Epilepsy PDF

EPILEPSY An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain, causing an event that is discernible by the person experiencing the seizure and/or by an observer. According to the International League against...

EPILEPSY An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain, causing an event that is discernible by the person experiencing the seizure and/or by an observer. According to the International League against Epilepsy (ILAE), epilepsy is defined by any of the following conditions: 1. at least two unprovoked (or reflex) seizures occurring more than 24 hours apart; 2. one unprovoked seizure (or reflex) and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; 3. diagnosis of an epilepsy syndrome. A person with epilepsy will show recurrent epileptic seizures that occur unexpectedly and stop spontaneously. Epilepsy is recognized as a priority in effective healthcare delivery, and there are still a number of issues that health professionals should consider:  Epilepsy is a chronic neurological disorder that affects people of all ages  More than 50 million people worldwide have epilepsy.  Nearly 80% of people with epilepsy are found in resource poor settings.  Epilepsy responds to treatment 70% of the time. Despite this, approximately more than two-thirds of people affected in poor countries are not treated.  People with epilepsy and their families suffer from stigma and discrimination in many parts of the world Pathophysiology Epilepsy differs from other neurological conditions because it has no pathognomonic lesion. A variety of different electrical or chemical stimuli can easily give rise to a seizure in any normal brain. The hallmark of epilepsy is a rather rhythmic and repetitive hyper-synchronous discharge of neurons, either localized in an area of the cerebral cortex or generalized throughout the cortex, which can be observed on an electroencephalogram (EEG). A whole population of neurons discharges synchronously in an abnormal way that an epileptic seizure may be triggered. This abnormal discharge may remain localized or it may spread to adjacent areas, recruiting more neurons as it expands throughout the brain via cortical and subcortical routes. The area from which the abnormal discharge originates is known as the epileptic focus. Clinical manifestations The clinical manifestation of a seizure will depend on the location of the focus and the pathways involved in its spread. ILAE has recently published a revised classification of seizure types. It divides seizures into three main groups according to its onset.  Generalized - It involves initial activation of both hemispheres of the brain simultaneously  Focal – The discharge starts in a localized area of the brain  Unknown onset - It’s not possible to classify as focal or generalized. Classification of Seizures Focal Aware/Impaired awareness Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic Non-motor onset: autonomic, behavior arrest, cognitive, emotional, sensory Generalized Motor: tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms Non-motor (absence): typical, atypical, myoclonic, eyelid myoclonia Unknown Onset Motor: Tonic-clonic, epileptic spasms Non-motor: Behaviour arrest Generalized seizures Generalized seizures are subdivided in motor and non-motor (absence) types. The motor includes tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic- atonic, atonic and epileptic spasms. The non-motor includes typical absence, atypical absence and absence with special features (myoclonic, eyelid myoclonia). Tonic-clonic seizures (Grand Mal Seizures)- Tonic-clonic seizures often begin with bilateral myoclonic jerks, followed by a tonic contraction of the extremities and trunk sustained by a short period. Then contractions become progressively longer and interrupted, resulting in clonic jerking. Cyanosis, incontinence and tongue biting may occur. The seizure ceases after a few minutes and may often be followed by a period of drowsiness, confusion, headache and sleep. Typical absence seizures (Petit Mal Seizures) - Typical absence seizures happen almost exclusively in childhood and early adolescence, and are characterized by behavioral arrest for a few seconds. The child goes blank and stares; fluttering of the eyelids and flopping of the head may occur. The attacks last only a few seconds and afterwards normal activity is resumed as if nothing had happened. They are seen in developmentally normal people. Atypical absence seizures - Atypical absence seizures