154. Khan RB , Onar A . Seizure recurrence and risk factors after 140. Hildebrand J , Lecaille C , Perennes J , Delattre JY . Epileptic seizures during follo w-up of patients treated for primary brain tumors . Neurology 2005 ; 65 : 212 \200\223 15 . antiepilepsy drug withdrawal in children with brain tumors . Epilepsia 2006 ; 47 : 375 \200\223 9 . 141. Wagner GL , Wilms EB , Van Donselaar CA , Vecht Ch J . Levetiracetam: preliminary expe rience in patients with primary brain tumors . Seizure 2003 ; 12 : 585 \200\223 6 . 155. Frenay MP , Fontaine D , Vandenbos F , Lebrun C . First-line nitrosourea-based chemotherapy in symptomatic non-resectable supratentorial pure low-grade astrocytomas . Eur J Neurol 2005 ; 12 : 685 \200\223 90 . 142. Maschio M , Albani F , Baruzzi A , Zarabla A , Dinapoli L , Pace A , et al . Levetirac etam therapy in patients with brain tumor and epilepsy . J Neurooncol 2006 ; 80 : 97 \200 \223 100 . 156. Brada M , Viviers L , Abson C , Hines F , Britton J , Ashley S , et al . Phase II stud y of primary temozolomide chemotherapy in patients with WHO grade II gliomas . Ann Oncol 20 03 ; 14 : 1715 \200\223 21 . 143. Newton HB , Goldlust SA , Pearl D . Retrospective analysis of the ef \201 cacy and tolerability of levetiracetam in brain tumor patients . J Neurooncol 2006 ; 78 : 99 \200\223 102 . 157. Panda S , Radhakrishnan VV , Radhakrishnan K , Rao RM , Sarma SP . Electro-clinical characteristics and postoperative outcome of medically refractory tumoral temporal lobe epilepsy . Neurol India 2005 ; 53 : 66 \200\223 71; discussion 71-62 . 144. van Breemen MS , Rijsman RM , Taphoorn MJ , Walchenbach R , Zwinkels H , Vecht CJ . Ef \201 cacy of anti-epileptic drugs in patients with gliomas and seizures . J Neurol 2009 ; 256 : 1519 \200\223 26 . 158. Radhakrishnan A , Abraham M , Radhakrishnan VV , Sarma SP , Radhakrishnan K . Medicall y refractory epilepsy associated with temporal lobe ganglioglioma: characteristics and post operative outcome . Clin Neurol Neurosurg 2006 ; 108 : 648 \200\223 54 . 145. Newton HB , Dalton J , Goldlust S , Pearl D . Retrospective analysis of the ef \201 cacy and tolerability of levetiracetam in patients with metastatic brain tumor s . J Neurooncol 2007 ; 84 : 293 \200\223 6 . 159. Cascino GD . Epilepsy and brain tumors: implications for treatment . 146. Maschio M , Dinapoli L , Sperati F , Pace A , Fabi A , Vidiri A , et al . Levetiraceta m monotherapy in patients with brain tumor-related epilepsy: seizure control, safety, and q uality of life . J Neurooncol 2011 ; 104 : 205 \200\223 14 . Epilepsia 1990 ; 31(Suppl 3) : S37 \200\223 44 . 160. Awad IA , Rosenfeld J , Ahl J , Hahn JF , Luders H . Intractable epilepsy and structur al lesions of the brain: mapping, resection strategies, and seizure outcome . Epilepsia 199 1 ; 32 : 179 \200\223 86 . 147. Usery JB , Michael LM , 2nd , Sills AK , Finch CK . A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and sei zures . J Neurooncol 2010 ; 99 : 251 \200\223 60 . 161. Cascino GD , Jack CR , Jr . , Parisi JE , Sharbrough FW , Schreiber CP , Kelly PJ , et al . Operative strategy in patients with MRI-identi \201 ed dual pathology a nd temporal lobe epilepsy . Epilepsy Res 1993 ; 14 : 175 \200\223 82 . 148. Milligan TA , Hurwitz S , Brom \201 eld EB . Ef \201 cacy and tolerability of leveti racetam versus phenytoin after supratentorial neurosurgery . Neurology 2008 ; 71 : 665 \200\223 9 . This page intentionally left blank CHAPTER 21 Epilepsy in Renal, Hepatic, and Other Conditions Aidan Neligan type 1 (GLUT-1) de \201 ciency syndrome in which seizures frequently occur. Etiology is an important determinant of prognosis in epilepsy yet is largely ignored in the International League Against Epilepsy clas- si \201 cations of seizures ( 1 ) and epilept ic syndromes ( 2 ). This is of particular relevance when discussing seizures occurring in t he con- text of systemic diseases and where they should \201 t in such a classi- \201 c ation. Seizures in systemic diseases are not an inconsiderable problem, especially in the c ritically ill. The currently used terms, acute and remote symptomatic seizures (as differen tiated