Week 10: Treatment of Neurological Disorders Flashcards
Define and classify seizures
Seizures may result as a consequence of a medical condition affecting the brain (secondary – about 1/3), or as an inherent tendency of an individual towards seizures (primary-about 2/3). It is always important to consider secondary causes of convulsions when assessing patients presenting with fits. A useful clinical classification of fits divides them into 2 main categories:
- Partial Seizures: here, the discharges begin in a localised area of the brain. Thus, the symptoms reflect the area affected, but might include abnormal sensations or thoughts, a change in behaviour, or an involuntary motor action.
- Generalised Seizures: the whole brain is affected, including the reticular system, and there is immediate loss of consciousness. These are further divided into the tonic-clonic seizure and the absence seizure. Tonic clonic seizures are described below and are the most dramatic.
A seizure may have no antecedent (especially in primary epilepsy) but many conditions are associated with either a fit in a person who does not have epilepsy, or the lowering of the fit threshold in those that do.
Relevant conditions to consider when appropriate include:
Head injury (traumatic or "chemical" Drugs and alcohol Hypoglycaemia Infections (especially CNS but elsewhere too), particularly in children CVA / subarachnoid haemorrhage etc Metabolic disturbances Poor compliance with AED therapy
Uncontrolled epilepsy is not a benign condition. Whilst individuals with rare fits can lead essentially normal lives, those with severe disease can have significant morbidity and mortality. Some of these are a result of:
Status epilepticus in particular is a life and brain threatening emergency
Physical injury through a seizure (fall, accident etc)
SUDEP – sudden death in epilepsy
Significant adverse reactions to medication
Association with higher risk of serious psychiatric disease
Association of cognitive impairment (in those with serious seizures)
Stigma associated with epilepsy
The mechanisms of action of the AEDs are described by the known pharmacology associated with what targets?.
Enhancement of GABAA Action (benzodiazepines, phenobarbitone but ironically not gabapentin!)
Inhibition of sodium channel function (phenytoin, valproate, carbamazepine, lamotrigine)
Inhibition of calcium channel function (ethosuximide, gabapentin) Inhibition of glutamate release or function
List some common anti epileptic drugs.
- Carbamazepine
- Valproate Sodium
- Benzodiazepines
- Phenytoin
- Lamotrigine (increasingly first line nowadays)
for prescription of AED very basic rule of thumb would be to consider:
valproate sodium as first line therapy for primary generalized seizures,
carbamazepine for partial seizures (or generalized seizures).
lamotrigine can be used in either circumstances, and is probably the
drug of choice for women of childbearing age.
benzodiazepines and phenytoin are first line therapies for acute life
threatening status epilepticus. Phenytoin has non-linear kinetics and so can reach therapeutic (and toxic) levels rapidly.
AEDs and pregnancy
There is considerable difficulty in the management of women of child- bearing age and potential who also have epilepsy requiring pharmacological therapy. There are several points to consider regarding treatment:
The risk of seizures to mother and foetus if treatment is stopped. Careful history taking is required to ascertain the frequency and severity of seizures in the individual patient. Those with extremely rare and mild seizures might tolerate being off treatment during gestation quite well. Those with frequent fits run the risk of status epilepticus and harm to both themselves and the baby if treatment is stopped.
Certain anti-epileptics drugs have been associated with congenital malformations. The risk of foetal abnormalities in a normal pregnancy is about 2%. Valproate has been associated with about a 9% risk of foetal abnormalities, including neural tube defects, and possible learning difficulties later in life. Other monotherapy is associated with a doubling of the baseline risk of malformation.
what is status epileptics?
Status epilepticus is a prolonged seizure of any type. The most common and dramatic is convulsive status epilepticus, although non-convulsive status epilepticus also occurs. It is defined as either a single convulsion lasting > 30 minutes or convulsions occurring back to back with no recovery between them.
However, any convulsion lasting longer than 5 minutes or two convulsions without full recovery of consciousness in between should receive emergency treatment.
Uncontrolled convulsions can lead to hypoxia and irreversible brain damage or death
Outline emergency treatment protocol for seizures.
Priorities include airway protection, the delivery of supplemental oxygen, identification of the cause and its reversal, and the termination of the seizure as quickly as possible. Investigations should include a bedside glucose, a lab urea & electrolytes (U&Es) and calcium, blood gases and further tests (perhaps later) to ascertain underlying cause (e.g. CT/MRI head – especially in trauma or focal fits).