differ from the previous types because they are mostly seen in people with developmental delay, the behavioral arrest may be longer, the EEG shows background abnormalities (diffuse slowing). Absence seizures with special features - Absence seizures with special features are absence seizures associated with other characteristics such as eyes myoclonic (Jeavons syndrome) or myoclonic movements. Myoclonic seizures - Myoclonic seizures are abrupt, very brief, involuntary, shocklike jerks, which may involve the extremities and/or axial trunk muscles. They usually happen in the morning, shortly after waking. They may sometimes cause the person to fall, but recovery is immediate. There are non-epileptic myoclonic jerks that occur in a variety of other neurological diseases and may also occur in healthy people, particularly when they are just going off to sleep (hypnic jerks). Tonic seizures - Tonic seizures occur during sleep with a duration of approximately 20 seconds. They usually involve all or most of the brain, affecting both sides of the body. If the person is standing when the seizure starts, they may fall. Clonic seizures - Clonic seizures are rare alone, but most often are part of a tonic-clonic seizure. They are characteriZed by a rapidly alternating contraction and relaxation of a muscle – clonus. Brief and infrequent clonic seizures in infants usually disappear on their own within a short time. Atonic seizures - Atonic seizures comprise a sudden loss of muscle tone, causing the person to collapse to the ground. Recovery afterwards is quick. They are rare, accounting for less than 1% of the epileptic seizures seen in the general population, but more common in people with severe epilepsy starting in infancy. Focal seizures In focal seizures, discharges are localized, and manifestations often reflect activation of the underlying cortical areas. They are primarily divided according to awareness in focal aware and focal with impaired awareness. Then subdivided according to motor or non-motor onset. The motor onset includes automatism (e.g. chewing, lip smacking, fumbling), atonic, clonic, epileptic spasms, hyperkinetic, myoclonic and tonic seizures. The non-motor onset includes autonomic (e.g. pallor, tachycardia), behavior arrest, cognitive, emotional and sensory seizures. Diagnosis Diagnosing epilepsy can be difficult because it is first necessary to demonstrate a tendency to recurrent epileptic seizures. The one feature that distinguishes epilepsy from other conditions is its unpredictability and transient nature. The diagnosis is clinical and depends on a reliable account of what happens during the events, if possible, from the individual and from an eyewitness. Investigations may help and the EEG is usually one of them. These investigations, however, cannot conclusively confirm or refute the diagnosis. Other conditions may cause impairment or loss of consciousness which can be misdiagnosed as epilepsy; these include syncope, breath-holding attacks, transient ischaemic attacks and psychogenic attacks. People may also present with acute symptomatic seizures or provoked seizures as a result of other problems such as drugs, metabolic dysfunction, infection, head trauma or flashing lights (photosensitive seizures). These conditions have to be clearly ruled out before a diagnosis of epilepsy is made. Epilepsy must only be diagnosed when at least one of the three defining ILAE conditions is present. The diagnosis must be accurate because the label ‘suffering with epilepsy’ carries a social stigma that has great implications. Neuroimaging with magnetic resonance imaging (MRI) is the most valuable investigation when structural abnormalities (e.g. stroke, tumor, developmental abnormalities, hydrocephalus) are suspected. TREATMENT Convulsive seizures may look frightening, but the person is not in pain, will usually have no recollection of the event afterwards and is usually not seriously injured. Emergency treatment is seldom necessary, but the person should, however, be made as comfortable as possible, preferably lying down (ease to the floor if sitting), cushioning the head and loosening any tight clothing or neckwear. During seizures, the individual should not be moved unless he or she is in a dangerous place, for example, in a road, by a fire or hot radiator, at the top of stairs or by the edge of water. No attempt should be made to open the person’s mouth or force anything between the teeth. This usually results in damage and broken teeth or other objects