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Ann Neurol 2008 ; 64 : 35 \200\223 41 . of epileptiform discharges on magnetoencephalography in comparison CHAPTER 11 The Biochemical, Hematological, Histological, Immunological, and Genetic Investigation of E pilepsy Simon Shorvon care and assessment should be carried out in consultation with a clinical chemical biochemi st. In all the conditions listed, there are other clinical signs or associated clinical sym ptoms. In most patients with newly diagnosed epilepsy, a number of simple tests are routinely carr ied out. These are listed in Table 11. 1 , and the neurophysiological and imaging tests are described in more detail in Chapters 1 and 10. Depending on the clinical context, however, other tests are sometimes needed to establish the cause of epilepsy. In this chapter a ran ge of laboratory investigations which are used in the investigation of the cause of epileps y in selected patients, are outlined. Tests for cerebral infection depend on local- ity and clinical context, and are not included here. Blood biochemistry In Table 11. 3 are listed some of the biochemical tests in blood which c an be helpful in diagnosing patients with epilepsy. As with the urinary tests, many of the conditions being sought are rare and relevant mainly to pediatric epileptology. Some of the abnormali- ties can be detected by urinary analysis also, although blood bio- chemistry in most cases is more reliable and more sensitive. It must be also strongly emphasized that a detailed clinical his- tory, including the famil y history, and examination, including a search for associated neurological or systemic dist urbances, are as important in assessing cause as any test. The value of many of the tests l isted here is dependent on clinical context. Failure to account for the clinical context ma y lead to misinterpretation and erroneous conclusions. Porphyria is a not uncommon cause of epilepsy in some parts of the world and the biochemica l investigation is crucial in its diagno- sis and characterization. In Table 11. 4 are list ed urinary, fecal, and serum tests which can be helpful in differentiating the types of por - phyria in which epilepsy is a common presentation. A detailed discussion of the indications, interpretation, and place of these tests in clini cal practice is beyond the scope of this short chapter. It is intended here simply to provi de brief lists of available tests. The lists are not exhaustive, but cover many tests used in spe- cialist clinical practice to identify epilepsy etiology. Some of the conditions bei ng investigated are extremely rare, and others more common. Hematological tests A variety of disorders can be detected by hematological examination of a blood sample (Table 11. 5 ). Table 11.1 Minimum dataset of screening investigations to be carried out in most cases of n ewly diagnosed epilepsy where the cause is not immediately apparent Biochemical tests in urine and blood Urinary biochemical tests Table 11. 2 lists a variety of urine investigations for biochemical defects which might present with epilepsy or includ e epilepsy in the presentation. Most of these conditions are relevant mainly in pediatric e pileptology and will be seldom helpful in adults. Exceptions to this rule are the tests for Wilson disease, ornithine transcarbamylase de \201 ciency, porphyria (and rarely others) which can present at any age. Many of these tests are prone to false posi- tives, and are a ffected by renal dysfunction, or in some cases exog- enous substances. Thus, abnormalities should be interpreted with Electroencephalogram (EEG) Magnetic resonance imaging (MRI) scan (and in some cases, computed tomographic (CT) scannin g) Electrocardiogram (routine ECG in all cases, and in selected cases more extensive cardiolog ical investigation) Full blood count and differential Biochemical tests including urea, electrolytes, sugar, liver function tests, thyroid functi on, and autoimmune screen oxford textbook of epilepsy and epileptic seizures 128 Table 11.2 Urinary biochemical tests that can be helpful in determining the cause of epilep sy Investigation Condition being tested for Clinical epilepsy presentation Alpha-aminoadipic semialdehyde ( -AASA) Pyridoxine-dependent epilepsy Neonatal seizures and later refractory epilepsy in childhood Acylcarnitines Disorders of fatty acid oxidation or organic acidurias Acute metabolic encephalopathy and epilepsy with learning disability and often other signs Amino acids a Various metabolic de \201 ciency states-aminoacidopathies (phenylketonuria, homocysteinuri a, pyridoxal phosphate-responsive epilepsy) Epilepsy with learning disability and often other signs Copper