Treatment of the seizures is vital. First line treatment includes benzodiazepines (e.g. lorazepam) and then IV phenytoin. Phenytoin is not widely used for long term control but because of its zero order kinetics, a therapeutic level can be reached quickly. It is however, toxic and has a narrow therapeutic index. If these measures are failing, or if the patient’s airway is compromised, ITU referral and paralysis and intubation will be required.
Define Parkinsons disease
Parkinson’s disease (PD) is a neurodegenerative disorder that has a progressive clinical course. It is characterised by motor and non-motor symptoms. The motor symptoms include; tremors, rigidity, bradykinesia and postural instability. These relate to low dopamine levels through loss of dopaminergic neurones and disturbances to other neurotransmitter levels.
How does Levodopa exert its effect?
Levodopa (L-DOPA) is a precursor to dopamine. It is used as it is able to cross the blood brain barrier, whereas dopamine cannot. L-DOPA has a half-life of 2 hours and thus requires a short dose interval. It is estimated that less than 1% enters the CNS. L-DOPA must then be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine. However with fewer remaining cells it is less reliable and prone to motor fluctuations.
To date dopamine receptor agonists while being direct acting have a lower efficacy than L-DOPA, but do exhibit less motor complications.
In contrast both MAOI type B inhibitors and COMT inhibitors act by prolonging the presence of dopamine by blocking its metabolism,
What causes Epilepsy?
Increase in Cerebral Neurone Excitability either by : - • Increased Excitation • Decreased Inhibition • Loss of Homeostatic Control • Spread of Neuronal Hyperactivity
Epilepsy : Classification TWO main types
- FOCAL seizures –(previously named PARTIAL) affect one (unilateral) hemisphere
- GENERALISED seizures – affect both (bilateral) hemispheres
what are they types of Focal seizures and mechanism?
- Simple focal - but remaining conscious
- Complex focal with impaired consciousness
- Focal with progression to generalised seizure
Mechanism
• Increased discharges in a focal cortical area e. g frontal, temporal, occipital lobes
symptoms of Focal (Partial) seizures
Symptoms reflect area affected • Involuntary motor disturbance • Behavioural change • Impending focal spread accompanied by ‘Aura’ eg unusual smell or taste, déjà vu / jamais vu, e.g. Temporal lobe • May become secondarily generalised
describe the mechanism of Generalised Seizures
- Generated centrally and spread through both hemispheres with loss of consciousness via ↓Reticular Arousal Centre
- Tonic-clonic seizures (“GRAND MAL”) 60%
- Absence seizures (“PETIT MAL”) 5%
- Many other types recognised e.g. Tonic, atonic, myoclonic
“GRAND MAL” Sequence (tonic-clonic convulsions)
- Aura - few seconds – strange smell or feeling
- Tonic Phase –10 to 30 secs ; unconscious, fall down, tonic muscle contraction with arms flexed, legs extended, respiratory spasm, cyanosis
- Clonic Phase - 1-5 minutes -violent jerking of face and limbs, tongue biting, mouth foaming, incontinence and potential for injury
- Post-ictal Phase – minutes to hours: flaccid limbs, deep coma, headache , confusion, slow reawakening
“PETIT MAL” Sequence (Absence Seizures)
- Often short duration (seconds)
- Normal activity ceases with blank stare, failure to respond, maybe eyes rolling, followed by rapid return to normal state
- Often brief and not noticed by others
- More common in children and adolescents
what is Status Epilepticus?
