D) Seizures due to acute metabolic or toxic factors They are very frequent and usually do n ot need a chronic AED treatment. 21 . Isnard J , Gu not M , Ostrowsky K , Sindou M , Maugui re F . The role of the insular cortex in temporal lobe epilepsy . Ann Neurol 2000 ; 48 : 614 \200\223 23 . oxford textbook of epilepsy and epileptic seizures 80 (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence (3rd edn) , pp. 305 \200 \223 12 . London : John Libbey , 2002 . 22 . Ryvlin P , Minotti L , Demarquay G , Hirsch E , Arzimanoglou A , Hoffman D , et al . Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can or iginate in the insula . Epilepsia 2006 ; 47 : 755 \200\223 65 . 40 . Dedek K , Kunath B , Kananura C , Reuner U, Jentsch TJ, Steinlein OK. Myokymia and neo natal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K + channel . Proc N atl Acad Sci U S A 2001 ; 98 : 12272 \200\223 7 . 23 . Salanova V , Andermann F , Rasmussen T , Olivier A , Quesney LF . Parietal lobe epilep sy. Clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988 . Brain 1995 ; 118 : 607 \200\223 27 . 41 . Singh NA , Charlier C , Stauffer D , DuPont BR , Leach RJ , Melis R , et al . 24 . Coppola G . Malignant migrating partial seizures in infancy: an A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns . Na t Genet 1998 ; 18 : 25 \200\223 9 . epilepsy syndrome of unknown etiology . Epilepsia 2009 ; 50 : 49 \200\223 51 . 25 . Berkov ic SF , Scheffer IE . Genetics of the epilepsies . Epilepsia 2001 ; 42 . Berkovic SF , Heron SE , Giordano L , Marini C , Guerrini R , Kaplan RE , 42 : 16 \200\223 23 . et al . Benign familial neonatal-infantile seizures: characterization of a new sodium chann elopathy . Ann Neurol 2004 ; 55 : 550 \200\223 7 . 26 . Italian League Against Epilepsy Genetic Collaborative Group . Concordance of clinical forms of epilepsy in families with several affected members . Epile psia 1993 ; 34 : 819 \200\223 26 . 43 . Marini C , Guerrini R . The role of the nicotinic acetylcholine receptors in sleep-rel ated epilepsy . Biochem Pharmacol 2007 ; 74 : 1308 \200\223 14 . 44 . Kalachikov S , Evgra fov O , Ross B , Winawer M , Barker-Cummings C , Martinelli Boneschi F , et al . Mutations in LGI1 cause autosomal- dominant partial epilepsy with auditory features . Nat Genet 2002 ; 30 : 335 \200\223 41 . 27 . Dravet C , Bureau M , Roger J . Benign myoclonic epilepsy in infants . In: Roger J , B ureau M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 67 \200\223 74 . London : John Libbey , 1992 . 28 . Guerrini R , Belmonte A , Genton P . Antiepileptic drug-induced worsening of seizures in children . Epilepsia 1998 ; 39 : S2 \200\223 10 . 45 . Scheffer IE , Berkovic SF . Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes . Brain 1997 ; 120 : 479 \200\223 90 . 29 . Wolf P . Juvenile absence epilepsy . In: Roger J , Bureau M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 30 7 \200\223 12 . London : John Libbey , 1992 . 46 . Bonanni P , Malcarne M , Moro F , Veggiotti P , Buti D , Ferrari AR , et al . Generali zed epilepsy with febrile seizures plus (GEFS + ): clinical spectrum in seven Italian famil ies unrelated to SCN1A, SCN1B, and GABRG2 gene mutations . Epilepsia 2004 ; 45 : 149 \200 \223 58 . 30 . Wolf P . Juvenile myoclonic epilepsy . In: Roger J , Bureau M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 313 \200\223 27 . London : John Libbey , 1992 . 31 . Fittipaldi F , Curr A , Fusco L , R uggeri S , Manfredi M . EEG discharges on awakening: a marker of idiopathic generalized epi lepsy . Neurology 2001 ; 56 : 123 \200\223 6 . 47 . Baulac S , Huberfeld G , Gour \201 nkel-An I , Mitropoulou G , Beranger A , Prud \200 \231homme JF , et al . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene . Nat Genet 2001 ; 28 : 46 \200\223 8 . 48 . Binnie CD, Jeavons PM . Photosensitive epilepsy . In: Roger J , Bureau 32 . Medina MT , Suzuki T , Alonso ME , et al . Impairment of consciousness in temporal lob e seizures: a stereoelectroencephalographic study . In: Canger R , Angeleri F , Penry JK (e ds) Advances in Epileptology: XI Epilepsy International Symposium , pp. 111 \200\223 14 . New York : Raven Press , 1980 . M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childh ood and Adolescence , pp. 299 \200\223 305 . London : John Libbey , 1992 . 49 . Guerrini R , Dravet C , Genton P et al . Idiopathic photosensitive occipital lobe epilepsy . Epilepsia 1995 ; 36 : 883 \200\223 91 . 33 . Cossette P , Liu L , Brisebois K , Dong H , Dong H , Lortie A , Vanasse M , et al . Mu tation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy . Nat Genet 2 002 ; 31 : 184 \200\223 9 . 50 . Rosenow F , L ders HO . Startle-induced seizures . In: L ders HO , Noachtar S (eds) Epileptic Seizures. Pathophysiology and Clinical Semiology , pp. 585 \200 \223 92 . New York : Churchill Livingstone , 2000 . 