by the temporal relationship to the provoking factor), are confusing and probably to o simplistic as most seizures occurring in systematic disease are likely to be multifactori al, even if one cause predomi- nates. In a recently proposed aetiological classi \201 cati on of epilepsy ( 3 ), epilepsy is divided into four broad categories: idiopathic, symptomat ic, provoked, or cryptogenic epilepsy. The term \200\230pro- voked seizures \200\231 seems more appropriate for seizures in the context of systematic disease which may occur as a di rect consequence of the underlying condition, its predisposing factors, its treatment, or a combination of all three. Pathophysiology of seizures in systemic diseases Any critically ill person can develop seiz ures if the provoking stimu- lus is severe enough to lower their seizure threshold suf \201 ciently, much the same as people with epilepsy may experience an exacerba- tion in the ir seizure control in the context of concurrent illness. Nevertheless, the systemic insult required to provoke seizures is much greater in people without a prior history of epilepsy. Conditions in which seizures can occur, listed by system, are shown in Table 21.1 . Electr olyte imbalances such as sodium, glucose, calcium, magne- sium, and, rarely, low levels of potassium, can affect neuronal excitability and are important precipitants of seizures in t he criti- cally ill. Seizures as a consequence of electrolyte disturbances typi- cally occu r in the context of encephalopathy, drowsiness, headache, stupor, and other neurological sy mptoms ( 6 ). Similarly, distur- bances in the balance of neurotransmitters can predispose to sei- zures such as depletion of the inhibitory neurotransmitter gamma-aminobutyric acid or accumulation of excitatory amino acids such as glutamate and aspartate which occurs afte r hypoxic- ischaemic brain injury, leading to increased neuronal excitability and neuronal damage ( 7 ). Estimating the true frequency of seizures in people with prima- rily non-neurological condi tions is dif \201 cult as this has rarely been subject to systematic examination. Neverthe less it does seem that seizures are one of the more common neurological manifestations of s ystemic disease. In a prospective study of all admissions to a medical ITU over a 2-year pe riod, 1850 people were identi \201 ed, of whom 92 were admitted with a primary neurologica l condition. Of the remaining 1758 people, 217 (12.3 % ) developed neurological complicatio ns of which 61 (28 % ) were seizures ( 4 ). Table 21.1 Systematic conditions in which seizures are a feature Seizures arising as a consequence of systemic disease can be con- vulsive or non-convulsive , focal or generalized (either primary or secondary generalized), and particularly status e pilepticus (convul- sive and non-convulsive), the majority of which occurs in people with n o prior history of epilepsy ( 5 ). A high index of suspicion for the possibility of subtle convulsive or non-convulsive status epilep- ticus as well as the possibility of non-epilept ic seizures needs to be maintained in the critical care setting. Renal disease Uraemic encephalopathy Haemodialysis associated seizures Haemolytic uraemic s yndrome Renal transplants Dialysis disequilibrium syndrome Hepatic disease Hepatic encephalopathy Wilson \200\231s disease Liver transplants Porphyria s Respiratory conditions Neurosarcoidosis Endocrine conditions Hypothyroidism Thyrotoxicosis GLUT-1 de \201 ciency Hashimoto \200 \231s encephalopathy (SREAT) Malignant hypertension/hypertensive encephalopathy In this chapter, we will primarily deal with what are termed situ- ation-related seizures a nd as such the seizures can be explained by the provoking circumstances. We shall not deal further with epi- leptic syndromes in which systemic disease features prominently such as t he progressive myoclonus epilepsies, action-myoclonus renal syndrome or metabolic condition s such as glucose transporter Rheumatological conditions Systemic lupus erythematosus Vasculitis Cancer oxford textbook of epilepsy and epileptic seizures 240 with resultant transient cerebral oedema ( 8 , 13 ). Awareness of