 cation The comprehensive care of people with epilepsy (PWE) should star t with careful history taking and the thorough identi \201 cation of seizure-inducing fact ors, which may alert the patient to the impor- tance of such factors and how to avoid them, or to take speci \201 c countermeasures that may prevent a seizure. Habitual triggering f actors of seizures include irregular sleep habits, inconsiderate con- sumption of alcoholic beverages and recreational drugs, excessive psychophysical stress, and others. According t o Aird (5) addressing these factors contributed to \200\230appreciable bene \201 t \200 \231 in 43 % , and seizure control in 17 % of 500 patients with refractory seizures. Instru ctions on these aspects are a central part of a patient educa- tion program that in a contr olled investigation has been shown to signi \201 cantly improve treatment success (12). Th is approach depends, as much as pharmacotherapy, on patients \200\231 adherence to the regi men. But many patients appreciate being given some responsibility for their treatment and c ooperate very well. In some patients, pharmacotherapy fails (3) and treatment alter- natives become desirable. Surgical treatment and stimulation methods have their own chapters in this book, but speci \201 c diets are another possibility and are in some cases more effective than drugs. The widely varied approaches which are the subject of this chap- ter, have in common that t hey give the patients a much more active role in the treatment of their condition than both drug treatment and surgery. Individual seizures as targets of intervention Theoretical background A diagnosis of epilep sy does not indicate that the seizure suscepti- bility of the affected individual is always more or less identical. Some people have seizures only in sleep, others only soon after wa king up. Cyclic recurrence of seizures is a well-known pattern where a few days of high sei zure susceptibility alternate with inter- vals of up to some weeks without seizures. In wom en, seizure sus- ceptibility may be related to the menstrual cycle, which is called catamen ial epilepsy (4). Typically, this approach is part of a comprehensive therapy program. Here it can make the d ifference between becoming seizure free or not, and can sometimes ensure success with a low er dose of AEDs. In selected patient groups, behavior modi \201 cation may be the only tre atment. Of 25 prospective patients who, for various reasons (AED failure in 11), did not accept pha rmacotherapy (6), 16 were advised and instructed about systematic avoidance of seizure-prov oking fac- tors. After follow-up for 2 years or more, seven of them had remained seizure fr ee. Most responders had mild idiopathic gener- alized epilepsies. In addition, exogenous modulators of seizure activity exist, such as disturbances of sleep \200\223waking cycle, increased alcohol intake, or extraordinary stress (5, 6). Lifestyle i ssues such as social habits like party-going, or long-distance air travel may be relevant ( 7). Therapeutic interventions can focus on endogenous and exoge- nous facilitating factors of seizures. oxford textbook of epilepsy and epileptic seizures 136 Table 12.1 Possible applications of acute drug administration prevention at perceived risks (sleep deprivation, jet lag, party, etc.) or preparing for so cially sensitive situations; prevention of clusters of seizures after a \201 rst seizure. \227\206 Status epilepticus , any type \227\206 Febrile (and non-febrile) convulsions in children \227\206 Seizure clusters (habitual or at AED withdrawal) \227\206 Catamenial ep ilepsy \227\206 Prophylaxis of seizures at perceived risk: \227\206 Rectal diazepam or clonazepam is used when rapid effect is required: prolonged fe brile (and non-febrile) seizures; incipient status epilepticus ; prevention of impending co nvulsive seizure at identi \201 ed prodromes of any kind. \226 AED withdrawal \226 Lifestyle situations \226 Unavoidable disturbance of sleep \226 Long-distance travel \226 Re \202 ex seizures \227\206 Individual triggers \227 \206 Response to \200\230warnings \200\231 \227\206 Getting prepared for a situation wher e a seizure must by no means occur \227\206 Buccal or nasal midazolam or lorazepam: same indications as rectal diazepam but w ith circumstances where this route of administration is more rapid, easier to apply, or bet ter accepta- ble. Midazolam when very short action is desired. Arrest of incipient seizure activity The seizure events of some patients don \200\231t have a rapid or immediate onset but evolve over periods of seconds to some minutes, some- times more. This applies both to generalized and focal epilepsies. (job interview, social occasions) Acute drug administration Strictly speaking, acute drug administration (ADA) is not a non- pharmacological therapy, but it is fundamentally different from usual antiepileptic pharmac otherapy, and primarily a variety of behav- ioural intervention because it is based on the patients \200\231 (and their carers \200\231) identi \201 cation of an imminent risk, and their response to it. The GTCSs of some patients with idiopathic generalized epilepsy are habitually preceded by repetitive absences or myoclonic sei- zures. If patients or their carers are aware of this relationship, they can use the minor seizures as an indicator of an impending convul- sive seizure and possibly prevent it. Which