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Epilepsy — the aetiology and pat

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Epilepsy — the aetiology and pat Powered By Docstoc
					                                                                   Special Feature
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          — the aetiology and pathogenesis

                                                                                                                Epilepsy is one of the most
                                                                                                                common neurological
                                                                                                                conditions. In the first article in
                                                                                                                this month’s special feature
                                                                                                                the authors discuss the
                                                                                                                classification of seizures, the
                                                                                                                cellular and genetic basis of
                                                                                                                epilepsy and some of the
                                                                                                                known causes of the condition
EEG of an epileptic seizure – orange traces show electrical activity in the brain picked up by
electrodes placed on different parts of the patient’s head

             pilepsy is the tendency to experi-                 explosion of knowledge about the funda-              sought to establish uniform terminology, so
             ence seizures — intermittent,                      mental basis of the condition.                       facilitating communication and further
             usually unprovoked and stereo-                                                                          research and allowing targeted treatment of
             typed episodes that result from                           EPIDEMIOLOGY                                  particular variants and conditions. Such clas-
abnormal electrical discharge of neurons of                                                                          sification is evolving constantly and,
the cerebral cortex. Seizures can manifest
themselves as a motor or sensory disorder, or
as altered behaviour, consciousness or emo-
                                                                B    oth seizures and epilepsy are common.1
                                                                     Series of epidemiological studies agree
                                                                that an individual’s lifetime risk of a seizure is
                                                                                                                     unfortunately, the process has inherent
                                                                                                                     potential to generate both complex termi-
                                                                                                                     nology and over-simplification. The
tion. That epilepsy is so variable a disorder                   2-3 per cent and the prevalence of active            International League Against Epilepsy
reflects the fact that, due to the specialised                  epilepsy in economically advantaged coun-            (ILAE) has developed the system of classifi-
function of different cortical regions, any                     tries is 400-600/100,000. The annual                 cation that has been most widely accepted,
individual’s symptoms will depend on the                        incidence of epilepsy is 40-70/100,000 in            particularly by those with an interest in the
area(s) of the brain that experiences abnormal                  Europe and North America and, when con-              field. The ILAE has classified both seizures
electrical activity.                                            sidered by age, is highest in children               (the manifestation of the neurological disor-
   Furthermore, although epilepsy frequent-                     (approximately half of all first seizures occur      der) and syndromes (the disorder itself)
ly occurs in isolation, it may be associated                    in those under 20 years old). Developing             (Panels 1 and 2).
with a large number of other conditions. It is                  countries show approximately twice the inci-            The ILAE seizure classification2 relies on
also one of the most frequently encountered                     dence of epilepsy as that in developed               observation, both clinical and electroen-
neurological conditions. Clear descriptions                     countries.This is explained by a higher rate of      cephalographic (EEG, the recording of
of seizures can be found dating from antiq-                     cerebral parasites and by poorer medical care.       cortical electrical activity), rather than the
uity (epilepsy is derived from the Greek for                                                                         underlying pathophysiology or anatomy.
“to seize”), and past decades have seen an                             CLASSIFICATION                                Seizures are classified as to whether at their
                                                                                                                     onset the abnormal neuronal discharge is
 Dr Parton is specialist registrar and Dr Cockerell is senior
 lecturer/horonary consultant neurologist, at the
                                                                A    s knowledge of epilepsy has increased, a
                                                                     succession of attempts has been made to
                                                                codify the various forms of seizures and
                                                                                                                     confined to one area (partial seizure) or
                                                                                                                     involves the whole cortex (generalised
                                                                                                                     seizure). This distinction is crucial because
 Department of Neurology,The Royal London Hospital,
 Whitechapel, Barts and The London NHS Trust
                                                                epileptic syndromes. This approach has               focal seizures are thought to result from

288     •                                                                   H O S P I TA L P H A R M AC I S T                    J U LY / A U G U S T 2 0 0 3   •   VO L . 1 0
                                                    lying cause, such as, say, a temporal lobe        epilepsies usually have their onset between
 Panel 1: ILAE classification                       lesion, can be assumed but not confirmed)
                                                    or idiopathic (where no underlying cause
                                                                                                      childhood and early adult life in otherwise
                                                                                                      neurologically healthy individuals; they
      of epileptic seizures2                        can be suggested).