may be inhaled, causing secondary lung damage. When the seizure stops, the person should be turned over into the recovery position and the airway checked for any blockage. Focal seizures are usually less dramatic. During automatisms, people may behave in a confused manner and should generally be left undisturbed. Gentle restraint may be necessary if the automatism leads to dangerous wandering. Attempts at firm restraint, however, may increase agitation and confusion. No drinks should be given after the seizure, nor should extra antiepileptic drugs (AEDs) be given. It is commonly felt that seizures may be life threatening, but this is seldom the case. After a seizure, it is important to stay with the person and offer reassurance until the confused period has completely subsided and the person has fully recovered. Status epilepticus Status epilepticus is traditionally defined as ongoing seizure activity for ≥30 minutes, but from a pragmatic point of view, a seizure that lasts longer than 5 minutes warrants pharmacological intervention. Initial management of status epilepticus is supportive and may include: secure airway and resuscitate, administer oxygen, assess cardiorespiratory function, establish intravenous access. Buccal midazolam (10 mg) is first-line treatment in the community. Rectal diazepam is an alternative if preferred or if buccal midazolam is not available. If intravenous access is already established and resuscitation facilities are available, intravenous lorazepam is administered. First-line AED for hospital management of status epilepticus is intravenous lorazepam. If unavailable, then intravenous diazepam should be administered or buccal midazolam if immediate intravenous access cannot be secured. If seizures continue, intravenous phenytoin or valproate or phenobarbital should be administered as second-line treatment. In the refractory status, general anaesthesia with propofol, midazolam or thiopentone may be necessary. Febrile convulsions Febrile convulsions may occur in the young without epilepsy. Brief events are managed conservatively with the primary aim of reducing the child’s temperature. Tepid sponging and use of paracetamol is usual. Prolonged febrile convulsions lasting ≥ 10–15 minutes or in a child with risk factors, active management is required to avoid brain damage. The drug of choice is diazepam by intravenous or rectal administration. Prophylactic management of febrile convulsions may be required in some children, such as those with pre-existing risk factors or a history of previous prolonged seizures. Long-term treatment In most cases, epilepsy can only be treated by regular, long term drug treatment aiming at suppressing seizures. Full seizure control can be obtained in most cases, and in others drugs may reduce seizure frequency or severity. Therapy is long-term, usually for at least 3 years and, depending on circumstances, sometimes for life. AED treatment will fail unless the person fully understands the importance of regular therapy. Poor adherence is still a major factor which results in hospital admissions and poor seizure control, and leads to the clinical use of multiple AEDs. General principles of treatment The primary aim of epilepsy treatment is to control seizures using one drug, with the lowest effective dose causing the fewest side effects possible. The established AEDs, those licensed before 2000, are still an important part of the antiepileptic armamentarium, and include;  carbamazepine (Tegretol),  clobazam,  clonazepam,  ethosuximide,  gabapentin ,  lamotrigine,  phenobarbital,  phenytoin (Epanutin),  piracetam,  primidone,  sodium valproate (Epilim),  tiagabine,  topiramate and  vigabatrin. Since 2000, new AEDs have been introduced such as  eslicarbazepine acetate,  brivaracetam,  felbamate,  lacosamide,  Levetiracetam (Keppra 250mg, 500mg)  oxcarbazepine,  perampanel,  Pregabalin (Lyrica 25mg, 50mg, 75mg, 100mg, 150mg),  stiripentol,  ruinamide and  zonisamide The choice of drugs depends largely on the seizure type, and so correct diagnosis and classification is very essential. The newer AEDs are generally used as second-line drugs when treatment with established first-line drugs has failed. Exceptions to this are levetiracetam and oxcarbazepine. Overall, newer AEDs are not more effective than the established drugs but seem to be better tolerated. Initiation of therapy in newly diagnosed epilepsy A first-line AED suitable for the person’s seizure type should be introduced slowly, starting with