acute drug is used will depend on what, in the patie nt \200\231s experience, is the shortest interval between the onset of minor seizures and t he GTCS. If it is less than 20 \200\22330 minutes, rectal, buccal or nasal BZD administrati on would apply. If it is longer, an oral BZD will be used. The topic was recently reviewed by Wolf (13). Apart from status epilepticus , the indicatio ns are listed in Table 12.1 . ADA is most often used in combination with continuous AED tre atment where it can make the difference between becoming seizure free or not; allow for a l ower dose of continuous AEDs; or prevent clusters of seizures and prolonged seizures (e.g. prolonged febrile seizures). ADA can be used as monotherapy in the occasional instances tha t all seizures occur in situations of identi \201 ed risk where they can be prevented (14) . Focal seizures typically originate in a restricted local neuronal network from where they s pread to other parts in the same hemi- sphere, sometimes to both. This evolution takes an a mount of time which interindividually is variable but intraindividually rather constant and can sometimes be used to intervene, typically with a rapidly acting BZD. However, even the very rapid routes of BZD administration take some 3 \200\2235 min to act effectively, whic h is too slow for many of these situations, and interventions with more immediate impact wo uld be welcome. The drugs used for ADA in the vast majority are benzodiazepines (BZDs), i.e. drugs with a s trong antiepileptic action that are not commonly used for continuous AED treatment because of fre- quent development of secondary tolerance. The choice of BZDs will depend upon their routes of administration, speed and dura- tion of their action, and their availability (no t all BZDs are available in all countries). Intravenous administration is not considered he re. Some basic pharmacokinetic facts for the choice of drug are presented in Table 12.2 . It is known that about two-thirds of patients with focal epilepsies develop spontaneous man euvers to arrest or counteract incipient seizures (15, 16), in up to 80 % with success (17) . This was a well- established therapeutic approach before the advent of modern pharmacothe rapy (18) and is still a treatment option for the rare patients who decline AED therapy (6) . Successful cure of epilepsy with systematic seizure arrest by an olfactory stimulus was d escribed in detail by Efron (19, 20). \227\206 Oral clobazam or diazepam is indicated when no immediate effect is required but m edium duration action is desired: seizure Table 12.2 Pharmacokinetic key data Drug Route Onset action Peak level Half-life Diazepam Oral 15 \200\22320 min 30 \200\22360 min 20 \200\22350 hrs Rectal <5 min 10 \200\22320 min 20 \200\22350 hrs Clonazepam Rectal 6 \200\22310 min 10 \200\22340 min 20 \200\22350 hrs Clobazam a Oral 15 \200\22320 min 1 \200\2232.5 hrs 20 \200\22340 hrs Midazolam Buccal <5 min 20 \200\22330 min 1 \200\2233 hrs Lorazepam Nasal <5 min 15 \200\22360 min 12 \200\22316 hrs a Slow active metabolite. CHAPTER 12 non-pharmacological therapy of epilepsy 137 Seizure prodromes The term prodrome is used for \200\230warnings \200\231 that in some pat ients habitually precede a seizure for more than 1 hour. In the majority, they express mini mal or \200\230subclinical \200\231 status-like seizure activity such as absence status or aura status (8). Prodromes offer excellent conditions for ADA with an oral BZD. In practic e, it is often neces- sary to get relatives or carers involved because reduced awareness an d reactivity may be part of the prodromal symptoms. (PRE), and hot-water epilepsy (HWE) as re \202 ex epilepsies. These are summarized in Tabl e 12.3 , but there may be others. A variety of HWE in infants was described by Plouin and V igevano (48), and the large population of photosensitive subjects includes a small group wi th triggered GTCS only and no spontaneous seizures. These are generally not considered as r epresenting a separate syn- drome but may be therapeutically addressed differently from pat ients with both spontaneous and re \202 ex seizures. Pathophysiology of re \202 ex epileptic ictogenesis With elementary stimuli the latency fr om the stimulus onset to the clinical or EEG response is typically short (1 \200\2233 secon ds) and with complex stimuli, longer (usually some up to many minutes). Re \202 ex seizures and re \202 ex epilepsies The reproducibility of some patients \200 \231 seizures by well-de \201 ned trig- gers can sometimes provide possibilities of target ed prevention. A complex interaction between factors and stimuli from the endogenous (e.g. hormones, elect rolytes, state of consciousness, and body temperature) and exogenous environment (e.g. sens ory, electrical, and biochemical) may lower the seizure threshold, selec- tively activate i ctogenesis in speci \201 c hyperexcitable cortical systems or functional networks, and pro voke the initiation of a seizure (21, 49, 50). De \201 nition, precipitating stimuli, clinical manifestations, and diagnosis Re \202 ex seizures Re \202 ex, stimulus-sensitive, triggered, or sensory-evoked epileptic seizures a re synonyms (21) and they represent seizures that are \200\230objectively and consistently evoked by a speci \201 c afferent stimulus or by activity of the patient \200\231 (22). T he afferent stimuli may be elementary/unstructured (e.g. light \202 