                                                       Syndromic classification works well when
                                                                                                      respond well to anticonvulsant medication.
                                                                                                      By contrast, symptomatic generalised
                                                    the characteristics of a particular form of       epilepsies typically manifest in infants or
  I Partial seizures                                epilepsy are specific and easily differentiated   young children with neurodevelopmental
                                                    from others. With our current knowledge,          problems and often are resistant to anti-
  A — Simple partial seizures (consciousness        however, many variants can only be                epileptic drugs even in combination.
  preserved)                                        described imprecisely. As a consequence,            Seizure and syndromic classification play
                                                    some syndromes almost certainly represent a       an important role in the selection of anti-
  1.With motor, sensory or somatosensory            large number of different conditions, each        convulsant medication.
  symptoms (eg, movements, tingling or              with their own distinct aetiology. The syn-
  visualising flashing lights)                      domic classification also lumps together                 MECHANISMS OF EPILEPSY
  2.With autonomic symptoms or signs (eg,           focal/partial seizures with those that under-
  flushing, sweating)
  3.With psychic symptoms (eg, déjà vu,
  structured hallucinations)
                                                    go secondary generalisation, again stressing
                                                    the crucial distinction between that group
                                                    and primary generalised epilepsy.
                                                                                                      B    riefly, neuronal discharge involves the
                                                                                                           generation across a cellular membrane
                                                                                                      of a difference in electrical potential (voltage
                                                       Although the ILAE classification of            or, more simply, charge — dictated by the
  B — Complex partial seizures (impaired            epileptic syndromes has its drawbacks, and to     number of positive and negative ions pre-
  consciousness)                                    the non-specialist may appear to generate a       sent). Neurons exhibit a resting potential
                                                    list of arcane conditions, closer examination     between discharges, with the interior of the
  1. Delayed impairment of consciousness            reveals that four broad groups of epileptic       cell maintained as more negative by the
  2. Immediate impairment of consciousness          syndromes exist and that some general com-        active export of sodium ions. Discharge —
                                                    ments can be made about each of them.             the generation of a more positive action
  C — Partial seizures (simple or complex)          Idiopathic partial epilepsies begin in child-     potential — involves a complex interwoven
  evolving into generalised seizures                hood and are usually benign. Symptomatic          process by which ions (sodium, potassium,
                                                    partial epilepsies may present at any age, but    magnesium, calcium and chloride) flow
  II Generalised seizures                           certain conditions are associated with partic-    across membranes under the influence of
                                                    ular age groups. Idiopathic generalised           both inhibitory and excitatory modulators
  A — Absence seizures
  B — Myoclonic seizures
  C — Clonic seizures                                Panel 2:   ILAE classification of epilepsies and syndromes3
  D — Tonic seizures
  E — Atonic seizures                                1 Location related (focal or partial)                   Other symptomatic generalised
  F — Tonic-clonic seizures                          epilepsies                                              epilepsies not defined above
                                                     1.1 Idiopathic (with age-related onset)          2.2.2 Specific syndromes/aetiologies
  III Unclassified seizures due to incomplete               Benign epilepsy of childhood with                Cerebral malformations
  information, or those that do not fit the                 centrotemporal spikes                            Inborn errors of metabolism
  above categories                                          Childhood epilepsy with occipital         2.3 Cryptogenic
                                                            paroxysms                                        West’s syndrome
                                                            Primary reading epilepsy                         Lennox-Gastaut syndrome
entirely distinct mechanisms to primary              1.2 Symptomatic                                         Epilepsy with myoclonic-astatic
generalised epilepsy (see below).The classifi-              Epilepsy partialis continua                      seizures