the condition and slow in itial HD in people with high serum urea has decreased the incidence of DDS. It is also possible that some people who do not normally have seizures may have molecular g enetic or mitochondrial DNA defects which predispose them to having seizures in the context of critical illness ( 7 ). Seizures also occur in PD in the particular context of non-ketotic hyperosmolar coma as a r esult of glucose fast exchanges. Such seizures are best prevented by monitoring the dialysi s glucose content ( 9 ). Seizures in renal disease Seizures are one of the most common manifestations of neurologi- cal dysfunction in uraemic encephalopathy which can occur in either acute or untreated chro nic renal failure, either as a direct consequence of the condition itself or as a complicat ion of its treat- ment, or both. The administration of erythropoietin (EPO) for the treatment of renal anemia may result in a rapid rise in blood pressure with hypertension in 35 % and a hypertensive encephalopathy, which can result in seizures, in about 5 % . The reported incidence of sei- zures with EPO ranges from 2 \200\22317 % with higher rates typically observed in the early years of trea tment and with supratherapeutic doses. There is little evidence of an increased risk of sei zures with EPO in people with normal blood pressures ( 8 , 14 \200\223 16 ). Depending on the rapidity of the onset and degree of renal fail- ure, people with uraemic e ncephalopathy present with headaches, irritability, \202 uctuating levels of consciousnes s, seizures (epilepsia partialis continua, convulsive and non-convulsive status epilepti- c us), coma and death ( 8 ). The precise pathophysiology of uraemic encephalopathy is poorly understood but an accumulation of metabolites, hormonal disturbance, imbalance in inhibitor y and excitatory neurotransmitters and disturbance of the intermediary metabolism have all been postulated as potential contributing fac- tors ( 8 ). In a phase III trial of the use of EPO for the treatment of anemia in people, 5.4 % of thos e receiving EPO had seizures ( 14 ). Similarly in a meta-analysis of randomized control tri als of the use of EPO for the treatment of renal anemia, the risk of seizures in EPO treatm ent versus non-EPO treatment groups was assessed. There was a higher risk of seizures in th e non-EPO group (lower haemo- globin) (four trials, 219 patients; relative risk (RR) 5.25; 95 % con- \201 dence interval (CI) 1.13, 24.3; p = 0.03) compared with the group treated with EPO ( 15 ). It has been estimated that one-third of people presenting with uraemic encephalopathy have seizures, sometimes as the initial symptom ( 9 , 10 ). A signi \201 cant cause of seizures is hypocalcaemia which be can be exacerbated by shifting towards alkalosis by bicar- bonat e treatment in people with metabolic acidosis ( 11 ). People with chronic renal failure are at increased risk of cere- brovascular disease (both ischaemic and haemorrhagic strokes), which is a signi \201 cant risk for the development o f subsequent sei- zures particularly in the elderly. The risk of cerebrovascular disease fo r people with end-stage renal disease (ESRD) on dialysis is esti- mated to be 4 \200\22310 times higher than the general population in part due to accelerated atherosclerosis and ane mia in people with ESRD ( 17 , 18 ). Seizures also occur during haemodialysis, although the tendency to initiate dialysis early in uraemic patients has reduced the inci- dence of dialysis-associated seizures (DAS). In a retrospective review of 180 children and adolescents receiving dialysis over a 14-year per iod, 7.2 % (13/180) experienced DAS, with a signi \201 - cantly increasing risk of DAS in people receiving haemodialysis (HD) only (9 % , 7/78) compared with people receiving perito neal dialysis (PD) only (0 % , 0/79) (chi-squared = 5.5, 1 degree of free- dom (df), P = 0. 