51 . Roger J , Genton P , Bureau M , Dr avet C . Progressive myoclonus 34 . Nicolson A , Appleton RE , Chadwick DW , Smith DF . The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idio pathic generalized epilepsies . J Neurol Neurosurg Psychiatry 2004 ; 75 : 75 \200\223 9 . epilepsies in childhood and adolescence . In: Roger J , Bureau M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 38 1 \200\223 400 . London : John Libbey , 1992 . 35 . Genton P , Gelisse P , Thomas P , Dravet C . Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 2000 ; 55 : 1106 \200\223 9 . 52 . Dalla Bernardina B , Colamaria V , Capovilla G , Bondavalli S . Nosological classi \201 cation of epilepsies in the \201 rst three years of life. In: Ni stico G , Di Perri R , Meinardi H (eds) Epilepsy: An Update on Research and Therapy , pp. 1 65 \200\223 183 . New York : Alan Liss , 1983 . 53 . Barlow WE , Davis RL , Glasser JW , R hodes PH , Thompson RS , Mullooly JP , et al . The risk of seizures after receipt of whole- cell pertussis or measles, mumps and rubella vaccine . New Eng J Med 2001 ; 345 : 656 \200 \223 1 . 36 . Doose H . Myoclonic astatic epilepsy. In: Roger J , Bureau M , Dravet C , Dreifuss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 1 03 \200\223 14 . London : John Libbey , 1992 . 37 . Oguni H , Tanaka T , Hayashi K , Funatsuka M , Sakauchi M , Shirakawa S , et al . Trea tment and long-term prognosis of myoclonic-astatic epilepsy of early childhood . Neuropedia trics 2002 ; 33 : 122 \200\223 32 . 38 . Tassinari CA , Bureau M , and Thomas P . Epilepsy with myoclonic absences . In: Roger J , Bureau M , Dravet C , Dreifuss FE , Perret A , Wol f P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 151 \200\223 60 . London : John Libbey , 1992 . 54 . O \200\231Donohoe N . Febrile convulsions . In: Roger J , Bureau M , Dravet C , Dreifu ss FE , Perret A , Wolf P (eds) Epileptic Syndromes in Infancy, Childhood and Adolescence , pp. 45 \200\223 52 . London : John Libbey , 1992 . 55 . Wallace S . Febrile seizures : In: Wallace SJ , Farrell K (eds) Epilepsy in Children (2nd edn ), pp. 123 \200\223 30 . London : Arnold , 2004 . 39 . Bureau M , Tassinari CA . Epilepsy with myoclonic absences . In: Roger J , Bureau M , Dravet Ch , Genton P. , Tassinari CA , Wolf P CHAPTER 8 Differential Diagnosis of Epilepsy Kristina Malmgren , Markus Reuber , and Richard Appleton (19.3 % ), con \201 rming the importance of the level of experience of the treating physic ian. There have also been several hospital-based studies on misdiagnosis of epilepsy in chi ldren. A prospective Dutch study in which experienced neuropaediatricians used de \201 ned criteria and consensus discussions to make diagnoses reported a rate of false-positive err ors in 4.6 % of cases ( 4 ), while a Danish study found that 30 % of 184 children referred from their local pediatricians to a tertiary referral center because of \200\230drug- resi stant epilepsy \200\231 did not have epilepsy at all ( 5 ). Introduction A comprehensive discussion of the differential diagnosis of epilepsy cannot be limited to the description of the range of super \201 cially similar disorders but must i nclude an account of the diagnostic process for paroxysmal events in general, the criteria for the diagno- sis of epileptic seizures, and the problem of misdiagnosis. In this chapter we will focus on the differential diagnosis of paroxysmal manifestations as they present i n outpatient clinics or emergency rooms. We will not cover special situations such as statu s epilepticus or the epileptic encephalopathies, nor will we discuss underlying pathologies or acute symptomatic seizures. Whilst the most impor- tant differential diagnoses listed i n Table 8.1 will be discussed in greater depth, less important diagnoses will be covered mo re brie \202 y; and the least common or important will not be addressed at all. \200\230Gold standard \200\231 diagnoses of epilepsy can be achieved by simulta- neous vid eo-electroencephalogram (EEG) recording, although even this test will only capture a limite d number of seizures, and inter- rater agreement on video-EEG data is only moderate if expe rienced clinicians are asked to rate seizure recordings without knowing any- thing about th e patient \200\231s history or subjective seizure experience ( 6 ). In clinical practice, v ideo-EEG can only prove the diagnosis in a small minority of cases. Most patients do not ha ve suf \201 ciently regu- lar seizures to allow ictal recordings ( 7 ), and some have seiz ures not reliably associated with scalp EEG changes (such as frontal lobe sei- zures or sei zures without impairment of consciousness). The choice of treatment for paroxysmal neurological symptoms