and Gunhild Waldemar1
Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Not long ago, neurologists had hardly anything else to offer patients than a diagnosis and words of comfort. Indeed, the discrepancy between the elegance and precision of the clinical neurological diagnosis on one hand and the heartbreaking lack of any substantial therapeutic opportunities on the other was painfully clear to everyone. Fortunately, this situation has completely changed. Advances in our understanding of neurological disease due to modern neuroimaging, molecular neuroscience, and genetic testing, as well as more rigorous standards for the conduction of clinical trials, have translated into striking new therapeutic options. Apart from an ever-increasing drug arsenal, these include surgical therapies (e.g., deep brain stimulation for Parkinson’s disease and hemicraniectomy for middle cerebral artery stroke), intravenous thrombolysis and mechanical thrombectomy for ischemic stroke, and a variety of immunomodulatory biological agents. Although many neurological diseases remain incurable, nowadays practically no disorder is untreatable. This chapter provides an overview of available medical and selected nonmedical treatment options in neurological diseases. Due to space limitations, the information is restricted to indications and, where feasible, suggestions for drug dosages. The treatment of cerebrovascular disorders and epilepsy, however, is covered in greater detail since it usually constitutes the largest and most urgent part of the workload for neurology residents on call. Many neurological disorders may have implications for driving and medicolegal issues. Specific rehabilitation programs may improve motor or cognitive functions significantly and are important for improving quality of life and for preventing functional decline. Counseling and regular follow-up should be an integral part of neurological management. Although not covered by this book, the neurologist should therefore be aware of local regulations and programs for medicolegal issues, neurorehabilitation, counseling, as well as primary prevention of neurological disorders and palliative end-of-life care.
KeywordsDeep brain stimulationDrug treatmentEndovascular stroke treatmentHemicraniectomyIntravenous thrombolysisMechanical thrombectomyImmunomodulatory therapy
In this chapter on treatment of neurological diseases, every effort has been made to ensure the accuracy of the information, but medicine is an ever-changing science, and therefore neither the authors nor the publisher can take any responsibility for possible mistakes and their consequences that may arise from the information in this chapter. For data on pharmacokinetics, pharmacodynamics, contraindications, precautions, and side effects, you are strongly urged to consult the usual references. Importantly, keep in mind that the treatment suggestions are, indeed, suggestions only. Despite the rise of evidence-based medicine, therapeutic decisions including the choice of drugs and dosages vary widely from country to country, from hospital to hospital, and from physician to physician. Checking with the national standard drug references, local protocols, and colleagues is always strongly recommended.
6.1 Coma and Acute Encephalopathies
Thiamine 400 mg IV and vitamin B combinations IM (for possible Wernicke’s encephalopathy).
Dextrose 50% solution, 50 mL intravenously (IV) (for possible hypoglycemia, but do not administer glucose to a patient with suspicion of alcohol abuse without prior parenteral thiamine administration).
Naloxone 0.4–2 mg IV may be repeated or given as continuous infusion, e.g., 0.8 mg/kg/h (for possible opiate intoxication, beware of withdrawal delirium and opiate rebound)
Flumazenil 0.3 mg IV may be repeated (max 2–5 mg for possible benzodiazepine intoxication).
High ICP, general measures
Elevation of the head to 30°, avoid lateral neck bending
Normovolemia or mild hypervolemia
Adequate cerebral perfusion pressure (CPP) (e.g., >60 mmHg)1
Normothermia (e.g., acetaminophen 1000 mg every 6 h, surface cooling)
Adequate nutrition and pain management
High ICP, specific measures
Hypertonic saline (3–10%) IV 1–2 mL/kg at 20 mL/min
Mannitol (20%); IV bolus 1 g/kg as needed or 0.5 g/kg every 4–6 h
ICP monitoring devices (ventricular catheter, intraparenchymal probe, epidural transducer)
Pharmacological coma (pentobarbital, thiopental, phenobarbital, propofol)
Corticosteroids with tumors (e.g., dexamethasone 4–10 mg IV every 6 h, oral prednisolone 1 mg/kg once daily)
Surgical decompression (hemicraniectomy with malignant MCA infarction, posterior fossa decompression with cerebellar infarction)
Hypothermia after cardiac arrest
Idiopathic intracranial hypertension
Acetazolamide 500–1000 mg ×2–4 p.o.