02). In the 101 people receiving HD (78 HD only, 23 HD and PD), the risk of DSA was signi \201 cantly higher in those with a prior history of seizures (29 % , 6/21) compared with th ose without a history of seizures (8 % , 6/80) (chi-squared = 5.2, 1 df, P = 0.02). A prior history of seizures did not increase the risk of DAS in people having PD ( 12 ). Seizures are a relatively common occurrence after renal trans- plants ( 19 , 20 ). In a ser ies of 154 children who underwent 207 renal transplants for ESRD, 48 (31 % ) had convulsive seizures before, during, or after transplantation ( 17 ), although this is likely to be an underestimate of the true incidence as non-convulsive seizures are rarely recognized ( 10 ). Sixty per cent of seizures were single seizures with few of the remaining children developi ng long-term seizures. The main aetio- logical factor was hypertension with seizures often heralding onset of hepatic encephalopathy. The majority of people with seizures did not a r ecurrence of seizures following control of hypertension ( 19 ). In a series of 119 renal tr ansplants in 109 children over a 10-year period, 20 children (17.6 % ) (21 transplants) had seizures. Seizures occurred within 8 weeks of transplantation in 13 (62 % ) and within 6 m onths in 18 (85.7 % ) with seizures signi \201 cantly more common in younger children (age s 5 \200\22310 years) (p = 0.03). Of the seizures in the 21 transplant patients, 13 (62 % ) were single seizures, nine chil- dren experienced multiple seizures, and one child had sta tus epi- lepticus. Twenty-one children had a prior history of epilepsy (two were on antiepi leptic drugs (AEDs) at the time of transplantation), \201 ve (23.8 % ) of whom had furthe r seizures. Of the remaining 88 children, 15 (17.0 % ) developed seizures. The risk of seiz ures post transplant was not signi \201 cantly different between the two groups (p = 0.69) . The most commonly identi \201 ed etiology for the devel- opment of seizures was hyperten sion (15 (71.4 % )) either alone or in combination with other factors (fever, graft rejecti on, cyclosporine A toxicity, hypomagnesaemia). Overall the long-term prognosis was very goo d with only \201 ve children requiring long-term Seizures can also occur in people who develop chronic dialysis encephalopathy or dialysis d ementia, a subacute progressive con- dition with personality changes, apraxia, seizures, my oclonus, and dementia ( 8 ). This was linked to the use of aluminum-containing dialysate an d aluminum-based phosphate binders and is now a rare condition since the cessation of the u se of aluminum ( 8 , 9 ). Seizures are also associated with the dialysis disequilibrium syn- drome (DDS), which occur s during or immediately after dialysis with symptoms of muscle cramps, anorexia, nausea, an d headache in mild cases and confusion, seizures, coma, and death in more severe cases ( 13 ). Risk factors include rapid dialysis (particularly if the serum urea is > 60 mmol/L), se vere metabolic acidosis, young or old age, central nervous system (CNS) disease, and previo us sei- zures ( 13 ). Different theories explaining the pathogenesis of DDS exist in the li terature which is due to the rapid removal of urea during HD. The \200\230reverse urea hyp othesis \200\231 proposes that urea is more rapidly removed from plasma than the brain, thu s creating an osmotic gradient leading to a net \202 ow of water into the brain CHAPTER 21 epilepsy in renal, hepatic, and other conditions 241 present with psychiatric symptoms, such as euphoria, sleep distur- bance and depression in the early stages (I \200\223II), with neurological symptoms predominating in the latter sta ges (III \200\223IV). Neurological symptoms include ataxia, somnolence, confusion, seizures (both generalized and non-convulsive), and coma ( 29 ). Seizures occur- ring in the contex t of hepatic encephalopathy are often refractory to standard AEDs but may respond to speci \201 c treatment for the hepatic dysfunction including correction of the ammonia levels wi th lactulose, phosphate enemas for constipation, and antibiotic therapy for concurrent infe ctions ( 25 , 29 ). AED treatment (two of whom developed seizures as a consequence of signi \201 cant intracra nial pathology) ( 20 ). Haemolytic uraemic syndrome (HUS), characterized by the clinical triad of micro-angiopathic haemolytic anemia, thrombo- cytopenia, and acute renal injury, is one of the