a small dose. A hasty introduction may induce side effects that may challenge the person’s confidence. For most drugs, a gradual introduction will produce a therapeutic effect just as fast as a rapid introduction, and the person should be reassured about this. Antiepileptic drugs for different seizure types Seizure Type First-Line Treatment Adjunctive AEDs Generalized Seizures Tonic-clonic Carbamazepine (Tegretol®) Levetiracetam (Keppra®) Lamotrigine Clobazam Oxcarbazepine Topiramate Sodium valproate (Epilim®) Tonic or atonic Sodium valproate Lamotrigine Rufinamide Topiramate Absence Ethosuximide Clonazepam Clobazam Sodium valproate Lamotrigine Levetiracetam Topiramate Zonisamide Myoclonic Levetiracetam Clobazam Sodium valproate Clonazepam Topiramate Piracetam Focal Seizures Carbamazepine Brivaracetam Lamotrigine Clobazam Levetiracetam Eslicarbazepine Oxcarbazepine Gabapentin Sodium valproate Lacosamide Perampanel Phenytoin (Epanutin®) Pregabalin (Lyrica®) Topiramate Zonisamide Maintenance dosage There is no single optimum dose of any AED that will suit all because the required dose varies from person to person and from drug to drug. Drugs are introduced slowly and then increased incrementally to an initial target dose. Seizure control should then be assessed, and the dose of drug changed if necessary. For most AEDs, dosage increments are constant over a wide range. However, Phenytoin the serum level–dose relationship is not linear and small dose changes may result in considerable serum level changes. Phenytoin is currently rarely used.  Generic prescribing for epilepsy remains controversial. Most specialists would prefer people to remain on the same brand because it provides consistency. This is also preferred by the majority of people with epilepsy and is recommended.  Different preparations of some AEDs may vary in bioavailability or pharmacokinetic profiles. This is obviously important in those people in whom the dosage has been carefully titrated to achieve optimal control. Withdrawal of drugs AEDs should not be withdrawn abruptly. Withdrawal of individual AEDs should be carried out in a slow, stepwise fashion to avoid the precipitation of rebound seizures (e.g. over 2–3 months). This risk is particularly great with barbiturates (phenobarbital and primidone) and benzodiazepines (clobazam and clonazepam). If a drug needs to be withdrawn rapidly, for example, if there are life-threatening side effects, a benzodiazepine can be used to cover the withdrawal phase. Examples of withdrawal regimens are given below; Carbamazepine 100–200 mg every 2 weeks (as part of a drug change); 100–200 mg every 4 weeks (total withdrawal) Phenobarbital 15–30 mg every 2 weeks (as part of a drug change); 15–30 mg every 4 weeks (total withdrawal) Phenytoin 50 mg every 2 weeks (as part of a drug change); 50 mg every 4 weeks (total withdrawal) Sodium valproate 200–400 mg every 2 weeks (as part of a drug change); 200–400 mg every 4 weeks (total withdrawal)  Ethosuximide 125–250 mg every 2 weeks (as part of a drug change); 125–250 mg every 4 weeks (total withdrawal) Follow-up and monitoring of treatment It is essential to follow up people in whom AED treatment has been started. The reason for this is essentially to monitor the efficacy and side effects of treatment, upon which drug dosage will depend, but also to encourage good adherence. This follow-up is particularly important in the early stages of treatment, when an effective maintenance dose may not have been fully established, when the importance of adherence may not have been recognized by the person and when the psychological adjustment to regular treatment may not be resolved. Monitoring antiepileptic therapy Therapeutic drug monitoring (TDM) involves the measurement of serum drug levels and their pharmacokinetic interpretation. It is an integral component in the management of people who are taking phenytoin and carbamazepine but is less useful in people receiving other AEDs. Indeed, TDM has a very limited use for new AEDs, except in people who are acutely unwell, pregnant or in the elderly. It is also very useful to document AED side effects and in managing drug interactions. Adherence may also be a problem in these people, and hence TDM may be useful to establish treatment adherence. TDM is indicated: at the onset of therapy, if seizure control is poor or sudden changes in seizure control occur, if toxicity is suspected, if poor or non-adherence is suspected, to monitor the timescale of drug interactions, when