crucially depends on an accura te diagnosis. Often treatment will have to be administered in the absence of complete diagn ostic certainty. It is best to think of the diagnosis of seizure disorders as a process rat her than a single event. This process begins with the \201 rst meeting between the patien t and the diagnostician, continues as more information becomes available from tests and fur ther seizure accounts, and does not stop once an initial treatment decision has been made. The diag- nosis may even remain uncertain in a specialist clinic. Limited evi- dence sugges ts that acknowledging diagnostic uncertainty in epilepsy can reduce misdiagnosis rates ( 1 ). Understandably, patients and their families (and frequently their doctors), want to have a de \201 nitive diagnosis. The doctor, wanting to comply with this request, may \200 \230rush into \200\231 a diagnosis. However, clinicians should resist this tempta- tion and admit to uncertainty. Surprisingly, there are no generally accepted and validated diag- nostic criteria for the d iagnosis of epilepsy at present. A study in adult patients has shown that the use of diagno stic criteria formu- lated in simple descriptive terms and a consensus discussion between n eurologists improved the diagnostic agreement ( 8 ). In children the inter-rater agreement on the diagnosis of a \201 rst seizure has been shown to be no more than moderate, but th e use of a panel of paedi- atric neurologists increased inter-rater agreement considerably ( 4 ). The consequences of misdiagnosis may be far-reaching: an erro- neous diagnosis of ep ilepsy may cause psychosocial and socioeco- nomic problems (e g loss of employment and driv ing restrictions for adults, unnecessary limitations of activities both in and out of schoo l for children) and results in patients being treated with inap- propriate or ineffective d rugs, potentially resulting in side effects or teratogenicity. If a diagnosis of epilepsy i s incorrectly made in a patient where the reason for paroxysmal attacks is a cardiac disor- der, the consequences may be fatal ( 9 ). Death can also result from the inappropriate use of emergency interventions for people with psychogenic non-epileptic seizures (PNESs) ( 10 ). The rates of misdiagnosis of seizures and epilepsy vary widely in different studies and dep end on the clinical setting. In a primary care-based study in adults from the UK, 23 % of 2 14 patients were found to have been misdiagnosed ( 2 ). Another UK study in which patients registered as having epilepsy in their primary care records were reviewed in a specialist c linic reported that 16.3 % of 275 patients were misdiagnosed ( 3 ). The diagnostic error ra te in patients originally thought to have epilepsy by neurologists was lower (5.6 % ) than that initially \200\230diagnosed \200\231 by non-specialists oxford textbook of epilepsy and epileptic seizures 82 Table 8.1 Differential diagnosis of paroxysmal neurological disorders the Netherlands yielded similar numbers ( 12 ). If presentations to doc- tors mirrored popu lation incidence rates, patients with syncope would be seen more commonly and patients with PNES less commonly. In adults and adolescents \227\206 Syncope: The differential diagnosis of epilepsy in children is as large as that in adults, and estab lishing the correct diagnosis is particularly dif \201 cult in children under the age of 5 years. In the under-5s, the most important differential diagnoses include re \202 ex anox ic sei- zures, tic or behavioral mannerism, day-dreaming, self-grati \201 ca- tion, or fab ricated illness. In older children, additional diagnoses include vaso-vagal syncope, cardia c arrhythmias, PNES, or parox- ysmal dyskinesia. \226 Neurovasogenic \226 Cardiac causes \227\206 Psychogenic attack: \226 Psychogenic non-epileptic seizure \226 Depersonalization/derealization \226 Pani c attack \226 Hyperventilation attack The \201 rst step in the diagnostic process is the conversation between a healthcare prof essional and the patient. If the patient is a child, this conversation must always, whereve r possible, involve the child, as well as parents or carers. Diagnostically relevant infor- mation is not limited to the description of the onset, course and offset of the patient \200\231s paroxysmal symptoms. The precise circum- stances in which the symptoms occurred a lso have to be consid- ered, the past medical history, family history, and current medicati on may give important diagnostic clues. A witness account should be sought if at all possib le \200\224 even if the patient does not think that consciousness was impaired. The failur e to seek and take account of a witness \200\231s description of the attacks has been ident i \201 ed as one of the commonest reasons for misdiagnoses ( 13 ). \227\206 Sleep disorders: \226 Parasomnias \226 Narcolepsy with cataplexy \227\206 Movement disorders: \226 Paroxysmal dyskinesias \226 Myoclonus \226 Hyperekplexia \227\206 Transient ischaemic attack \227\206 Migraine \227\206 Transient global amnesia \227\206 Metabolic disorders: \226 Hypo/hyperglycaemia \226 Electrolyte disturbances Taking the history The process of recording the patient \200\231s history should begin with a period of attentive listening. Giving the patient time and space to produce an account o f their complaint without early interruption allows the healthcare professional not only to pay attention to factual features described by patients and witnesses but also to observe diag- nostically relevant interactional behaviors of the patient and accom- panying others ( 14 ). Documentation of the detailed description of the attack, using the patient \200\231 s own words if possible, is of critical importance. Epileptic seizures and syncopal TLOC te nd to be more stereotyped, whereas PNES are more likely to change with time. Additional differential diagnoses in children \227\206 Physiological startle response \227\206 Benign neonatal sleep myoclonus \227\206 Shuddering or shivering attacks \227\206 Extreme gastro-oesphageal re \202 ux (Sandifer syndrome) \227\206 Decerebrate (extensor) posturing (caused by cerebellar tonsillar herniation in ac ute hydrocephalus or raised intracranial pressure caused by meningitis/ encephalitis) \227\206 Dystonic spasms in severe, four-limb spastic/dyskinetic cerebral palsy What differentiates the three most common causes of TLOC: seizures, syncope, or PNES? Factu al distinguishing features Table 8.2 provides an overview of semiological features, which m ay be helpful in distinguishing between the three most common causes of TLOC. \227\206 Opsoclonus-myoclonus syndrome \227\206 Paroxysmal extreme pain syndrome \227\206 M nchhausen by proxy \227\206 \200\230Thought arrest \200\231 or day-dreaming There is some evidence that factual information clusters can help clinicians to distinguish reliably between epilepsy and syncope ( 15-17 ) and between cardiac and re \202 ex syncop e ( 18 ). Clinical experience suggests that clusters of clinical details in the seizure des cription may also allow healthcare professionals to differentiate between PNES and epilepsy , although taken on their own, ques- tions about seizures from sleep, ictal injuries or ton gue biting have little differentiating value ( 19 ). Diagnostic process Diagnosticians have to consider a wide range of causes for paroxys- mal neurological symptoms (see Table 8.1 ), however, the diagnos- tic process for patients pres enting with transient loss of consciousness (TLOC) can follow a simple pragmatic decision t ree in most cases (see Fig. 8.1 ). The relative frequency of diagnoses made in medical settings does not re \202 ect populati on incidence rates: One neurologist with a special interest in seizure disorders was able t o reach a diagnosis in 87 % of 158 consecutive cases. The most common diagnoses were epilep sy (43 % ), syncope (25 % ), and PNES (12 % ); 7 % of patients received other diagnoses ( 1 1 ). A study which captured 350 con- secutive TLOC presentations to doctors (in primary car e, emer- gency care, and specialist clinics) in a geographically limited area of Situation in which the attack occurred Most patients with epilepsy recognize triggers for t heir seizures or situations in which seizures are more likely to occur but the accu- racy o f these subjective observations is dif \201 cult to assess ( 20 ). In several idiopathic g eneralized epilepsy syndromes seizures typically occur within an hour or so of waking ( 21 ). Seizures are very closely CHAPTER 8 differential diagnosis of epilepsy 83 Transient loss of consciousness Secondary disturbance of CNS function Primary disturbance of CNS function Circulation: - Cardiac (structural/ rhythm disturbance) - Neurovasogenic syncope - Carotid sinus hypersensitivity - Hypovolaemia Epileptic: - Focal epilepsy - Generalized epilepsy - Unclassifiable epilepsy Metabolic/endocrine: - Hypo-/ hyperglycaemia - Electrolyte disorder Psychiatric: - Panic disorder/ hyperventilation - PNES - Factitious - M nchhausen by proxy - Malingered Fig. 8.1 A simple approach to the commonest causes of transient loss of consciousness. Table 8.2 Semiological features which may help to distinguish between the three most common causes of transient loss of consciousness Observation Generalized tonic \200\223clonic seizures Syncope Psychogenic non-epileptic seizures Gradual onset Focal onset possible (aura, duration typically <30 seconds) Common (presyncopal symptoms, duration often minutes) Not infrequent (often lasting several minutes) Motor activity Typical seizure patterns (tonic, clonic, tonic \200\223clonic) Myoclonic jerks common (short duration, rapid recovery) after loss of postural tone Commonly undulating motor activity with sudden pauses but stable frequency Asynchronous arm and leg movements Unusual Not rare (multifocal myoclonus) Common Purposeful movements Very rare Rare Occasional Rhythmic pelvic movements Rare Never Occasional Opisthotonus, \200\230arc de cercle \200\231 Very rare Occasional ( \200\230decerebrate \200\231 posturing) Occasional Prolonged ictal atonia Very rare Not > 60 seconds Occasional Skin Cyanosis common Pallor, sweating No cyanosis despite long seizure duration Ictal crying Very rare Very rare Occasional Closed eyes Rare Rare Very common Resistance to eye opening Very rare Very rare Common Maintained pupillary light re \202 ex Often abolished Common Very common Ictal reactivity Rarely preserved Rarely preserved Occasionally partially preserved Ictal incontinence Not rare Rare Not rare Seizure duration > 2 minutes Uncommon Very uncommon (only if patient supported in upright posture) Common Postictal reorientation Mostly over minutes <1 minute (exception: head injury caused by collapse/patient maintained in upright position ) Often unexpectedly quick or slow Tongue biting Not infrequent (lateral) Occasional (tip) Occasional (tip) Injury Common (burns) Rare Common Seizures at night (from \200\230sleep \200\231) Common Rare Not rare oxford textbook of epilepsy and epileptic seizures 84 GTCSs typically last 50 \200\22390 seconds ( 37 ). Loss of consciousness in syncopal attack s typically lasts less than 1 minute, unless the subject is maintained in an upright postur e. PNES typically last longer than epileptic seizures ( 31 , 37 , 38 ). Prolonged PNES trea ted as status epilepticus occur in about one-third of PNES-patients, and over one-fourth of patients diagnosed with PNES at an epi- lepsy center have received intensive care treatmen t for presumed status epilepticus at least once ( 39 , 40 ). Several types of PNES can be d ifferentiated, the commonest resembling GTCS or manifesting as TLOC and loss of muscle tone ( 41 ). The second type of PNES may easily be confused with syncope ( 42 ). In convulsive PNES, shaking is often asynchronous and asymmetrical ( 37 , 43 , 44 ). Phases of vigorous a nd less vigorous motor activity can come and go ( 45 ). Pelvic thrusting occurs in epilepti c seizures, particularly of frontal lobe origin, but is seen more commonly in PNES ( 37 , 4 6 ). Ophisthotonus ( \200\230arc de cercle \200\231) may be seen ( 43 ). The head may shake from side to side ( 37 , 47 ). Eyes and mouth are more likely to be closed than in epilept ic seizures ( 48 \200\22350 ). Ictal crying or verbal communication may be observed ( 37 , 51 , 52 ). associated with menstruation in catamenial epilepsy (although patients with PNES may also r eport an increase of seizures at the time of their periods). In addition to photically-indu ced seizures (which are not uncommon), there are other, rare, re \202 ex epilepsies in whi ch epileptic seizures are consistently triggered by particular activities (such as reading, eating, or hearing a particular piece of music) ( 22 ). Seizures occurring in the doctor \200\231s of \201 ce are more commonly reported by patients with PNES than patients with e pi- lepsy ( 23 ). PNES are also particularly likely to occur after medical procedures or an esthetics ( 24 ). Re \202 ex (neurovasogenic) syncope classically occurs when the patient has been upright a nd is more likely when they are also hot and dehydrated. Re \202 ex syncope can also be tr iggered by micturition, coughing, emotions, dental examination, or blood tests ( 25 ) and, in children, vaccinations. Syncope rarely arises from sleep ( 26 ). One- half of adult pati ents with PNES (as many as patients with epilepsy) describe attacks from sleep, although vi deo-EEG observation reveals that patients are usually awake at the start of the attacks. Ho wever, PNES are unlikely if attacks exclusively occur from sleep ( 27 , 28 ). PNES from app arent sleep are also uncommon in children. The end of the attack Whilst epileptic seizures tend to cause positive neurological symptom s during the ictus these are often followed by negative symptoms in the postictal phase. Po stictal disorientation and anterograde amnesia (typically lasting for minutes) are most com mon, but focal weakness (Todd \200\231s paresis) is also well recognized. Attack onset The onset of an epileptic seizure may be sudden or gradual (over seconds or ev en minutes). Symptoms such as d j or jamais vu, olfactory and gustatory hallucinations, or rising epigastric sensa- tions commonly feature in patients \200\231 accounts of partial epileptic seizures (especially seizures of temporal lobe origin) but are not speci \201 