cation is then further refined on the basis of              Syndromes characterised by seizures              Epilepsy with myoclonic absences
the seizure characteristics — for partial                   with specific modes of presentation
seizures, whether consciousness is impaired          1.3 Cryptogenic                                  3 Syndromes undetermined as to
or not, or whether subsequent (or “sec-                                                               whether focal or generalised
ondary”) generalisation occurs, ie, the              2 Generalised epilepsies                         3.1 With both generalised and focal seizures
seizure spreads from the initial site to involve     2.1 Idiopathic (with age-related onset)                Neonatal seizures
the entire cortex.                                          Benign neonatal familial convulsions            Severe myoclonic epilepsy in infancy
   By contrast, the ILAE classification of                  Benign neonatal convulsions                     Epilepsy with continuous spike waves
epileptic syndromes3 makes use of details of                Benign myoclonic epilepsy in infancy            during slow-wave sleep
the seizure type plus the associated anatomy                Childhood absence epilepsy                      Acquired epileptic aphasia
and aetiology, together with clinical and                   Juvenile absence epilepsy                       Other undetermined generalised
EEG features of those affected (the age at                  Juvenile myoclonic epilepsy                     epilepsies not defined above
onset, any family history, a characteristic pat-            Epilepsy with generalised seizures on     3.2 Without unequivocal generalised or focal
tern of discharges, etc). This method                       wakening                                        features
considers the assembly of symptoms, signs                   Seizures precipitated by specific modes
and associated information as a whole (ie, as               of activation (reading, reflexes)         4 Special syndromes
a syndrome). Initially, the site of seizure onset           Other idiopathic generalised epilepsies   4.1 Situation-related seizures
is considered (ie, focal/partial or generalised;            not defined above                                Febrile convulsions
other categories exist where the onset is            2.2 Symptomatic                                         Isolated seizures/status epilepticus
uncertain or when seizures are associated            2.2.1 Non-specific aetiology                            Seizures occurring only with acute
with certain situations). Sub-classification is             Early myoclonic encephalopathy                   metabolic or toxic event (alcohol,
then made on the basis of the aetiology of                  Early infantile epileptic encephalop-            eclampsia, etc)
the seizure as symptomatic (if a distinct cause             athy with suppression burst                      Reflex epilepsy
is identified), cryptogenic (where an under-

J U LY / A U G U S T 2 0 0 3   •   VO L . 1 0                   H O S P I TA L P H A R M AC I S T                                            •      291
and the voltage over the neuron’s mem-
brane.Afterwards, the cell must regenerate its     Table 1:   Monogenic causes of epilepsy (from reference 5)
resting potential difference before it can dis-
charge again.                                          Syndrome                                   Gene and protein                                       Locus
   It is disturbance of this basic physiological
mechanism that leads to seizure generation.            (a) Autosomal dominant (AD) inheritance
But at present much remains to be under-               AD nocturnal frontal lobe epilepsy CHRNA4, nicotinic ACh receptor subunit 20q13
stood of the details of epileptogenesis and no                                              CHRNB2, nicotinic ACh receptor subunit      1p21
overall explanation yet exists.4 It does how-          Benign familial neonatal convulsions KCNQ2, potassium channel subunit           20q13
ever appear that focal and generalised                                                      KCNQ3, potassium channel subunit            8q24
seizures arise by different mechanisms and so          Generalised epilepsy with febrile
we will consider them separately.                      seizures plus                        SCN1A, sodium channel subunit               2q24
                                                                                            SCN1B, sodium channel subunit              19q13
Focal epileptogenesis Crucial to the abnor-                                                 GABRG2, GABAA receptor subunit           5q31-33
mal discharge of neurons is their                      Juvenile myoclonic epilepsy          GABRA1, GABAA receptor subunit              5q34
intermittent but sustained depolarisation –            AD partial epilepsy with auditory
the paroxysmal depolarisation shift (PDS).             features                             LGI1, leucine-rich, glioma-inactivated 1   10q24
Generation of a PDS is made more likely by                                                  (unknown function, not an ion channel)
any of three situations, occurring either
alone or in combination. First, the excitatory         (b) Sporadically occurring
neurotransmitters aspartate and glutamate              Severe myoclonic epilepsy of infancy SCN1A, sodium channel subunit                                 2q24
may be present in excess, relative to the
inhibitory      gamma-aminobutyric        acid         (c) Uncertain association — only found in some patients
(GABA). Secondly, the voltage-gated ion                Febrile and afebrile seizures        SCN2A, sodium channel subunit                            2q23-24