changing AED therapy or making changes to other aspects of a person’s drug regimen that may interact with the AED. The frequency of undertaking TDM varies. Those with stabilized epilepsy may require their serum levels to be checked only once a year. A number of the newer AEDs do not require routine TDM. However, because most are used as adjuvant therapy, it is useful to establish baseline levels of existing drugs before the new agent is introduced. Clinical effects should be monitored and TDM, where appropriate, carried out at 6 to 12 month interval. ANTIEPILEPTIC DRUG PROFILES 1. Carbamazepine (Tegretol®plain/CR 200mg; 400mg) Carbamazepine is a first-line drug for generalized tonic-clonic seizures and focal seizures. It is not effective in absence seizures and myoclonic seizures, where it may even be deleterious. Carbamazepine acts through blockage of voltage-gated sodium channel. Adverse Events - Adverse events may occur in up to a third of people treated with carbamazepine, but only about 5% of these events will require drug withdrawal, usually because of skin rash, gastro- intestinal disturbances or hyponatraemia. Dose-related adverse reactions including ataxia, dizziness, blurred vision and diplopia are common. Idiosyncratic reactions, such as skin rash, occur in up to 10%, but rarely cause severe skin eruptions as erythema multiform and Stevens–Johnson syndrome. Others serious adverse events including hepatic failure and bone marrow depression are extremely uncommon. Pharmacokinetics - Carbamazepine exhibits auto-induction, that is, induces its own metabolism as well as inducing the metabolism of other drugs. It should, therefore, be introduced at low dosage, and this should be steadily increased over a period of a month. The slow-release preparation (Tegretol® CR 200mg; 400mg) of carbamazepine has distinct advantages, allowing twice-daily ingestion and avoiding high peak serum concentrations. 2. Diazepam (Valium®) Diazepam is used mainly in the treatment of status epilepticus, intravenously or in the acute management of febrile convulsions as a rectal solution. Absorption from suppositories or following intramuscular injection is slow and erratic. 3. Ethosuximide (zarontin®) Ethosuximide is a drug of first choice for generalised absence seizures, and it has no useful effect against any other seizure type. It mechanism of action is through blockage of low-voltage activated calcium channel. Tolerance does not seem to be a problem. Adverse effects - include gastrointestinal symptoms, which occur frequently at the beginning of therapy. Behavior disorders, anorexia, fatigue, sleep disturbances and headaches may also occur. The initial dosage is 500 mg daily in two divided doses and increased in steps of 250 mg every 5–7 days. The absorption of ethosuximide is complete, and the bioavailability of the syrup and capsule formulations is equivalent. 4. Gabapentin Gabapentin is occasionally used as a second-line treatment of focal seizures. Although initially developed as an AED, its main use currently is for the treatment of neuropathic pain. It exerts its effect through blockage of high-voltage activated calcium channels. It’s usually started with 300 mg once daily. 5. Levetiracetam (Keppra® 250mg; 500mg) Levetiracetam is a broad-spectrum drug, indicated both as a first-line and as an add-on for the treatment of focal and generalized seizures. Mechanism of action is not fully understood, but it binds to the synaptic vesicle protein 2A. The usual dosage is between 1000 and 3000 mg/day, divided in two daily doses. 6. Sodium valproate (Epilim® 200mg; Epilim® Chrono 500mg) Sodium valproate is a broad-spectrum AED, effective over the complete range of seizures type, but with particular value in the idiopathic generalised epilepsies. This is mainly due to its broad mechanism of action, known to act on voltage-gated sodium and calcium channels, and also in the turnover of GABA. Adverse effects - include nausea, diarrhoea, weight gain, alopecia, skin rash and thrombocytopenia. TDM should only be performed in cases of suspected toxicity, deterioration in seizure control, to check adherence or to monitor drug interactions. Sodium valproate is more teratogenic than other commonly used AEDs and should be avoided in women of childbearing age. PARKINSON DISORDERS The presence of tremor at rest, rigidity, bradykinesia, and postural instability (instability of balance) are considered the hallmark motor features of idiopathic Parkinson disease (PD), a disorder of the