c for this disorder \200\224 they are also frequently reported by patients with PNES ( 29 ) . These symptoms are more likely to point to a diagnosis of epilepsy if patients highlight that the precise nature of what they experience is dif \201 cult to explain ( 30 ). Idiopa thic gen- eralized tonic \200\223clonic seizures (GTCSs) may be preceded by series of myocl onic seizures. Postictal symptoms tend to be shorter and less marked in patients with PNES ( 53 ), althoug h prolonged dissociative states are not uncommon. The absence of postictal disorientation o r amnesia after an episode of loss of consciousness associated with collapse is suggestive of syncope ( 16 , 17 ), but prolonged syncopal episodes can result in a more extensive peri od of confusion. Recurrence of TLOC on rapid resumption of an upright posture is typical of syncope. The combination of a sensation of feeling hot, sweaty, light- headed, visual (seeing stars, vision going white, black, gray, becoming blurred or closing in) and auditory symptoms (so unds seeming distant, muf \202 ed or distorted) is so characteristic that these symptoms a re often summarized as \200\230pre-syncopal \200\231, i.e. warn- ing symptoms of syncope ( 25 ). Minor injury, including carpet burns, bruising, and lacerations, are common in PNES, and ne ither a history of such injuries nor of urinary incontinence distinguishes securely between PNES and epi- leptic seizures ( 54 ). However, in children, these physical symptoms (and p articularly carpet friction burns and urinary incontinence) are very rare and typically lim ited to patients with more chronic and refractory PNES. Severe lateral tongues bites are mo re likely in epileptic seizures although tongue biting is also reported frequently by patie nts with PNES and can occur in syncope ( 23 , 29 ). The onset of a PNES is more commonly gradual than that of epileptic seizures ( 31 , 32 ). A lthough about half of patients with PNES will claim that their seizures tend to come out of the blue ( 29 ), PNES can be preceded by a prodrome of symptoms of physi- ological arousal (heart racing, dry mouth, tremor, sweaty hands) and typically with little cognitive awaren ess of anxiety ( 33 ). Past medical history Patients \200\231 previous interactions with health services can give impor- tant diagnostic clues. During the attack Whereas there is a gradual decline in the frequency and increase in ampli tude of muscle contractions during the clonic phase of GTCS, jerking in PNES with signi \201 cant motor activity is tremor-like and tends only to involve changes in amplitude. The onset and offset of the jerks in a PNES is usually sudden, unlike the more characteris- ti c crescendo and decrescendo seen in a GTCS. Frequency remains unchanged throughout the atta cks ( 34 ). Myoclonus or repeated jerks (clonic movements) during syncope are common, as is vocal- ization, brief limb posturing, upward and/or lateral deviation of the eyes, and eye lid \202 ickering ( 35 ). Cyanosis is more common in epilepsy than syncope or PNES ( 36 ) . Table 8.3 lists features from the medical history that can help to determine the likelihood of the three most common causes of TLOC. Epileptic seizures may develop after stroke, brai n injuries, or infections, and, in children, prolonged (complex) febrile sei- zures and may complicate systemic disorders. Patients with cardiac syncope often have a history of other cardiac symptoms ( 18 ). Patients with PNES often have a history of other unexplained phys ical symptoms including pain and \201 bromyalgia ( 23 ), and may have much more voluminou s health records than other people of the same age and gender ( 55 ). CHAPTER 8 differential diagnosis of epilepsy 85 Table 8.3 Features in the medical history that help to determine the likelihood of epilepsy , syncope, and psychogenic non-epileptic seizure (PNES) Feature in history Epileptic seizures Syncope PNES Manifestation <10 years of age Common Occasional Unusual Change of seizures semiology Rare Rare Occasional (more dramatic with time) High seizure frequency Occasional Rare Common Recurrent seizure status Rare Never Common Worsening with antiepileptic drugs Rare Rare Occasional Seizure provocation Rare (e.g. photosensitive epilepsy) Common (e.g. pain, fear) Not rare (arguments, stress, doctor \200\231s of \201 ce) Seizures in front of a doctor Unusual Common (blood tests) Common Multiple unexplained physical symptoms Rare Rare Common Multiple surgical procedures and investigations Rare Rare Common Psychiatric treatment Rare Rare Common Vascular risk factors, history of heart disease Rare (except in elderly patients) Not rare (common in patients with cardiogenic Rare syncope) Sexual and physical abuse Rare Rare Common History of suicide attempts Rare Rare Common History of