• Most seizures are short lived ( up to 5 mins)
• But some are prolonged or repeated frequently
without recovery interval
• Referred to as Status Epilepticus
• Treat as a Medical Emergency
• Untreated Status Epilepticus can lead to brain damage (by hypoxic encephalopathy)
or death (SUDEP)
Dangers of Severe Epilepsy
Uncontrolled epilepsy is not a benign condition • Physical injury relating to fall /crash
• Hypoxia – respiratory muscles in spasm
• SUDEP – sudden death in epilepsy
• Varying degrees of brain dysfunction/damage • Cognitive impairment
• Serious psychiatric disease
• Significant adverse reactions to medication
• Stigma / Loss of livelihood / life changing event
Epilepsy : Aetiology
Primary
• No identifiable cause (as yet) – “idiopathic”(70%) • Channelopathies (ion channel mutations) Secondary
• Medical conditions affecting brain ( 30%)
Vascular disease
Tumours
In elderly (60+) secondary metastases responsible for 60% seizures – important diagnostically
Epilepsy: Seizure Triggers
Sensory stimuli:
• eg flashing lights/strobes / other periodic sensory stimuli Brain Disease/ Trauma:
• Brain Injury
• Stroke / Haemorrhage
• Drugs/Alcohol
• Structural abnormality/Lesion
Metabolic disturbances
• Hypo– glycaemia /calcaemia / natraemia Infections
• Febrile convulsions in infants Therapeutics
• Some drugs can lower fit threshold
• AEDs + Polypharmacy: PKs may lower levels
Therapeutic Targets for AEDs
- Voltage Gated Sodium Channel Blockers
* Enhancing GABA Mediated Inhibition
Mechanism of VGSC Blockers
- Local loss of membrane potential homeostasis starts at focal point
- Relatively small number of neurones form generator site
- Neurones heavily depolarise
- Hyperactivity spreads via synaptic transmission to other neurones
VGSC Blockers reduce probability of high abnormal spiking activity
• With VGSC Blocker – gets access to binding site only during depolarisation - hence voltage dependent!
• Prolongs inactivation state – firing rate back to normal
VGSC blockers: Carbamazepine, Pharmacology and pharmacokinetics
Pharmacology:
• Carbamazepine prolongs VGSC inactivation state Pharmacokinetics:
• Well absorbed 75% protein bound – Linear PK
• Initial t1/2 = 30 hrs but strong inducer of CYP450 (3A4). • Affects its own Phase 1 metabolism
• Repeated use t1/2 = 15 hrs.
ADRs
VGSC blockers: Carbamazepine, ADRs and DDI
ADRS
• Wide ranging Type As: CNS - dizziness drowsy ataxia motor disturbance numbness tingling
• GI - upset vomiting
• CV – can cause variation in BP
• Contraindicated with AV conduction problems
• Others: Rashes Hyponatraemia
• Rarely: Severe bone marrow depression – neutropenia
DDIs
• Because CYP450 inducer can affect many other drugs
• Phenytoin (AED) ↓ + PK binding - CBZ plasma conc. ↑ • Warfarin ↓
• Systemic Corticosteroids ↓
• Oral contraceptives ↓
• Antidepressants - SSRIs MAOIs TCAs & TCA • interfere with action of Carbamazepine
Epilepsy types treated with Carbamazepine and Phenytoin
- Generalised Tonic - Clonic
- Partial - All
- Not Absence Seizures
VGSC blockers: Phenytoin Pharmacology and pharmacokinetics
Pharmacology:
• Phenytoin prolongs VGSC inactivation state
Pharmacokinetics:
• Well absorbed – but 90% bound in plasma competitive binding can increases levels (see DDIs)
• Also CYP450 inducer (CYP3A4 - not CYP2C9 & CYP2C19 which metabolise Phenytoin)
• Sub-therapeutic concs linear PK but NON-LINEAR PK at therapeutic concns - very variable t1/2 = 6-24 hrs
VGSC blockers: Phenytoin ADRs and DDIs
ADRs
Very wide ranging Type A’s: CNS – dizziness ataxia headache nystagmus nervousness
• Gingival Hyperplasia (20%) • Rashes - Hypersensitivity
• + Stevens Johnson (2-5%) DDIs
• Competitive binding eg with Valproate (AED) NSAIDs/salicylate increases plasma levels- exacerbates Non-Linear PKs
• Very wide range of interactions including
• Oral Contraceptives ↓
• Cimetidine - Phenytoin ↑
VGSC blockers: Lamotrigine Pharmacology and pharmacokinetics
Pharmacology:
• Lamotrigine (LTG) prolongs VGSC inactivation state • Ca2+ channel blocker & Glutamate release ↓? Pharmacokinetics:
• Well absorbed – Linear PK t1/2 = 24 hrs (Phase II)
• No CYP450 induction → fewer DDIs
VGSC blockers: Lamotrigine ADRs and DDIs
ADRs
• Less marked CNS Dizziness ataxia somnolence
• Nausea. Still some mild (10%) and serious (0.5%) • skin rashes
DDIs
• Adjunct therapy with other AEDs.