Furosemide 40–160 mg/day
Methylprednisolone (second choice due to negative impact on body weight)
Serial lumbar punctures
Ventriculoperitoneal shunt (or rarely, optic nerve sheath fenestration), in case of imminent visual impairment
Idiopathic and symptomatic intracranial hypotension (idiopathic or after lumbar puncture)
Bed rest, fluids, and paracetamol.
Caffeine 500 mg IV may be repeated once.
Surgery if CSF leakage detected and operable.
Lactulose 30–50 mL three times daily
Neomycin (up to) 1 g every 6 h (or metronidazole)
Treat dehydration and electrolyte abnormalities
Stop sedative and other CNS medications
Transjugular intrahepatic portosystemic shunt
Acute hyponatremia: water restriction and saline IV (correction rate not to exceed 10 mM/24 h and 20 mM/48 h, monitor electrolytes every 2 h).
Central pontine myelinolysis: 1000 mL glucose 5% can decrease sodium plasma levels by 5 mmol/L and, only if given acutely, may sometimes reverse symptoms, when iatrogenic correction of hyponatremia has been too fast.
Thiamine 400 mg IV ×3 daily for 3 days and vitamin B combinations IM for 3 days, followed by p.o. substitution
50% dextrose 50 mL IV (in malnourished patients 100 mg thiamine IV prior to glucose)
Glucagon 1 mg SC
Inflammatory encephalopathies (e.g., paraneoplastic and non-paraneoplastic autoimmune encephalitis, Hashimoto’s encephalitis)
Methylprednisolone 1 g/day for 3–5 days IV, then oral prednisolone taper
IVIG 0.4 g/day for 5 days
Plasma exchange (e.g., five to seven times in total, administered every other day)
Treat underlying tumor, if present
Carbon monoxide: hyperbaric oxygen
Cyanide: hyperbaric oxygen, hydroxocobalamin
Organophosphate: atropine, pralidoxime
Heavy metals: dimercaprol, penicillamine
Opioids: naloxone 0.2–0.8 mg IV as needed (beware of short half-life and opioid rebound)
Benzodiazepines: flumazenil 0.2 mg IV as needed (beware of decreased seizure threshold)
Neuroleptic malignant syndrome
Withdraw neuroleptics, admit to ICU
Bromocriptine 2.5 mg p.o. test dose, increase to ×2–4 for 48 h
Dantrolene 25 mg p.o. or IV several times daily
Apomorphine SC with pretreatment with rectal domperidone may be an alternative
Neuroleptic malignant–like syndrome (acute withdrawal of dopaminergic or GABAergic medication)
Reinstitution of dopaminergic (e.g., l-dopa) or GABAergic (e.g., baclofen) medication
Treatment in analogy to neuroleptic malignant syndrome
Withdraw offending drugs, admit to ICU
Cyproheptadine (serotonin antagonist) 8 mg p.o., repeat after 2 h, if effective up to 8 mg every 6 h daily
Minimal conscious state following traumatic or anoxic–ischemic brain injury (arousal and alertness may improve following amantadine treatment)
Amantadine 50 mg twice daily, increase to 100 mg twice daily after 3–7 days.
If necessary, the dose can be increased to 200 mg twice daily.
Migraine (mild pain during attack)
Nonsteroidal anti-inflammatory drugs (NSAID) (e.g., naproxen sodium 750 mg, not exceeding 1250 mg/24 h)
Migraine (moderate pain during attack)
Triptans during early and mild pain following the aura (contraindicated in complicated migraine, heart disease, stroke, uncontrolled hypertension, and/or severe liver disease). There are various triptans, including almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan; they can be administered as:
Nasal spray, e.g., zolmitriptan 2.5 mg or 5 mg; for second dose, wait 2 h, max. 10 mg/24 h
Soluble tablets, e.g., zolmitriptan 2.5 mg or 5 mg; for second dose, wait 2 h, max. 10 mg/24 h
Tablets, e.g., zolmitriptan (see zolmitriptan tablets); sumatriptan 50 or 100 mg, max. 200–300 mg/24 h; and almotriptan 12.5 mg, max. 25 mg/24 h Injection, sumatriptan 6 mg SC; for second dose wait 1 h, max. 12 mg/24 h
Dihydroergotamine 1 mg/mL SC is rarely used as an alternative but is contraindicated in patients with ischemic cardiac disease (metoclopramide 10 mg IM should be given prior to dihydroergotamine to avoid nausea and vomiting).