alcohol excess Not uncommon Infrequent Not uncommon History of learning disability/other CNS disorder Not uncommon Rare Not uncommon Interactional distinguishing features seizure-suppression attempts. In contrast, patients with PNES resist the doctor \200\231s f ocus on speci \201 c attacks ( 57 ). Instead they tend to highlight the adverse consequenc es of their seizures and the dangerous or embarrassing situations in which seizures occurre d ( 58 ). Rather than making recurrent and complex attempts to communicate an experience to the interviewer which is clearly dif \201 cult to share interindividually, their accounts of attacks often remain limited to \200\230holistic \200\231 statements such as \200\230 I was out \200\231 or \200\230I don \200\231t remember anything \200\231. The differences in TLOC presentations are not limited to what patients say but also how the y interact with their doctor ( 30 ). A number of interactive and linguistic features have b een described which may be used to differentiate between patients with epilepsy and PNES (T able 8.4 ) ( 56 ). Patients with epilepsy tend to give (unprompted) detailed accounts of the symptoms of their seizures, which are character- ized by significant formulation effort (hesitations, re-sta rts, reformulations, etc.) and may include meta-analytic comments such as \200\230this is really dif \201 cult to explain \200\231, clear contours of the period of impaired conscio usness ( \200\230the last thing I remember \200\231, \200\230the next thing I remember. \200\231), or volunteered descriptions of Taking the history in children Much of the history-taking approach in adults also applies t o chil- dren and the history must include the periods before, during, and Table 8.4 Interactional and linguistic features which can help in the differentiation of ep ileptic seizures and psychogenic non-epileptic seizure (PNES) Feature Epilepsy PNES Subjective seizure symptoms Volunteered, detailed Avoided, no detail Formulation work Extensive Practically absent Seizure suppression attempts Volunteered Not mentioned Gaps in consciousness Exact description Little description Metaphors Seizure as independently acting agent, patient often depicted as \200\230victim \200\231 o f the seizure Seizures as a place or space, which patients travel through Seizure labels No resistance to use of \200\230medical \200\231 labels (e.g. \200\230seizures \200\231, \200\230grand mal \200\231 for episodes) Resistance to the use of \200\230medical \200\231 labels (e.g. seizure). Preference of lay terms ( \200\230 \201 t \200\231, \200\230blackout \200\231) oxford textbook of epilepsy and epileptic seizures 86 prove diagnostic, particularly if the history is vague or the epi- sodes are dif \201 cult to describe. This is particularly useful for epi- sodes that occur from sleep, the rarer p aroxysmal dyskinesias, and also PNES. after the episodes. In particular, speci \201 c questions should be asked about whether th ere was a likely or even possible trigger for the episodes. In the active, high-achieving t eenager (most often female) with PNES, a relatively common trigger is a new activity or pur suit that proves to be the \200\230 \201 nal straw \200\231; rather than appearing to fai l at this activity, the child becomes sick and is therefore unable to par- ticipate \200 \224 and not just in this new activity but everything else. PNES is a common manifestation of this behavior. Clearly, most of the history will be obtained from the child \200\231s pa rents or carers but it is crucial to always ask the child themselves about any aspects of t he episodes. Even young children may be able to provide valuable information that may actua lly con \201 rm the nature of the paroxys- mal episodes. If the parent or carer has not ac tually witnessed the child \200\231s episodes then it is important to obtain information fr om those who have observed them. This may include contacting or talking with another family member, friend, schoolteacher, or other individuals, such as a swimming pool attendant or lifeguard. The sort of information \200\224 and how it is given to the doctor \200\224 th at may suggest an adult is experiencing PNES, may similarly be heard from a mother who is f abricating her child \200\231s \200\230seizures \200\231 with the child being a victim of M nchhausen syndrome by proxy. Investigations Interictal tests Interictal tests are greatly overrated in the differential diagnosis of TLOC. \200\230Brain tests \200\231 are often normal in patients with epilepsy , \200\230cardiac tests \200\231 are often normal in patients with syncope. In the series of 158 consecutive outpatients cited previously, interictal EEG only changed the diagnosis in one patient. Neuroimaging revealed a relevant abnormality