Wilson disease Epilepsy can be a feature but usually subordinated to movement disorder or hepatic dysfunct ion Creatine Creatine synthesis disorders Early epilepsy, movement disorders, and developmental delay Glycosaminoglycans Mucopolysaccharidoses (e.g. MPS II, Hunter, MPS III, San \201 lippo) Developmental delay and regression, epilepsy, dysostosis Guanidinoacetate Creatine synthesis disorders Early epilepsy, movement disorders and developmental delay Oligosaccharides Oligosaccharidoses (e.g. mannosidosis, sialidosis, fucosidosis) Learning disability, skeletal deformities and myoclonic epilepsy Organic acids (carboxylic acids) Organic acidurias (e.g. glutaric aciduria type 1, propionic acidaemia, methylmalonic acidae mia). Fatty acid oxidation disorders Encephalopathy, movement disorders and epilepsy Orotic acid Some urea cycle defects (e.g. ornithine transcarbamylase de \201 ciency) Encephalopathy (precipitated by intercurrent illness, fasting, protein load, valproate) Porphyrins Porphyria (see Table 11. 4 ) Seizures, often precipitated by exogenous cause Pterins Disorders of biogenic amine metabolism (e.g. tetrahydrobiopterin de \201 ciency disorders) Developmental delay and seizures Purine and pyrimidine metabolites Disorders of purine or pyrimidine metabolism Psychomotor retardation and epilepsy Uracil Ornithine transcarbamylase de \201 ciency or disorders of pyrimidine metabolism Encephalopathy (precipitated by intercurrent illness, fasting, protein load, valproate) Uric acid Disorders of purine metabolism (e.g. Lesch \200\223Nyhan syndrome) Psychomotor retardation and epilepsy a The presence of amino acids in the urine depends on the renal threshold, and so decreases or mild elevations will only be seen in blood (plasma). For that reason diagnosis of pheny lke- tonuria (and most other aminoacidopathies) is nowadays always made in blood/plasma. Si milarly, if homocysteinuria is suspected, measurement of plasma homocysteine is preferable, though some labs still use the urine nitroprusside test as a non-quantitative screen for h omocysteinuria. The main use of urine amino acids is to look for renal transportation defec ts associ- ated with aminoaciduria, e.g. cystinuria. Cerebrospinal \202 uid examination Cerebrospinal \202 uid (CSF) examination has a limit ed role in the diagnosis of biochemical disorders and should be ordered usually after consu ltation with a chemical biochemist. Most of the condi- tions being sought are rare and CSF examination complements other investigations. The range of tests is listed in Table 11. 6 . Immunological investigations The range of identi \201 able immunological causes of epileps y has increased in recent years. These now form an important group of conditions, presentin g in childhood or adult life, and seizures can be a prominent or presenting feature. The ra nge of tests is outlined in Table 11. 8 . CSF examination has a more important role in the investigation Genetic investigations Many epilepsies have a genetic basis, although often this is com- pl ex. For a number of well-de \201 ned conditions, genetic testing is widely available, but for most of genes, genetic testing is only avail- able in a limited fashion, and is further more expensive. For many of these, cheaper diagnostic alternatives exist. Some of the com- moner available genetic tests are given in the tables, according to phenotype. It should be recognized, however, that as testing becomes more widely used, the recognized phenotype as sociated with genetic defects invariably broadens, and no simple corre- spondence between g enotype and phenotype is found. The same of infectious and immunological disease (see also Table 11. 8 ). Histological investigations and biopsy In Table 11. 7 , some of the more common biopsies ca rried out in patients presenting with epilepsy (almost always associated with other feature s) are listed. These tend to be con \201 rmatory tests undertaken fairly late in the cours e of investigation, and should be arranged after full consultation with the neuropathologic al depart- ment. A detailed discussion of the histological \201 ndings in cerebral tumors , cerebral malformations, or other structural lesions is beyond the scope of this chapter. CHAPTER 11 biochemical, hematological, histological, immunological, and genetic investigati on 129 Table 11.3 Blood biochemical tests that can be helpful in determining the cause of epilepsy Investigation Condition being tested for Clinical epilepsy presentation Alpha-aminoadipic semialdehyde ( -AASA) Pyridoxine-dependent epilepsy Neonatal seizures and later refractory epilepsy in childhood Acylcarnitines and carnitine levels Disorders of fatty acid oxidation