Orally: prochlorperazine 5–10 mg ×3–4 daily; metoclopramide 10–20 mg ×3 daily
Suppository: metoclopramide 20 mg ×3 daily
Intravenously and intramuscularly: metoclopramide 10 mg ×1–3 daily
Neuroleptics IV or IM, e.g., chlorpromazine 5–50 mg, haloperidol 5–10 mg, and prochlorperazine 5–10 mg
Migraine in pregnancy
Pregnancy: paracetamol and caffeine (<300 mg, after first trimester)
Migraine (preventive treatment)
Beta-blockers, metoprolol 100 mg once or twice daily or 200 mg once daily, and propranolol 20–80 mg once or twice daily
Angiotensin II receptor blockers: candesartan 8–16 mg once daily
Angiotensin-converting enzyme inhibitors: lisinopril 10–20 mg once daily
Antiepileptics: topiramate 25 mg once daily (up to 50 mg twice daily), valproate 300–600 mg ×2–3 daily
Calcium channel blockers: verapamil 120–180 mg twice daily, flunarizine 5–10 mg once daily
TCA: amitriptyline 10–75 mg once daily
Onabotulinum toxin A (for chronic migraine, defined as headaches occurring on 15 or more days each month, at least half of which have migrainous features)
Headache diary, drug withdrawal, and patient education; headaches may get worse for 1–4 weeks during drug withdrawal.
Transitional strategies for relief of withdrawal symptoms: promethazine 25 mg or levomepromazine 12.5–25 mg up to three times daily, in combination with antiemetics (e.g., domperidone 10 mg, metoclopramide 10 mg, or ondansetron suppositories 16 mg); alternatives include prednisolone 100 mg/day for 5 days and naproxen 750 mg once daily.
Non-pharmacological measures (i.e., regulation of lifestyle, including regular meals, sleep and exercise, cessation of smoking and excessive alcohol consumption, limited caffeine consumption, and relaxation techniques).
Comorbid depression and anxiety must be treated.
Start preventive treatment, if needed.
Close follow-up for 8–12 weeks.
Most patients with medication-overuse headache can be managed on an outpatient basis, but those with significant psychological conditions, abuse of opioids or barbiturates, or earlier treatment failures may benefit from hospital admission and a multidisciplinary approach, including physiotherapy and psychological treatment.
Tension headache, acute treatment (medication should not be taken more than 2–3 times/week in order to avoid medication-overuse headache)
Aspirin 500–1000 mg
Paracetamol 1000 mg
Ibuprofen 200–400 mg
Tension headache, chronic treatment
Amitriptyline 25–75 mg/day (or imipramine 25–75 mg, less sedating) plus paracetamol
Cluster headache, acute treatment
Inhalation of pure oxygen (e.g., 7–10 L/min for 10–15 min)
Sumatriptan 6 mg SC, 20 mg intranasal, zolmitriptan 5 mg intranasal
Cluster headache, transitional treatment
Prednisolone 60 mg/day p.o. for 3–5 days, taper by 10 mg every 3 days
Ergotamine 1–2 mg, p.o. or as a suppository once or twice daily
Methylprednisolone (120 mg) with lidocaine injected into the greater occipital nerve ipsilateral to the site of attack
Avoidance of triggering factors, e.g., alcohol, daytime naps, and nitroglycerin
Cluster headache, maintenance treatment
Verapamil (sustained release), start dose 120 mg twice daily, may be increased by 120 mg/week to 480 mg/day (or more).
Lithium 600–900 mg (requires monitoring of serum levels, usually 0.4–0.8 mEq/L).
Verapamil and lithium (300–600 mg daily) may be combined.
Methysergide, corticosteroids, topiramate, and melatonin can be tried alternatively.
Surgery (trigeminal nerve, autonomic pathways, hypothalamic DBS).
Paroxysmal hemicrania and hemicrania continua
Indotest (indomethacin 25 mg ×3 daily for 3 days; if necessary, 50 mg ×3 daily for another 3 days).
Maintenance up to 300 mg/day (often indefinite, but long-term remission possible) and 25–50 mg ×4 daily is usually effective.
If indomethacin is not tolerated, preventive therapy as for cluster headache can be tried.