in 12/43 scanned (27.9 % ) ( 1 1 ). Electroencephalography The EEG is a very useful test in the classi \201 cation of the epil epsy syndrome, but the role of the EEG in the initial diagnosis of patients who have experi enced a TLOC is controversial. There is a risk of non-experts overinterpreting the diagnost ic signi \201 cance of non-speci \201 c EEG changes ( 13 ): in one study such changes wer e seen in 55 % of adults with a clinical diagnosis of epilepsy but also in 45 % of people w ho had experienced syncope ( 15 ). Another study found non-speci \201 c EEG changes in 18 % of adults with PNES ( 64 ). Examination Ictal examination The observation and examination of a patient during a seizure is rarely possible, especially in patients \201 rst presenting with seizures. However, t he observation of closed eyes during the seizure, resisted eye opening, gaze avoidance, ret ained pupillary light re \202 ex, semi- purposeful movements, responsiveness to tickle or corneal re \202 ex, and normal plantar responses would be very helpful and support a diagn osis of PNES rather than epilepsy ( 59 , 60 ). Examination \201 ndings during a faint may include abnormalities of heart rhythm and hypotension. The examination soon after a GTCS m ay show evidence of a severe (typically lateral) tongue bite, bruising or skel- etal injury , and petechial hemorrhages around the eyes or in the conjunctiva. As in adults, the EEG is an often over-used investigation in chil- dren. In view of the nor mal maturation of the EEG, which ranges from preterm through infancy and early childhood to the adult pattern by 12 \200\22314 years, there is an even greater danger of misinter- pre ting children \200\231s EEGs. It is of concern that in the UK, approxi- mately half of the clinicians who routinely report pediatric EEGs have not received formal training in pediatr ic electroencephalog- raphy ( 65 , 66 ). In addition, many pediatricians continue to believ e that the EEG is a \200\230diagnostic test \200\231 for epilepsy and hold on to the erron eous belief that the child \200\231s paroxysmal episodes cannot be epileptic if the EEG is normal and conversely that the episodes must be epileptic if the EEG is abnormal. Interictal examination Interictal examination \201 ndings in patients with epilepsy may p ro- vide a clue to the underlying pathology (e.g. focal central nervous system dysfunction, neurocutaneous syndromes, intracranial space occupation). Patients with syncope may have a postural blood pres- sure drop, a cardiac murmur or arrhythmia. However, in one con- secut ive case series of 158 adult patients attending a TLOC clinic, physical examination \201 ndings did not contribute to the diagnosis in a single case ( 11 ). A brief screen for adve rse life events and psy- chiatric morbidity may yield potential aetiological factors in pat ients with PNES ( 61 ), although rates of adverse life events and mental illness are also h igher in patients with epilepsy and patients with refractory syncope than in the general po pulation ( 62 , 63 ). Neuroimaging Neuroimaging is never a diagnostic test for epilepsy, and even if abnormal doe s not necessarily mean that the patient \200\231s paroxysmal episodes are epileptic. Howeve r, neuroimaging should be carried out in all patients with suspected epilepsy to exclude un derlying pathology (with the exception of those with a clear history and typical EEG change s of idiopathic generalized epilepsy). In one study, nearly 30 % of MRI scans in adults wit h a clinical diagnosis of epilepsy showed abnormalities, but abnormalities were also seen i n 4 % of MRI scans in patients with syncope ( 12 ). One study described abnormalities in 27 % of adults with PNES ( 67 ). As the quality of MRI scans improves, the risk of identifyin g non-speci \201 c changes and misinterpreting these as potential causes of epileptic seiz ures is likely to increase. Examination in children The examination \201 ndings in children, both interictally and ic tally, will generally be similar to those described in adults. Young chil- dren will often be distressed following a GTCS and will usually sleep; this is unlikely if the child has ex perienced a syncopal attack or a PNES. Increasingly, parents will attend the \201 rst new patient appointment with a video of their child \200\231s episodes which may In children with early-onset seizures (speci \201 cally myoclonic, tonic, or focal seizure s and infantile spasms), or in adolescents aged older than 14 years with a new focal epilep sy, neuroimaging is also mandatory and may identify an underlying structural lesion, includ ing cortical dysplasia, a neuronal migration abnormality, neurocutaneous disorders, and, ra rely (in contrast to adults), a tumor. CHAPTER 8 differential diagnosis of epilepsy 87