main causes o f acute renal injury in young children. It is typically caused by a shiga- toxin-producing Escherichia coli (usually E . coli 0157) (90 % of cases occur in children) with a typical p rodrome of abdominal pain, diarrhea, and vomiting immediately followed by the typical sympt oms ( 21 \200\223 24 ). Seizures are the most common neurological manifestation affecting up to 25 % of children with HUS ( 21 ) and may be the presenting symptom in 15 % ( 22 ). Mo st seizures are short, single, generalized seizures which are well controlled with AEDs ( 2 1 , 22 , 24 ). Children with CNS manifestations including seizures have a poorer prognosis with increased mortality and development of long-tem ESRD ( 23 ). Children with generalized seizures in association with HUS have a better prognosis than chil- dren with focal-onset seizures who are more likely to have struc- tural lesions particularly stroke, have neurolo gical sequelae and develop epilepsy ( 24 ). Based on the premise that subclinical seizures are common in patients with acute liver fail ure and therefore in \202 uences prognosis, a randomized controlled trial of prophylactic phenytoin in patients with acute liver failure was performed. Twenty people were rand- omiz ed to receive phenytoin and 22 to placebo control. There was no difference between the two groups in the number developing cerebral oedema (12 (60 % ) in the phenytoin group versus 1 0 (45 % ), p = 0.35), the number requiring mechanical ventilation (10 (50 % ) versus 12 (55 % ), p = 0.77), the number developing seizures (all generalized: 5 (25 % ) versus 5 (22.7 % ), p = 0.86) or mortality (14 (70 % ) versus 15 (68.2 % ), p = 0.89). Overall there was n o evi- dence for the bene \201 t of prophylactic AEDs in people with acute liver failure ( 30 ). The management of seizures in renal disease Renal failure alters the pharmacokinetics of ma ny AEDs necessitat- ing changes in doses. Wilson disease Seizures are reputedly rare in Wilson disease (WD) with isolated reports of seizures and status epilepticus occurring with treatment with D-penicillamine (which can ca use pyridoxine de \201 ciency with resultant seizures). When seizures occur in such a cont ext, treat- ment with copper chelators such as trientine, or replacement with pyridoxine, i s recommended ( 25 ). Proteinuria (albuminuria) and metabolic acidosis which occur in renal failure reduce serum albumin levels and its protein bind- ing af \201 nity, thus increasing the free active lev els of AEDs. Small changes in serum albumin can lead to marked increases in the free fracti on of AEDs. Similarly, reduced glomerular \201 ltration and tubular secretion increase dr ug elimination half-lives ( 25 , 26 ). The newer AEDs such as gabapentin, topiramate, levet iracetam, viga- batrin, and the older drug ethosuximide are highly water soluble, have a lo w volume of distribution, and have lower protein-binding af \201 nity and therefore accumu late in renal disease. They are largely removed by HD and therefore postdialysis dose suppl ementation is required ( 25 , 26 ). In contrast, HD has little impact on the dos- ages of t he older highly lipophilic protein-bound AEDs like car- bamazepine, phenytoin, benzodiazepi nes, and valproate. These AEDs are therefore preferable in patients with seizures and ESRD ( 26 ). The effect of PD on AEDs levels is unpredictable. The dose of phenytoin may need to be adjusted in people with severe hypoalbu- minaemia (either due to renal or hepatic disea se); free (biologically active) phenytoin levels can accumulate leading to toxicity and par adoxical seizures despite a low or low-therapeutic total pheny- toin level (10 \200\22320 m g/L). Phenytoin should be monitored by thera- peutic free phenytoin levels (maintaining lev els between 1 \200\2232 mg/L) ( 26 , 27 ). Gabapentin has been reported to cause multifocal myo- clonus and altered mental states in people with ESRD without a history of epilepsy an d should therefore be used cautiously in renal failure ( 28 ). Two large cohort studies of patients with WD followed over 30 years, suggest that the preva lence of epilepsy is signi \201 cantly higher than