ashes) or elaborated/ struc- tured (e.g. a particular musical work). Activities may be elementary (e.g. a particu lar movement) or elaborate (e.g. involving visuomo- tor coordination) (22). Re \202 ex sei zures may occur in patients with focal and generalized epilepsy syndromes who also get spon tane- ous seizures. Isolated re \202 ex seizures can also occur in situations that do not necessarily require a diagnosis of epilepsy (21). Whereas the anatomical substrate of ictogenesis in many re \202 ex epilepsies remains poor ly understood, in others recent EEG and sophisticated neuroimaging studies (positron emissi on tomogra- phy, single-photon emission computed tomography, EEG/electro- myography-functio nal magnetic resonance imaging) have highlighted the important role of corticoreticular and corticocorti- cal circuitry, including the occipitotemporal regions in the genera- tion of seizures in PRE (41, 51), photoparoxysmal response generated in an hyperexcitable occipita l cortex and participation of frontorolandic regions in IPOLE (10, 24), ictal hypermetaboli c uptake in the medial temporal structures and hypothalamus in HWE (52), these areas corres pond only to a part of the neural net- work that underlies the function of reading, vision, or thermoregu- lation, which are complex processes that comprise different functions of th e brain and are integrated into a network that expands over different brain areas. Accordin g to Moeller et al. (53), the generation of spikes and waves in the photoparoxysmal respons e is an intracortical event different from the corticotha- lamic circuit producing spontane ous spikes and waves in absence epilepsies. Considering these aspects, re \202 ex epilepsi es could be considered excellent models of \200\230system epilepsies \200\231, in which se i- zures are the result of hyperexcitability of a network of either genetic or acquired ori gin, with possible age-related clinical expres- sion, and give rise to an epileptic process after the stimulus speci \201 c for that area is applied (30, 49, 54, 55). Visual stimuli are the most common external factors triggering seizures in humans. They may include: \202 ickering lights/intermittent photic stimulation, \202 ickering sunlight, arti \201 cial light, television, Pok mon cartoon, videogames; and also, speci \201 c v isual patterns (geometric), striped patterns as from Venetian blind, clothes (23 \200\22325 ). In addition, many other precipitating stimuli were also described: higher mental activit ies such as calculation, reading, speaking, writ- ing, and other language functions, praxis , thinking, decision- making, and neuropsychological electroencephalogram (EEG) activation (26 \200\22330); unexpected touch or noise and startle (31); somato- sensory or propriocept ive stimuli; micturition (32, 33); music (34); eating (35); tooth-brushing (36); and hot wa ter. Re \202 ex epileptic mech- anisms were recently extensively reviewed by Wolf and Koep p (9). The epileptic response may consist of clinical seizures \200\224 generalized (absences, my oclonia, GTCSs) or focal (e.g. visual, motor, or somatosensory) \200\224 or of epileptifor m EEG patterns (subclinical or ictal), alone or in combination. The role of the EEG is fund amental in establishing the relationship between the precipitating stimulus and the re \202 ex seizures (21). The importance of re \202 ex mechanisms recognition in the comprehensive treatment of pati ents with epilepsy The arrest of seizure activity at the stage of the aura (i.e. at the sta ge of locally restricted neuronal discharge) can be achieved both by non-speci \201 c (i.e . relaxation, concentration techniques or both, biofeedback, vagal nerve stimulation) and b y specific focus- targeted sensory or cognitive inputs. Speci \201 c focus-targeted inputs activate circumscribed cortical areas that are not yet involved in the epileptic discharge but are likely to become it during its spread from the primary epileptic focus to other ar eas and, eventually, both cerebral hemispheres (30, 49). Re \202 ex triggers of seizures need to be distinguished from factors that temporarily inc rease seizure propensity such as intense emo- tional stress, sleep deprivation and tirednes s, fever, menstruation, alcohol consumption, and many others. Re \202 ex epilepsies Re \202 ex epilepsies constitute epileptic syndromes in which all e pi- leptic seizures are precipitated by sensory stimuli, and the 2006 International League Against Epilepsy Commission on Clas- si \201 cation and Terminology Report (37) listed idi opathic photosen- sitive occipital lobe epilepsy (IPOLE), primary reading epilepsy oxford textbook of epilepsy and epileptic seizures 138 Table 12.3 Re \202 ex epilepsy syndromes recognized by the ILAE Commission on Classi \201 cation and Terminology Report (25) IPOLE (10, 21, 24, 37, 38) PRE (27, 39, 40) HWE (41 \200\22346) Synonyms \200\223 \200\223 Water-immersion epilepsy, bathing epilepsy First reported Guerrini et al. (1995) Bickford et al. (1956) Allen (1945) De \201 nition All seizures induced by photic stimuli, particularly videogames and TV Seizures occurring in relation to reading (especially aloud), progressing to a GTCS if stim ulus continued CFS precipitated by bathing with hot water (40 \200\22350 C) poured over the head Prevalence 0.4 % of all epilepsies Very low 6.9 % of all epilepsies in the Bangalore community (60/100,000) Age of onset