channels of neuronal membranes may be                  Episodic ataxia type 1 with partial
abnormal, favouring the conductance of                 epilepsy                             KCNA1, potassium channel subunit                             12p13
sodium and calcium to that of potassium, so            Episodic ataxia type 2 with spike
making the interior of the neuron more pos-            wave epilepsy                        CACNA1A, calcium channel subunit                           19p13
itive. Finally, an imbalance may exist                 Juvenile myoclonic epilepsy          CACNB4, calcium channel subunit                          2q22-23
between other neuromodulators: dopamine
favours neuronal stability but acetylcholine
(ACh) enhances depolarisation. Genetic             quent to hypoxia or pro-epileptic drugs, etc)         that do frequently vary (implying that other
studies have revealed abnormalities in ion         or a local structural abnormality (see below).        factors — environmental or genetic —
channels, GABA and ACh receptors (see              Increasing evidence points to a key role for          beyond the single mutation influence the
below).                                            calcium T channels in generating the corti-           phenotype).
   For a focal seizure to be generated, neigh-     co-thalamo-cortical oscillation. T channels              The idiopathic epilepsies are, by defini-
bouring neurons must be recruited to the           are found at high density in neurons of the           tion, of uncertain cause, although a family
same synchronised pattern of discharge.            thalamus and are activated by relatively low-         history may be apparent. First-degree rela-
Spontaneous but asynchronous activity              voltage discharges (as would come from the            tives have their risk of developing epilepsy
(“burst firing”) has been demonstrated in          cortex) after sustained depolarisation.               raised approximately two or three times, but
certain neurons of the cortex and hip-                                                                   clear generation-to-generation inheritance
pocampus, but how synchronisation occurs                 GENETICS OF EPILEPSY                            is rare. Studies of monozygotic twins show
remains uncertain. The mechanism by                                                                      that single genes of complete penetrance are
which focal discharges are propagated to
other neurons — a chain reaction — is also
incompletely understood. It is, however,
                                                   A    s would be expected for such a clinical-
                                                        ly and aetiologically diverse group of
                                                   conditions, the genetics of epilepsy are com-
                                                                                                         not responsible. Instead, the heritability of
                                                                                                         epilepsy (its genetic component, as opposed
                                                                                                         to that determined by environmental fac-
apparent that propagation demands intact           plex.5 Rarely, families demonstrate the               tors) is estimated as 70 per cent. Closer
excitatory cortico-cortical connections and        transmission of the same seizure disorder             attention to the particular epileptic syn-
a failure of inhibitory regulation.                from one generation to the next as a clear            drome may reveal that relatives in fact suffer
                                                   genetic trait. In some such kindreds, muta-           from distinctly different seizure disorders but
Generalised epileptogenesis Generalised            tions of single genes have been identified as         it does appear that when monozygotic twins
seizures differ from the localisation-related      the cause, and this knowledge has advanced            both develop epilepsy, it is highly likely to be
epilepsies. Instead of propagation from one        our understanding of how neuronal dys-                of the same type.
area, generalised seizures involve the entire      function underlies epilepsy (Table 1[a]). It             A number of attempts have been made to
cortex simultaneously.The basis of this is an      should be noted that, with one exception,             identify shared genetic variants in large
abnormality of the looped connection               the identified genes encode components of             numbers of patients with idiopathic epilepsy
between the thalamus and the cortex.A dis-         ion channels.                                         (association studies, as opposed to linkage
turbance of this leads to the development of          Further examination of the monogenic               analysis, which seeks a shared chromosomal
a generalised discharge (the so-called “spike      epilepsies reveals other points of interest.          area in affected members of single families).
and wave” phenomenon seen on EEG).                 Either partial or generalised seizures may            The most statistically significant results have
While hyperexcitation causes neurons to            result. More than one gene disorder can pro-          followed restriction of cases to particular
discharge spontaneously (spikes), this alter-      duce the same phenotype (the physical                 subtypes (eg, juvenile myoclonic epilepsy).