that of the general population. In a case series from Cambridge, UK of 200 cases the prevalence of epilepsy was 6.2 % (10/1 61 cases surviving) (estimated incidence 430 per 100,000/year) while in a review of the lit erature, 47/856 (5.5 % ) of people with WD had seizures ( 31 ). Prior to the availabil- ity of treatment with D-penicillamine in 1955, seizures typically occurred late in the course of the condition and were a prelude of death, with a median survival of 1 year following on set of seizures. Thirteen of 200 people (6.5 % ) with WD had epilepsy of whom \201 ve had focal-onset seizures and eight had generalized seizures. Two people had at least one episo de of generalized convulsive status epilepticus. In almost half of cases, seizures started before the start of copper chelating therapy, with the majority of seizures felt not to be related to D-penicillamine. Seven had no further seizures fol- lowing commencement of AED t reatment with 75 % seizure free for 2 years or more at last follow-up ( 32 ). In a cohort of 490 patients with WD seen in a tertiary center in India, 41(8.3 % ) had seiz ures. The predominant seizure types were simple partial ( 8 ), complex partial ( 6 ), secon dary generalized ( 2 ), generalized tonic \200\223clonic ( 29 ), and periodic myoclonus ( 1 ). The onset of seizures varied with seizures (along with other symptoms of WD) noted befo re diagnosis in 19 (46.3 % ) and were part of a termi- nal event in two. Overall, seizures occurred before other symptoms of WD in seven (17.1 % ), concomitant with other symptoms in 17 (41.5 % ), and during treatment in 14 (34.1 % ). Overall seizure Seizures in hepatic disease Fulminant liver failure can occur as a consequence of many diff er- ent causes including viral or drug-induced hepatitis, alcohol- induced cirrhosis, sepsi s, hemorrhage of oesophageal varices, hypoxia, hypovolaemia, and infections, including suba cute bacte- rial peritonitis. People with hepatic encephalopathy typically oxford textbook of epilepsy and epileptic seizures 242 extensively metabolized by the liver with the potential for toxicity in people with hepatic disease ( 25 ). prognosis was good with complete seizure control obtained in 28 (68.3 % ), intermittent bre akthrough seizures in seven (17.1 % ), and poor seizure control in four (9.7 % ) (two patie nts were lost to follow- up). All were treated with D-penicillamine and AEDs with no thera- peutic or demographic factors predictive of seizure prognosis ( 31 ). Newer AEDs with low protein-bound pro \201 les which are not metabolized by the liver shou ld be used for the treatment of sei- zures in hepatic disease. Preferred AEDs include levet iracetam, zonisamide, gabapentin, vigabatrin, and tiagabine which have no effect on the CYP 450 isoenzymes ( 35 ). Overall it appears that the prevalence of epilepsy in people with WD is not as rare as prev iously claimed with the vast majority of seizures not occurring as a result of D-penicillam ine induced pyri- doxine de \201 ciency. The prognosis of seizures often mirrors that of t he underlying condition with worsening seizure control heralding the terminal stage of WD. Successful treatment of seizures in WD requires treatment with AEDs and chelating agents. Management of people with hepatic porphyria-induced general- ized seizures is dif \201 cul t as many AEDs are hepatic enzyme P-450 system inducers increasing haeme and porphyrin synt hesis with worsening seizures (phenobarbital, phenytoin, carbamazepine, valproate, clonazep am, lamotrigine). Treatment with non-enzyme- inducing AEDs such as levetiracetam or gabapen tin is recom- mended. Oxcarbazepine, which has a low level of hepatic enzyme induction, has also been shown to be effective in the management of seizures with hepatic porphyria ( 36 ). Liver transplantation Neurological complications are common after liver transplanta- tion w ith seizures being the second most common neurological complication after encephalopathy. I n a retrospective study of all liver transplantations carried out at a single specialist ce nter over a 12-year period, 630 people who underwent liver transplantation were identi \201 ed. Of