• Oral Contraceptives reduce LTG plasma level
• Valproate ↑ LTG in plasma (competitive binding)
Epilepsy types treated with LTG
- Partial Seizures
- Generalised - Tonic-clonic and Absence Seizures and other subtypes
- LTG increasingly first line AED for Epilepsy
- Not first line paediatric use as ADRs ↑
- Appears safer in pregnancy ?
Enhancing GABA Mediated Inhibition - list the pharmacological targets
• Major role in post synaptic inhibition – 40% synapses in brain are GABA-ergic
• GABA↑ is natural anticonvulsant or excitatory ‘brake’ Distinct pharmacological targets I
Binding with GABAA receptor
• Direct GABA agonists
• Benzodiazepine Site – Enhance GABA action • Barbiturate Site – Enhance GABA action
General Mechanism
GABA Mediated Inhibition Enhancement
- Increased Chloride current into neurone - increases threshold for action potential generation
- Reduces likelihood of epileptic neuronal hyperactivity • Makes membrane Potential more negative
Enhancing GABA Mediated Inhibition Benzodiazepines
Pharmacology and pharmacokinetics
Pharmacology:
• Benzodiazepines (BZDs) act at distinct receptor site on GABA Chloride channel (see earlier slide)
• Binding of GABA or BZD enhance each others binding
• Act as positive allosteric effectors
• Increases Chloride current into neurone – increases threshold for action potential generation
Pharmacokinetics:
• Well absorbed 90-100% highly plasma bound 85-100% • Linear PK t1/2 vary 15-45 hrs
ADRs
Enhancing GABA Mediated Inhibition Benzodiazepines
ADRs and DDIs
ADRs • Sedation • Tolerance with chronic use • Confusion impaired co-ordination • Aggression • Dependence/Withdrawal with chronic use • Abrupt withdrawal seizure trigger • Respiratory and CNS Depression DDIs • Some adjunctive use • Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia.
Epilepsy types treated with BZDs
- Side effects limit first line use
- Lorazepam / Diazepam - for Status Epilepticus
- Clonazepam - for Absence seizures - short term use
Enhancing GABA Mediated Inhibition Valproate
Pharmacology and pharmacokinetics
Pharmacology:
• Evidence in vitro for mixed sites of action - pleiotropic
• Weak Inhibition of GABA inactivation enzymes - GABA ↑ • Weak Stimulus of GABA synthesising enzymes - GABA ↑ • VGSC blocker + Weak Ca2+ channel blocker - Discharge ↓ Pharmacokinetics:
• Absorbed 100% - then 90% plasma bound
• Linear PK t1/2 = 15 h
Enhancing GABA Mediated Inhibition Valproate ADRs and DDIs
ADRs
• Generally less severe than with other AEDs
• But teratogenic causing increased no. of birth defects • CNS sedation ataxia tremor - weight gain
• Hepatic function Transaminases ↑ in 40% patients
• Rarely - hepatic failure
DDIs
• Adjunct therapy with other AEDs –
• Care needed with adjunct therapy. Both Valproate and adjunct PKs affected
• Antidepressants - SSRIs MAOIs TCAs & TCA inhibit action of Valproate
• Antipsychotics - antagonise Valproate by lowering convulsive threshold.
• Aspirin - competitive binding in plasma.
Epilepsy types treated with Valproate
- Partial Seizures
* Generalised : Tonic-Clonic + Absence Seizures
AEDs and Pregnancy
• Balance of Risk between :-
potential for seizures damaging to mother and foetus versus potential risk of drug teratogenicity
• How to Manage ?
• Mild disease – consider stopping treatment -? • Severe disease or Status Epilepticus
– in most cases preferable to continue treatment
Failure of Contraception with AEDs
Failure rate x 4 with Carbamazepine/Phenytoin
Dangers to foetus during Pregnancy
- Congenital malformations
- Valproate - neural tube defects – spina bifida, craniofacial and digital abnormalities
- Learning difficulties / mild neurological dysfunction AED risk of birth defects 8% vs 2% normally
How to manage epilepsy in pregnancy?
• With multiple AEDs Teratogenic Risk ↑
• Use single AED agent if possible at lowest dose
• Valproate best avoided - neural tube defects ↑
• Lamotrigine may be safest - birth defect rate 2 %
AEDs and Dietary supplements
• Folate supplement - reduce risk of neural tube defects
• AEDs associated with Vitamin K deficiency in new born → coagulopathy and cerebral haemorrhage
• Vitamin K supplement 10 mg/day in last trimester.