nates with their heightened inhibition and         expression of genetic variation), as seen in             Taken together, these observations suggest
hyperpolarisation (waves).                         juvenile myoclonic epilepsy (Table 1[a and            an overall mechanism whereby rare genetic
   In humans it appears that the primary           c]). Moreover, even within the same family,           variants may cause epilepsy by themselves,
abnormality is hyper-excitability of the cor-      proven carriers of mutations may not devel-           but are subject to the influence of other
tex. This may follow either a metabolic            op seizures (ie, genetic penetrance) is not           genes or environmental factors. Usually,
disturbance (genetically determined, subse-        complete) and the clinical features of those          however, epilepsy is the product of several, if

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not many, genes plus the environment.Their         syndrome in which the mechanism of                epileptic focus after treatment.
interactions determine both an individual’s        epilepsy is complex or uncertain (eg, Fragile     Head injury The risk of post-traumatic
susceptibility to epilepsy, and how the            X syndrome and Angelman’s syndrome).              epilepsy is related to the nature and severity
seizures appear.                                                                                     of the cerebral insult: penetrating wounds
                                                   Infections A host of congenital infections,       carry a worse prognosis than closed trauma,
         AETIOLOGY                                 both viral and bacterial (for example,            and the degree of injury (length of uncon-
                                                   rubella, cytomegalovirus infection, syphilis,     sciousness and amnesia, plus any brain

W        e must stress that a seizure is a symp-
         tom and epilepsy merely the
tendency to experience seizures. Thus the
                                                   toxoplasmosis), can cause epilepsy subse-
                                                   quently. In later life, but especially
                                                   childhood, other conditions become more
                                                                                                     damage) correlates with the later risk of
                                                                                                     seizures. No benefit has been demonstrated
                                                                                                     for giving anticonvulsants prophylactically.
formal diagnosis of an individual’s epileptic      significant and together account for 2-3 per
syndrome involves examining the possibility        cent of all cases.The severity of infection and   Brain tumours Tumours are a rare cause of
that a seizure has resulted from some cere-        the age at which illness occurs are important     epilepsy but frequently present with seizures.
bral (or systemic) abnormality — of any            in determining whether or not epilepsy will       The chance that a first seizure is so associated
nature and that possibly originated some           result.                                           increases with the age of the patient.
time beforehand.                                                                                     Tumour-associated seizures are often difficult
   As medical knowledge has advanced, an           Bacterial meningitis — Epilepsy is more likely    to treat with antiepileptic medication. Cere-
increasing number of conditions have been          to develop where there are extremes of age,       bral secondaries from other cancers (notably
associated with seizures. From the review of       seizures during the original illness, delayed     lung, breast and melanoma) are more com-
classification above, it is apparent that a cru-   treatment or severe illness (bacteraemia,         mon than primary intracerebral tumours
cial difference exists between focal and           coma).                                            (principally malignant gliomas or primary
primary generalised seizures, as the former                                                          cerebral lymphomas, benign meningiomas).
suggest a localised brain lesion. Neuro-           Intracerebral abscess — Infections may arise in
imaging techniques have improved                   the brain from either local sites (sinuses,       Cerebrovascular disease Stroke — Stroke is
enormously in recent decades with CT and           middle ear, after skull fractures) or via the     the commonest cause of epilepsy in the
now MRI scanning becoming essentially              blood (from endocarditis, the lungs or in         elderly, accounting for around one-third of
routine investigations. As a consequence,          drug-users). Focal seizures are the most          new seizures in those over 60. Cerebral
more and more focal abnormalities can be           common sequelae.                                  infarcts are the most common type of stroke
diagnosed. An increased recognition of                                                               (85 per cent) but are less likely than haemor-
inborn errors of metabolism means that the         Viral encephalitis — Herpes simplex has a         rhages to cause epilepsy .