extrapyramidal system. These clinical features of PD were adeptly described in 1817 by James Parkinson. Epidemiology The prevalence of PD increases with age, affecting less than 0.5% of people in their 60s and 2.5% of those older than 80 years. The usual age at time of diagnosis ranges between 55 and 65 years. Overall, a higher preponderance of PD is reported among males. The estimated crude prevalence of PD in Nigeria is lower (10 to 249/100 000) compared to studies published in Europe (65.6 to 12 500/100 000). Etiology and Pathophysiology PD occurs sporadically and the true etiology is unknown. Both genetic and environmental factors are likely to contribute to the risk of development of PD, with environmental factors precipitating the onset of PD in a genetically susceptible individual. Environmental factors such as pesticide exposure, rural living, agricultural occupation and well water drinking alongside head injury are all associated with an increased risk of development of PD. At the cellular level, degeneration of dopaminergic neurons (axons and soma) projecting from the substantia nigra pars compacta (SNc) to the striatum (caudate nucleus and putamen) lead to a loss of dopamine at the terminal end. There is considerable reserve in this pathway, and a loss of more than 50% of nigral neurones occurs before overt motor features appear. Clinical Features Motor Features - A prerequisite feature for a diagnosis of PD is the presence of bradykinesia. This is the slowness of initiation of voluntary movement, with progressive reduction in speed of repetitive actions. The other cardinal features of the disease are tremor when at rest (pill-rolling tremor), postural instability (This problem comprises an impairment of righting reflexes, which leads to impaired gait and increased risk of falling) and cogwheel rigidity. Cogwheel rigidity describes the jerky resistance when limbs are moved. There is reduced blink frequency and facial expression (hypomimia), which, together with a low-volume (hypophonic), monotonous speech, may lead to significant difficulties in communication. All of this can easily be misdiagnosed as depression. Writing becomes small (micrographia) and barely legible, with the words falling off the line as the patient continues to write. Non-motor Features - A range of non-motor features encompassing autonomic, cognitive and psychiatric problems are seen in nearly all cases of PD and have a pronounced effect on quality of life. They can precede disease onset and tend to become more prominent as the condition evolves. These include;  Postural Hypotension (falling blood pressure on standing; which may contribute to falls and blackouts later in the disease course and is a leading cause of hospitalization for patients with PD)  Constipation (pathology in the enteric nervous system)  Depression (affecting approx. 40% of the patients)  Paranoia and hallucinations  Dementia (80% of PD patients)  Sleep disorders (especially the REM sleep behavioral disorder)  Restless leg syndrome and limb pain Diagnosis and Investigations The diagnosis of PD is a clinical one and should be based, preferably, upon validated criteria. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) may be necessary to exclude hydrocephalus, cerebrovascular disease or basal ganglia abnormalities suggestive of an underlying metabolic cause. TREATMENT General Approach The treatment of PD at the current time is wholly symptomatic and no drug has proven to have significant disease-modifying or neuroprotective capabilities. There is no accepted algorithm for the treatment of PD, although guidance has been produced by the National Institute for Health and Care Excellence (NICE, 2017). Treatment options depend upon whether the motor symptoms impact on the patient’s quality of life. Drug Treatment 1. Levodopa Preparations (Immediate Release and Control Release Levodopa) Levodopa remains the most effective and first-line oral symptomatic treatment for PD. It is administered with the peripheral dopa-decarboxylase inhibitors carbidopa or benserazide, where carbidopa plus levodopa is known as co-careldopa (Sinemet®) and benserazide plus levodopa is co- beneldopa (Madopar®). The decarboxylase inhibitor blocks the peripheral conversion of levodopa to dopamine and thereby allows a lower dose of levodopa to be administered. Levodopa readily crosses the blood–brain barrier and is converted by endogenous aromatic amino acid decarboxylase to dopamine and then stored in the surviving nigrostriatal nerve terminals. The first problem that patients typically describe with levodopa is a wearing-off effect, in which the patient finds that the effect of the medicine does not last until their next dose is due. The premature wearing off of the anti-Parkinsonian effects of levodopa and fluctuations in the response with the development of involuntary movements known as dyskinesia, typically occur after a number of years of treatment and relate as much to the duration of disease.  