Status Epilepticus- Drugs
Benzodiazepines
• IV Lorazepam (0.1 mg/kg) preferred – longer half life
• IV Diazepam (0.2 mg/kg) or Rectal Diazepam 10mg suppository • Buccal Midazolam 5-10 mg (Epistatus)
Phenytoin
• Zero order kinetics – (15-20 mg/kg)
• Rapidly reaches therapeutic levels IV
• Cardiac monitoring – arrhythmias + hypotension
Other drugs
• Midazolam Thiopentone Propofol
AEDs - Basic Prescribing Rules
- Drug choice tailored to each individual patient
- Preferably use ONE Drug and review
- But 2nd Drug often required
- Side effects are common
- Management by Team of Consultant Neurologist, Epilepsy Nurse and GP for best results
- Plasma levels monitoring may be required
AEDs – Which Drug to Use ?
- Decision normally by Consultant Neurologist
- Choose from range of 40 or more
- Guidelines constantly in flux
- NICE CG137: Epilepsies: diagnosis and management
AEDs : Simple rules for drug choice
- Valproate for Generalised and Absence seizures
- Lamotrigine in pregnancy
- Carbamazepine for Focal seizures e.g Temporal Lobe
- Lorazepam for Status Epilepticus + start Phenytoin
Clinical Features of Parkinsonism
- Tremor*
- Rigidity*
- Bradykinesia**
- Postural instability
Non motor manifestations PD
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorder
- Sweating
Diagnosis of IPD
• Clinical Features o Exclude other causes of Parkinsonism o Drug Induced Parkinsonism o Vascular Parkinsonism o Progressive Supranuclear Palsy o Multiple Systems Atrophy o Corticobasal Degeneration • Response to Treatment • Structural neuro imaging is normal • Functional neuro imaging - SPECT, PET
Pathology of IPD
• Neurodegeneration • Lewy bodies o synucleinopathy • Loss of pigment o 50% loss->symptoms o Increased turnover o Upregulate receptors • Reduced dopamine
Treatment of Parkinson’s Disease for movement disorder
• Levodopa (L-DOPA)
Levodopa must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine. Fewer remaining cells - less reliable effect of levodopa- motor fluctuations
Drug Classes in IPD
- Levodopa (L-DOPA)
- Dopamine receptor agonists • MAOI type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Levodopa (L-DOPA) (Pharmacokinetics)
• Oral administration
• Absorbed by active transport
o In competition with amino acids (NB high protein meals)
• 90% inactivated in intestinal wall
o monoamine oxidase & DOPA decarboxylase
• T1/2 2 hours
o short dose interval
o fluctuations in blood levels and symptoms
o (physiologically dopamine is produced tonically)
• 9% converted to dopamine in peripheral tissues o DOPA decarboxylase
• <1% enters CNS
o Again competes with amino acids for active transport across blood brain barrier
Formulations of L-DOPA
L-DOPA is used in combination with a peripheral DOPA decarboxylase inhibitor : • Co-careldopa Sinemet • Co-beneldopa Madopar • Reduced dose required • Reduced side effects • Increased L-DOPA reaching brain
L-DOPA Advantages
• Highly efficacious • Low side effects o Nausea/ anorexia • Vomiting centres o Hypotension • central and peripheral o Psychosis • Schizophrenia-like effects. Hallucination/delusion/ paranoia o Tachycardia
L-DOPA Disadvantages
• Precursor oneeds enzyme Conversion • Long term oLoss of efficacy (Only effective in presence of dopaminergic neurones) oInvoluntary movements oMotor Complications • On/off • Wearing off • Dyskinesias • Dystonia • Freezing
Interactions of L-DOPA
• Pyridoxine (vitamin B6) increases peripheral breakdown of L- DOPA
• MAOIs risk hypertensive crisis
o (not MOABIs at normal dose-lose specificity at high dose)
• Many antipsychotic drugs block dopamine receptors and parkinsonism is a side effect (newer, ‘atypical’ antipsychotics less so)
clases of Dopamine Receptor Agonists
Ergot derived Bromocryptine Pergolide Cabergoline Non Ergot Ropinirole Pramipexole Patch Rotigotine Subcutaneous Apomorphine
Dopamine Receptor Agonists Advantages
- Direct acting
- Less dyskinesias/ motor complications
- Possible Neuroprotection