or organic acidurias Acute metabolic encephalopathy Amino acids Various aminoacidopathies (e.g. phenylketonuria, homocysteinaemia [classical homocysteinuri a, cobalamin metabolism defects]) Epilepsy with learning disability and often other signs Ammonia Urea cycle defects (e.g. ornithine transcarbamylase de \201 ciency). Some organic aciduria s or fatty acid oxidation defects Encephalopathy (precipitated by intercurrent illness, fasting, protein load, valproate) Ceruloplasmin Menkes disease, Wilson disease Epilepsy, mental regression, neurological signs, hair changes Calcium Hypocalcaemia, hypoparathyroidism, pseudo-hypoparathyroidism, DiGeorge syndrome Neonatal seizures, other epilepsy, learning disability, other neurological signs Copper Menkes disease, Wilson disease Epilepsy, mental regression, neurological signs, hair changes Creatinine Creatine de \201 ciency syndromes (GAMT, AGAT, and transporter de \201 ciency) Epilepsy, learning disability Folate (serum folate and red cell folate) Folate de \201 ciency including the rare inherited metabolic diseases of folate malabsorpt ion and metabolism Megaloblastic anemia or macrocytosis will be present in most cases. Seizures can be present , usually associated with other features depending on cause. Glucose Hypoglycaemia (various causes) Epilepsy, acute encephalopathy Homocysteine Classical homocysteinuria, cobalamin absorption/metabolism defects, defects of folate metab olism, sulphite oxidase and molybdenum cofactor de \201 ciencies Seizures and other signs depending on condition Lactate Mitochondrial disorders (various types) Acute encephalopathy with seizures, myoclonic seizures, other neurological signs Magnesium Low magnesium Neonatal seizures Vitamin B12 (cobalamin) and where appropriate methylmalonic acid and homocysteine Vitamin B12 de \201 ciency (various causes, including the rare inherited disorders of coba lamin absorption, transportation, uptake and metabolism) Seizures are occasionally present as part of the phenotype Vitamin B1 (thiamine) Vitamin B1 de \201 ciency (various causes) Seizures are occasionally present as part of the phenotype Liver function tests POLG related disorders Regression with seizures and myoclonus Hepatic failure of various causes (including alcoholic liver disease) Variable phenotype frequently with epilepsy and/or myoclonus Renal function tests Renal failure of various causes Seizures are occasionally present as part of the phenotype Thyroid function levels Hypothyroidism Presentation with other features and on occasion seizures Uric acid Disorders of purine metabolism (e.g. Lesch \200\223Nyhan syndrome) Psychomotor retardation and epilepsy Enzyme activities: for instance, hexosaminidase A and B Hexosaminidase de \201 ciencies Wide neurological phenotype with occasional epilepsy available, but not of the other genes. These are all familial epilep- sies, and are rare (s ometimes only reported in a single family), and these genes are not routinely tested. genotype can result in different phenotypes (phenotypic heteroge- neity) and identical phen otypes may be due to different genotypes (genetic heterogeneity). Pure epilepsies There are a number of so-called \200\230pure epilepsies \200\231 in which epilepsy is the only or the predominant feature of the genetic defect (15 genes have been i denti \201 ed). Some of these syndromes are shown in Table 11.9 . Genetic testing of the S CN1A gene is fairly widely Cortical dysplasias In some patients with epilepsy, a cortical dysplasia can be identi- \201 ed. Some have intellectual impairment or other neurological signs, but in others epile psy can be the only or the most prominent \201 nd- ings. Some of the genes associated wit h cortical dysplasia are shown oxford textbook of epilepsy and epileptic seizures 130 Table 11.4 The diagnostic tests in the acute porphyrias associated with epilepsy Urine ALA and PBG levels Urine porphyrin levels Fecal porphyrin levels Red cell porphyrin levels Acute intermittent porphyria Normal Increased URO (may be normal if not in an acute attack) Normal Normal Variegate porphyria Increased (may be normal if not in an acute attack) Increased COPRO Increased CPPRO and PROTO Normal Hereditary coproporphyria Increased (may be normal if not in an acute attack) Increased COPRO Increased CPPRO Normal ALA, amino levulinic acid; COPRO, coproporphyrins; PBG, porphobilinogen; PROTO, protoporphy rins; URO, uroporphyrins. From Dean G, Shorvon S. Porphyria. In: Shorvon SD, Guerrini R, An dermann F. The Causes of Epilepsy: common and uncommon causes in adults and children , pp. 231 \200\2236. Cambridge: Cambridge University Press, 2011. 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.