Immediate-Release (IR) levodopa doses starts with 50mg three times daily and can be titrated to maximum dose of 600mg/day. It should be taken 30 minutes before food as protein diet can critically interfere with absorption. Controlled-Release (CR) levodopa - Both Sinemet and Madopar are available as controlled-release preparations. There is Sinemet CR (carbidopa/levodopa 50/200) and also Half Sinemet CR (carbidopa/levodopa 25/100). Levodopa in CR preparations has a bioavailability of 60–70%, which is less than the 90–100% obtained from immediate-release formulations. However, CR preparations may be of help in simplifying drug regimens, in relieving nocturnal akinesia, and in co-prescribing with immediate-release levodopa during the day to relieve end-of-dose deterioration. Side effects and Adverse Effects: Nausea, vomiting and orthostatic hypotension are the most commonly encountered side effects. These adverse events may be circumvented by increasing the levodopa dose more slowly, or co-prescribing domperidone (Motilium®) 10 or 20 mg three times daily. Later in the illness, and in common with all anti-Parkinsonian drugs, levodopa may cause vivid dreams, nightmares or even precipitate a confusional state, which tends to indicate that the patient is starting to develop a PD dementia. Drug Interactions: Clinically relevant drug interactions with levodopa include hypertensive crises with MAO-A inhibitors (e.g Phenelzine). Levodopa should, therefore, be avoided for at least 2 weeks after stopping the inhibitor, although the non-selective forms of these drugs are rarely prescribed nowadays. Levodopa can also enhance the hypotensive effects of antihypertensive agents and may antagonize the action of antipsychotics. The absorption of levodopa may be reduced by concomitant administration of oral iron preparations. 2. Dopamine agonists Dopamine agonists stimulate dopamine receptors, both post- and pre-synaptically, bypassing the degenerating nigrostriatal dopaminergic neurons. Unfortunately, the current oral agents are less potent than levodopa and less well tolerated, with significant risks of side effects, for example, impulse control disorders. Ergot- and Non-ergot derived Dopamine agonists differ in their affinity for different members of the dopamine receptor families (D2 and D3 subtypes). Ergot derived Dopamine agonist – Cabergoline (administered once daily with plasma half-life of 63 – 68hrs) Non-Ergot derived Dopamine agonists – Ropinirole, Pramipexole, Rotigotine have become the dopamine agonists of choice nowadays. Side effects: The principal side effects of the dopamine agonists are nausea and vomiting, postural hypotension, hallucinations, confusion and, in some cases, major behavioral problems linked to impulse control disorders. Ergot derivatives (Cabergoline) run the risk of causing pleuropulmonary fibrosis and therefore are not routinely used anymore. 3. Apomorphine  This is a specialized drug in the treatment of advanced PD, but almost certainly continues to be underused. It is the most potent non-selective dopamine agonist available but has a short half-life, a single bolus administration lasting for 45–60 minutes. 4. Catechol –O- methyl transferase inhibitors (COMT – Inhibitors) – Tolcapone, Entacapone Inhibitors of the enzyme catechol-O-methyl transferase (COMT) represent a useful addition to the range of therapies available for PD. COMT itself is a ubiquitous enzyme, found in the gut, liver, kidney and brain, among other sites. In theory COMT inhibition may occur both centrally, where the degradation of dopamine to homovanillic acid is inhibited, and peripherally, where conversion of levodopa to the inert 3-O- methyldopa is inhibited. In practice, both Tolcapone and Entacapone (Comtan®) act primarily as peripheral COMT inhibitors and by so doing increase the amount of levodopa that enters the CNS. When Entacapone is prescribed, a 200 mg dose is usually given with each dose of levodopa administered, up to a frequency of 10 doses/day. Entacapone can be employed with any other anti- Parkinsonian drug, although caution may be needed with apomorphine (rare case of Coomb’s hemolytic anemia: irreversible). Entacapone is also marketed as a compound tablet containing levodopa and carbidopa (Stalevo®). Side-effects: Tolcapone is hepatotoxic, requires strict liver function monitoring; however, Entacapone studies have not shown any derangement of liver function, thus used more. Some side effects with COMT inhibitors include exacerbation of dyskinesia, diarrhea, abdominal pain, dryness of the mouth and urine discoloration. 