Dopamine Receptor Agonists Disadvantages
- Less efficacy than L-DOPA • Impulse control disorders
- More psychiatric s/e o Dose limiting
- Expensive
Impulse Control Disorders
also called Dopamine Dysregulation Syndrome
- Pathological Gambling
- Hypersexuality
- Compulsive Shopping
- Desire to increase dosage • Punding
Dopamine Receptor Agonists -side effects
- Sedation
- Hallucinations • Confusion
- Nausea
- Hypotension
Monoamine oxidase B Inhibitors mechanism of action
• Monoamine oxidase B
o Metabolises dopamine
o Predominates in dopamine containing regions in brain o MAOB inhibitors enhance dopamine
o Prolong action of L-DOPA
o Smooths out motor response o May be neuroprotective
Catechol-O-methyl Transferase (COMT) Inhibitors mechanism of action
• Catechol-O-methyl Transferase (COMT) Inhibitors
o Entacapone – doesn’t cross BBB
o Tolcapone – crosses BBB but main effect peripheral » Monitor liver function
o Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa » 3-O-methyldopa competes with L-DOPA active transport into CNS
o No therapeutic effect alone
» Can use combination tablets COMT inhibitor and L-DOPA and peripheral dopa
decarboxylase inhibitor - Stalevo
o Have L-DOPA ‘sparing’ effect
o Prolongs motor response to L-DOPA » Reduces symptoms of ‘wearing off’
Anticholinergics mechanism of action and examples
• Acetyl Choline may have antagonistic effects to dopamine o Trihexyphenidydyl o Orphenadrine o Procyclidine o Minor role in treatment of PD
Anticholinergics advantages
- Treat tremor
* Not acting via dopamine systems
Anticholinergics disadvantages
• No effect on bradykinesia • Side effects o Confusion o Drowsiness o Usual anticholinergic s/e
Myasthenia Gravis definition
• Fluctuating, fatiguable, weakness skeletal muscle o Extraocular muscles – commonest presentation
o Bulbar involvement – dysphagia, dysphonia, dysarthria o Limb weakness – proximal symmetric
o Respiratory muscle involvement
Drug affecting neuromuscular transmission exacerbate Myasthenia Gravis
- Aminoglycosides
- Beta-blockers, CCBs, quinidine, procainamide • Chloroquine, penicillamine
- Succinylcholine
- Magnesium
- ACE inhibitors
Complications of myasthenia gravis
• Acute exacerbation o Myasthenic crisis
• Overtreatment
o Cholinergic crisis
Therapeutic management of myasthenia gravis
• Acetylcholinesterase inhibitors • Corticosteroids o Decrease immune response • Steroid sparing o Azathioprine • IV immunoglobulin oAcute decline or crisis – 60% will respond after 7-10 days • Plasmapheresis o Removes AChR antibodies and short-term improvement
How do Acetylcholinesterase inhibitors act to treat myasthenia gravis? give examples
• Acetylcholinesterase inhibitors
o Enhance neuromuscular transmission
o Skeletal and smooth muscle
o Excess dose can cause depolarising block – cholinergic crisis o Cholinergic side effects
• Pyridostigmine - oral
• Neostigmine – oral and IV preparations (ITU) o Quicker action, duration up to 4 hours
o Significant cholinergic side effects
A 24-year-old man presents with recent onset of funny turns. He experiences a warning aura consisting of a smell of burning rubber and a sensation of butterflies rising out of his stomach. He then becomes unresponsive for several minutes during which he plucks idly at his clothing and makes smacking movements of his lips. As a child he suffered several prolonged convulsions during febrile illnesses.
1. What type of seizure is this likely to be?
- What type of epilepsy does he have?
Partial seizure, complex
Temporal lobe epilepsy
A 24-year-old man presents with recent onset of funny turns. He experiences a warning aura consisting of a smell of burning rubber and a sensation of butterflies rising out of his stomach. He then becomes unresponsive for several minutes during which he plucks idly at his clothing and makes smacking movements of his lips. As a child he suffered several prolonged convulsions during febrile illnesses.
What investigations are indicated and what might they show?