these 28 (4 % ) developed seizures all of which were generalized (four secondar y generalized) with the majority occurring in the perioperative period. None had a previous history of epilepsy and there were no episodes of status epilepticus. The principal aetiol ogies of seizures were CNS neurotoxicity with immunosuppression agents in 17 (FK506 ( 6 ), cyclosporine ( 11 )), CNS infections (listeria, aspergillus, nocardia) in three, and cata- strophic CNS insults (intracranial hemorrhage, cerebral oedema with fulminant liver failure and hypovolaemic shock with postan- oxic ischaemic encephalopathy) in three. Seizure onset was a ter- minal event in seven. All were treated with intravenous phenytoin with seizures recurring in \201 ve. Phenytoin was successfully discon- tinued in all patients who surv ived, by 3 months with no seizure recurrence noted after a median follow-up of 2 years ( 33 ). Seizures in other conditions In this section we will brie \202 y discuss other conditions in which sei- zures feature prominently. A list of conditions categorized by system in whic h seizures can occur is shown in Table 21.2 . Systemic lupus erythematosus (SLE) Neurological symptoms are common in SLE, occurring in 10 \200\22380 % of people and form part of the diagnostic criteria for SLE. Seizures, which c an be partial or more usually generalized, are a common feature occurring in 10 \200\22320 % of people with SLE, the majority of which are single seizures ( 37 , 38 ). Seizures can be the \201 rst manifestation of the condition and usu- ally occur early in the course of the condition with younger age and more severe disease activity at onset ( 39 ). Factors found to confer an increased risk of seizures include previous history of strok e, male gender, the presence of immunoglobulin G (IgG) antiphos- pholipid antibodies, anti- cardiolipin IgG antibodies, anti-Smith antibodies, a history of psychosis, and abnormal neu roimaging (37 \200\22339). In contrast the presence of anti-La autoantibodies is asso- ciat ed with a lower risk of developing seizures (and lupus nephri- tis) ( 40 ). Other factors r eported to be associated with a lower risk In a series of 427 consecutive liver transplantations in 391 patients, seizures occurred in 12 (3.1 % ) and all neurological com- plications were more common in adults (nine adults ( 3.3 % ), three children (0.03 % )). The causes of seizures were cyclosporine toxic- ity in four, primary graft non-function in three, cerebrovascular accidents (two), CNS infection ( one), fever (one) and unknown (one). Three people with seizures post transplant died ( 34 ) . Overall the prognosis of people with seizures after liver trans- plantation, in which the s eizures do not represent part of an agonal process, is excellent with little evidence of a long-term propensity for further seizures. The most common causes of seizures are CNS neuro toxicity (cyclosporine, FK506) and CNS infections. Table 21.2 Potential causes of seizures in systemic disease Electrolyte disturbances Hypoglycaemia Hyperglycaemia Hypocalcaemia Hypercalcaemia (rare) H ypermagnesaemia Hyponatraemia Hypernatraemia Hypokalaemia (very rare) Metabolic disturbances Hyperammonaemia Pyridoxine/folate/thiamine de \201 ciency Immunosuppressive therapy Opportunistic Infections Graft rejection Management of seizures in hepatic disease AED metabolism is affected by hepatic dysfunction . As with renal disease, hepatic disease results in hypoalbuminaemia increasing the levels of free unbound AEDs (diazepam, phenytoin, and val- proate). AEDs with sedating side effect s such as the benzodi- azepines and phenobarbital may precipitate or worsen pre-existing he patic encephalopathy. Many of the AEDs (such as phenytoin, carbamazepine, and phenobarbital ) are potent hepatic CYP450 enzyme inducers, which increase the metabolic rate. Valproate s hould be used with extreme caution in people with hepatic dis- ease as it can cause idiosyn cratic hepatotoxicity. Lamotrigine is Miscellaneous Fever Infections Alcohol Sleep deprivation Organ failure Ischaemia, hypnoxia Hypertensive encephalopathy Postoperative Anesthetic related Medication related