5. Monoamine oxidase type B Inhibitors Selegiline and Rasagiline are inhibitors of MAO-B. Inhibition of this enzyme slows the breakdown of dopamine, effectively having a ‘levodopa-sparing’ effect in the striatum. The result of this is both a mild therapeutic effect and a possible delay in the onset of or reduction in existing motor complications. A single daily dose of 5 or 10 mg of selegiline is prescribed. Higher doses are associated with only minimal additional inhibition of MAO. Both Selegiline and Rasagiline may be used as de novo or adjunctive treatments in PD. 6. Amantadine Amantadine was introduced as an anti-Parkinsonian treatment in the late 1960s. It has a number of possible modes of action,including facilitation of presynaptic dopamine release, blocking dopamine reuptake, an anticholinergic effect (nicotinic antagonist), and also may act as a weak N-methyl-d- aspartate (NMDA) receptor antagonist. Initially employed in the early stages of treatment, where its effects are mild and relatively short-lived, it is more commonly used as an antidyskinetic agent in advanced disease, the only drug licensed for such use. Daily doses of 100–400 mg amantadine may be used. Some recommend even higher doses for improved antidyskinetic effect.  Side Effects: Although side effects become much more frequent at higher doses. These side effects include a toxic confusional state and peripheral & corneal oedema. Monitoring is not needed, but attention needs to be paid to patients reporting sudden visual changes. Livedo reticularis, a persistent patchy reddish-blue mottling of the legs, and occasionally the arms, is also a side effect. 7. Antimuscarinic Agents – Trihexyphenidyl, Orphenadrine Antimuscarinic drugs can have a moderate effect in reducing tremor but do not have any significant benefit upon bradykinesia. The use of antimuscarinic agents has declined because of troublesome side effects, including constipation, urinary retention, cognitive impairment and toxic confusional states. In selected younger patients, an antimuscarinic drug may still be helpful, but close monitoring is advised. Surgical Treatment Surgical approaches for the management of PD include both lesioning (-otomies) and deep brain stimulation (a high-frequency signal that functionally turns off the nucleus being stimulated). The intervention is costly, but significant benefits can be gained, especially for patients who have previously had a good response to levodopa but are experiencing major motor fluctuations or dyskinesia. New potential surgical approaches also include the delivery of growth factors, dopamine cells and viral vectors (for the delivery of growth factors or enzymes required for dopamine synthesis). PATIENT CARE After diagnosis, the provision of an explanation of the condition, education and support are essential. Accurate adherence with the timing of therapy may be particularly important in patients who are beginning to experience long term treatment complications. It can be helpful for patients to keep diaries when they begin to experience problems with either bradykinesia or dyskinesia, so that these symptoms can be related to drug and food intake. Other factors that need to be considered in patients with PD are the benefits of adequate sleep and rest at night, which may be made more difficult if they have urinary frequency or problems with nocturnal bradykinesia. Judicious use of hypnotic therapy may be appropriate, whereas a tricyclic antidepressant may offer the dual benefit of sedation with anti-muscarinic effects Patients’ relatives also need emotional and social support through what can be a very demanding period. It can be very difficult for relatives to cope with the patient’s loss of physical mobility, together with a personality change. The involvement of occupational therapists, social workers and specialists in palliative care in this situation is important. Akinola Alexander Dept of Clinical Pharmacy and Biopharmay