Bloods and cultures – electrolyte imbalance, inflammatory markers, raised WBC
Head CT – bleeding, space occupying lesion
Follow up EEG
Partial seizure, complex. Temporal lobe epilepsy. What drugs might be effective?
If initial therapy fails to stop his seizures, what might you do next?
If the seizures prove totally intractable what other options exist?
Lamotrigine Carbamazepine
Lamotrigine/carbamazepine - increase to maximum safe dosage
Add second line: benzodiazepine
Vagal stimulator
An 18-year-old woman presents after suffering a generalised tonic-clonic seizure shortly after getting out of bed. CT and EEG are normal. She then has a further seizure whilst on the ward witnessed by yourself. This does not appear to be self-terminating.
What immediate action will you take?
The fits continue despite this. Outline the next steps you might take.
ABC
Call for help
Rectal diazepam/IV lorazepam
Repeat Lorazepam after 5mins
After further 5 mins – give phenytoin IV
An 18-year-old woman presents after suffering a generalised tonic-clonic seizure shortly after getting out of bed. CT and EEG are normal. She then has a further seizure whilst on the ward witnessed by yourself. This does not appear to be self-terminating.. she is treated with Rectal diazepam/IV lorazepam. Repeat Lorazepam after 5mins
After further 5 mins – give phenytoin IV. She settles down and seems to make a full recovery. After this attack, she reluctantly agrees that drug therapy is warranted.
3. Which drugs would you consider and why? Outline their major side effects.
Carbamazepine – dizziness, blood dyscrasia, Hyponatraemia, blurred vision Sodium valproate – Nausea, gastric irritation, weight gain, thrombocytopaenia, transient hair loss
Lamotrigine – Nausea, diplopia, SJSyndrome
seizures. She asks about the risk of recurrence. What can you tell her?
Anticonvulsants reduce the risk of her having another seizure but don’t eliminate it. A trial of 397 first seizure patients showed recurrence of 39% of untreated and 18% in treated patients.
Recurrence fairly likely but risk reduced by compliance, by regular review and by avoiding trigger situations (e g flashing lights)
A 24-year old women with primary generalized epilepsy since childhood, maintained on valproate for 12 years comes to clinic for review. She tells you she is still having 2-3 fits per week on average. She has recently married, and wants to come off the oral contraceptive and start a family.
1. What factors do you need to consider in this lady?
Seizures need to be under control – optimize treatment Side effects of drugs
Folic acid – to prevent neural tube defects
Consultant led care
What are the particular problems with epilepsy around the time of labour?
Deliver in consultant led unit as risk of seizure in labour
A 57 year old lorry driver presents with a 6 month history of slowness of gait and difficulty with writing. Fine hand movements are poor. In the past he has seen a urologist with urgency of micturition and occasional incontinence. He is taking sildenafil and an inhaler for asthma.
On examination there is slowness of gait, facial hypomimia and cogwheel rigidity in all 4 limbs. Bradykinesia of hand movement is present. There is no tremor.
1. He is clearly Parkinsonian. Is there anything to suggest that this might not be idiopathic Parkinson’s disease?
Fairly young male, typical age of onset of multiple system atrophy (MSA) is 50-60s, slightly younger than idiopathic PD. Started with a history of bladder control symptoms and he is taking sildenafil (often first sign of MSA in men is erectile dysfunction)
NICE guidelines recommend: The diagnosis of PD should be reviewed regularly and reconsidered if atypical clinical features develop.
A 57 year old lorry driver presents with a 6 month history of slowness of gait and difficulty with writing. Fine hand movements are poor. In the past he has seen a urologist with urgency of micturition and occasional incontinence. He is taking sildenafil and an inhaler for asthma.
On examination there is slowness of gait, facial hypomimia and cogwheel rigidity in all 4 limbs. Bradykinesia of hand movement is present. There is no tremor. What treatment should he receive?
NICE CG35 recommends
“It is not possible to identify a universal first-choice drug therapy for people with early PD. The choice of drug first prescribed should take into account:
clinical and lifestyle characteristics
patient preference, after the patient has been informed of the short-
and long-term benefits and drawbacks of the drug classes.
Levodopa may be used as a symptomatic treatment for people with early
PD.
The dose of levodopa should be kept as low as possible to maintain good function in order to reduce the development of motor complications. Dopamine agonists may be used as a symptomatic treatment for people with early PD.