relative proportion of epilepsies that can be      predilection for the temporal lobes but
classified as symptomatic has increased.           other viruses can also cause direct damage        Arteriovenous malformations — Anomalous
Despite this, no specific aetiology will be        to the brain parenchyma. Presumably as a          vascular development leads to direct commu-
found for the majority of patients currently       result of this, the risk for later seizures is    nication of arterial and venous circulations as
diagnosed with epilepsy. We will                   higher than with bacterial meningitis.            a tangle of blood vessels.The malformations
briefly review some of the known causes                                                              have a 1-2 per cent annual risk of haemor-
below.                                             HIV infection — Although recent advances in       rhage and commonly present in this way but
                                                   antiretroviral therapy have greatly improved      may also present with focal epilepsy.
Perinatal causes Malformations/dysgenesis —        the outcome for people with HIV infection,
As well as gross abnormalities, it has become      those infected carry a greater risk of            Venous sinus thrombosis — This is an uncom-
apparent that many people with drug-resis-         seizures. HIV can cause a primary encephali-      mon disorder, in which thrombosis occurs
tant epilepsy have more subtle disorders of        tis, lead to secondary infections (especially     in the sinuses that drain venous blood from
brain structure, in particular sclerosis of the    toxoplasmosis), and increase the risk of cere-    the brain. It is often idiopathic but favoured
mesial temporal lobe. In such cases, neuro-        bral lymphoma, all of which can cause             by hypercoagulability, pregnancy or sepsis.
surgery may be considered, in which the            seizures.                                         Epilepsy is a frequent presentation or com-
epileptic focus is excised.                                                                          plication.
                                                   Tuberculosis — Although the common pre-
Hypoxic-ischaemic encephalopathy — This is         sentation of central nervous system               REFERENCES
the most frequently encountered cause of           infection by TB is an insidious meningitis,
seizures in the neonate, and is most common        focal seizures from cerebral tuberculomata        1.    Sander JWAS, Shorvon SD.The epidemi-
in term or post-term births.Asphyxia causes        may be the first manifestation of the disease.         ology of the epilepsies. J Neurol,
cerebral white matter infarction and necro-        Tuberculomata may develop during treat-                Neurosurg Psychiatry 1996;61:433-43.
sis.                                               ment and brain scanning should be                 2.   Commission on Classification and Termi-
                                                   considered if seizures occur later.                    nology of the International League
Cerebral haemorrhage — Peri- or intra-ven-                                                                Against Epilepsy. Proposal for revised clin-
tricular bleeding is more common in                Neurocysticercosis — The tapeworm Taenia               ical      and      electroencephalographic
premature infants.                                 solium is endemic in many parts of the                 classification of epileptic seizures. Epilep-
                                                   world. Its definitive host is the pig but when         sia 1981;22:489-501.
Hereditary conditions associated with              cysts are eaten by humans (typically through      3.   Commission on Classification and Termi-
epilepsy More than 200 conditions have             eating unwashed vegetables contaminated                nology of the International League
been associated with seizures that are the         by excrement, rather than meat itself,                 Against Epilepsy. Proposal for revised clas-
result of either single or multiple gene           because cooking kills the cysts) they will             sification of epilepsies and epileptic
defects. These disorders may produce a             develop in multiple organs, including the              syndromes. Epilepsia 1989;30:389-99.
structural lesion (such as neurofibromatosis,      brain. Cysticercosis is consequently one of       4.   Jeffrys JGR. Mechanisms and experimen-
tuberous sclerosis), a metabolic disorder (eg,     the most common causes of epilepsy in                  tal models of seizure generation. Curr
Baltic myoclonus — mutation of a protease          developing countries. Early administration             Opin Neurol 1998;11:123-7.
inhibitor, cystatin B, that causes myoclonic       of praziquantel can be curative, but later cal-   5.   Kullman D. Genetics of epilepsy. J Neurol
epilepsy) or a complex neurodevelopmental          cification of cysts may continue to act as an          Neurosurg Psychiatry 2002;73 Suppl II:
J U LY / A U G U S T 2 0 0 3   •   VO L . 1 0                  H O S P I TA L P H A R M AC I S T                                              •   295