CHAPTER 21 epilepsy in renal, hepatic, and other conditions 243 majority of cases, seizures are single seizures (less than half having a recurrence) or a s hort-lived period of recurrent seizures, which occur in the context of a clear precipitant (e.g. infection, fever). AED dosages may need to be adjusted in renal and hepatic dys- func tion. The long-term prognosis is excellent with few (<10 % ) developing persistent seizures . of seizures are mucocutaneous involvement, photosensitivity, and hydroxychloroquine use ( 3 9 , 40 ). Posterior reversible encephalopathy syndrome Posterior reversible encephalopathy syndrome ( PRES) or hyper- perfusion encephalopathy is a clinical radiological syndrome of heterogeneo us aetiologies which typically presents with headache, altered mental functioning, visual d isturbances, and seizures ( 41 ). The exact pathophysiology of the condition remains uncert ain but appears to be related to loss of cerebral autoregulation of blood pressure and endo thelial dysfunction ( 41 ). Conditions which may give rise to PRES include eclampsia, hyper tensive encephalopathy ( 16 ), renal disease, immunosuppressive, immunomodulatory and chemo therapy medications (e.g. cyclosporine A, intravenous immunoglobulins, tacrolimus) and vasc ulitis among others. Seizures are a prominent feature of the condition (87 % in one large s eries ( 42 )) and may be the presenting symptom ( 41 ). Seizures are usually generalized to nic \200\223clonic seizures (either primary or sec- ondary generalized), often with involve ment of the occipital lobes and visual hallucinations. Some people can present with status epi- lepticus as the initial manifestation of PRES ( 43 ). Management involves the rapid lo wering of the blood pressure with the use of parental antihypertensive agents like labetalo l and sodium nitro- prusside and dose reduction or withdrawal of the suspected pre- cipitat ing drug. Seizures are typically managed with IV phenytoin (except in the case of suspected eclampsia). Overall PRES has a good short-term prognosis with rapid resolution in the majo rity (with slower radiological resolution). Similarly long-term seizure prognosis is favora ble with only 2/25 having a recurrence after a mean follow-up of 2250 days ( 44 ). References 1. 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In: Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy , pp. 655 \200\223 63 . Cambridge : Cambridge U niversity Press , 2011 . 7. Delanty N , Vaughan CJ , French JA . Medical causes of seizures . Lancet 1998 ; 352 ( 9125 ): 383 \200\223 90 . 8. Brouns R , De Deyn PP . Neurological complications in renal review: a review . Clin Neurol Neurosurg 2004 ; 107 ( 1 ): 1 \200\223 16 . 9. Palmer CA . Neurologic manifestations of renal disease . Neurol Clin 2002 ; 20 ( 1 ): 23 \200\223 34 . 10. Danlami ZT , Obeid T , Awada A , Huraib S , Iqbal A . Absence status; an overlooked cau se of acute confusion in haemodialysis patients . J Nephrol 1998 ; 11 ( 3 ): 146 \200\223 7 . 11. Canavese C , Morellini V , Lazzarich E , Brustia M , Quaglia M , Stratta P . Seizures a nd renal failure: is there a link? Nephrol Dial Transplant 2005 ; 20 ( 12 ): 2855 \200\223 7 . Autoimmune encephalitis Seizures are a common feature of the newly described CNS autoim- mu ne diseases presenting with limbic or more diffuse encephalitis or encephalopathy ( 45 ). S eizures occur in almost all cases of limbic encephalitis and three-quarters of cases of ant i-NMDA receptor encephalitis ( 45 , 46 ). Voltage-gated potassium channel (VGKC)- complex/L gi1 antibodies can present with a distinctive seizure semi- ology typically involving the f ace and ipsilateral arm (faciobrachial dystonic seizures). These seizures may occur prior t o the onset of the typical limbic encephalitis ( 47 ). In a study of the causes of encepha- litis in 203 patients in England, seizures were much more common with antibody associated causes compared to other causes of encephalitis ((14/16 (88 % ); 95 % CI 62 \200\22398) ver sus (24/38 (63 % ); 95 % CI 46 \200\22378, p <0.001) for herpes simplex virus encephalitis) ( 48 ). 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