A dopamine agonist should be titrated to a clinically efficacious dose. If side effects prevent this, another agonist or a drug from another class should be used in its place.”
Can use MAOB inhibitors
A 57 year old lorry driver presents with a 6 month history of slowness of gait and difficulty with writing. Fine hand movements are poor. In the past he has seen a urologist with urgency of micturition and occasional incontinence. He is taking sildenafil and an inhaler for asthma.
On examination there is slowness of gait, facial hypomimia and cogwheel rigidity in all 4 limbs. Bradykinesia of hand movement is present. There is no tremor.
He is started on co careldopa but, when seen 4 months later, is not significantly improved. The dosage is therefore increased. 3 months later he is still no better.
3. What does this suggest?
Six months further on he complains of feeling light headed when he stands up. His BP is 140/80 lying and 70/40 on standing. His neurological status is no better.
5. What is the likely diagnosis?
Co-Careldopa is a mixture of carbidopa and levodopa; the proportions are expressed in the form x/y where x and y are the strengths in milligrams of carbidopa and levodopa respectively
Not responsive to dopamine agonists
Suggests this is not simple Parkinson’s but also autonomic dysfunction
Seems likely diagnosis is MSA Multiple System Atrophy (previously known as Shy Drager Syndrome)
MSA is typically unresponsive to dopamine agonists so suggests as first suspected MSA
Orthostatic hypotension >30mmHg, this is severe. MSA affecting brainstem causing autonomic dysfunction
what is the prognosis of MSA?
Patients with MSA have a poor prognosis. The disease progresses rapidly. Median survivals of 6.2-9.5 years from the onset of first symptoms. Bronchopneumonia and sudden death are common terminal conditions in MSA. Urinary dysfunction often leads to lower urinary tract infections and related complications.
Entacapone is a COMT inhibitor. How might it help patients with PD?
Used in combination with levodopa it blocks enzyme that breaks down levodopa thus prolongs its effect
What is the role of carbidopa – a peripheral decarboxylase inhibitor? How might it help patients with PD?
arbidopa inhibits aromatic-L-amino-acid decarboxylase (DOPA Decarboxylase or DDC) I.e. Inhibits peripheral breakdown of levodopa to dopamine. Levodopa can cross blood brain barrier whereas dopamine cannot. Carbidopa has no effect on central (brain) conversion thus more levodopa reaches brain to be converted to dopamine
Why are non-ergot dopamine receptor agonists such as ropinirole preferred to the older ergot preparations such as pergolide?
Ergot-derived dopamine agonists are prone to cause fibrosis reactions affecting cardiac valves, lung and retroperitoneal tissues, so now used infrequently.
If an ergot-derived dopamine agonist is used, the patient should have a minimum of renal function tests, erythrocyte sedimentation rate (ESR) and chest radiograph performed before starting treatment, and annually thereafter.
In view of the monitoring required with ergot-derived dopamine agonists, a non-ergot- derived agonist should be preferred in most cases.
What are the main side effects of DA receptor agonists?
When used alone, dopamine-receptor agonists cause fewer motor complications in long-term treatment compared with levodopa treatment but the overall motor performance improves slightly less. The dopamine- receptor agonists are associated with more psychiatric side-effects than levodopa.
Common side effects include:
nausea and vomiting
constipation
headaches
drowsiness and sudden ‘attacks’ of sleepiness
dizziness or fainting due to low blood pressure
Hallucinations or delusions and confusion
Existing dyskinesia worsening
What is meant by on/off fluctuations in patients who are taking levodopa preparations?
The “on-off” phenomenon in Parkinson’s disease (PD) refers to a switch between mobility and immobility in levodopa-treated patients, which occurs as an end-of-dose or “wearing off” worsening of motor function or, much less commonly, as sudden and unpredictable fluctuations
Wearing off of the effects of levodopa and peak dose dyskinesia is largely caused by pulsatile stimulation of dopamine receptors, which is related to the intermittent administration of exogenous immediate-release levodopa. One potential way to overcome this is to prolong the effect of each dose of levodopa by administering controlled or modified-release levodopa preparations. Such preparations of co-careldopa (Sinemet CR®) and co- beneldopa (Madopar HBS/CR®) have been developed.
What limits the dosage of levodopa in patients with advanced PD?
Dyskinesias