Does not respond to indomethacin
First choice: lamotrigine 100–200 mg/day
Second choice: carbamazepine, topiramate, and gabapentin
Does not usually require treatment but responds to indomethacin
Acute treatment: aspirin
Lithium 300–600 mg/day at bedtime
Indomethacin (25–75 mg at bedtime), flunarizine, caffeine (200 mg at bedtime)
Verapamil (as for cluster headache)
Primary thunderclap headaches
Cough headache: indomethacin 25–50 mg ×2–3 daily
Headache associated with physical exertion/sexual activity (if acute, make sure to rule out subarachnoidal warning leak; if chronic, make sure to rule out arterial hypertension!).
NSAIDs, e.g., indomethacin 25–75 mg 0.5–1 h prior to activity.
Beta-blockers, e.g., propranolol 20–40 mg 0.5–1 h prior to activity or daily for a 3-month period.
With orgasmic headache, a change of sex position is often helpful.
Giant cell arteritis
High-dose intravenous methylprednisolone in case of blindness, otherwise 60 mg/day p.o.; reduce to 20 mg over about 2 months, and thereafter reduce cautiously to 10 mg; mean treatment time 1.5–2 years; polymyalgia rheumatica without temporal arteritis can be treated with 5–10 mg/day.
Trigeminal neuralgia, related conditions, and atypical facial pain
See Sect. 6.11.
6.3 Cognitive Impairment and Dementia
AD, DLB, and PD with dementia, symptomatic treatment with a modest effect on cognitive functions, activities of daily living, and behavioral symptoms.2
Cholinesterase inhibitors (for mild to moderate AD, mixed AD, DLB, and PD with dementia)
Donepezil, tablets; starting dose 5 mg once daily, increase to 10 mg once daily after 4–6 weeks
Capsules: 1.5 mg twice daily, may be increased to 6 mg twice daily (by 3 mg/2–4 weeks)
Patch: 4.6 mg/24 h, after 4 weeks increase to 9.5/24 h
Galantamine, capsules, 8 mg once daily, may be increased to 24 mg once daily (stepwise by 8 mg/4–6 weeks)
Glutamate (NMDA) antagonist (for moderate to severe AD): memantine, tablets, 5 mg once daily, increase to 20 mg once daily (stepwise by 5 mg/week)
A combination of a cholinesterase inhibitor plus memantine may be given in patients with moderate to severe AD.
AD and other dementias, for severe behavioral disturbances and/or psychotic symptoms, where physical causes (e.g., infections) have been excluded or treated and where non-pharmacological interventions were not sufficient:
If indicated and not already initiated: cholinesterase inhibitor and/or glutamate (NMDA) antagonist (as shown above).
Risperidone 0.25 mg–0.5 mg p.o. once daily (before bedtime) may be increased to 1 mg p.o. once daily.
Olanzapine 2.5 mg p.o. once daily may be increased stepwise by 2.5 mg to 5 (−10)mg p.o. once daily.
Quetiapine 25 mg once daily may be increased stepwise by 25 mg, up to 50 mg ×2.
For patients with parkinsonian dementias: clozapine, start with 6.75 mg p.o. once daily, titrate by 6.75 mg every other day to 25 mg p.o. once daily.
There is insufficient evidence for the use of antipsychotics in patients with dementia. When prescribing antipsychotic treatments, always plan for a time-limited, short treatment period with regular review of treatment effect and side effects.
AD and other dementias, for depression, anxiety, stereotypical behavior, and sleep disturbance
For depression in dementia, there is uncertain evidence for the efficacy of antidepressive treatment. A treatment trial of a SSRI, e.g., sertraline 50(−100) mg p.o. once daily (start with 25 mg), citalopram 10–20 mg p.o. once daily (start with 10 mg), or escitalopram 5–10 mg once daily (start with 5 mg) may be tried in patients with moderate to severe depression.
Alternatively, try venlafaxine 37.5 mg p.o. once daily (may be increased to 75 mg once daily) or mirtazapine 15 mg p.o. once daily (may be increased to 30 mg p.o. once daily).
Anxiety: appropriate care, calm environments, and non-pharmacological interventions should be initiated as a first priority. Treatment with benzodiazepines should generally be avoided but may be necessary in cases of severe anxiety for a very short period of time; oxazepam 7.5 mg p.o. once daily, may be increased to 15 mg p.o. ×2–3 daily.
Stereotypical behavior in FTD: uncertain evidence, a SSRI may be tried (see above).
Sleep disturbance and REM sleep behavior disorder: See Sect. 6.5 and treat for a short-time period if necessary.
When possible, avoid psychopharmacological polypharmacia in patients with dementia.
Normal pressure hydrocephalus
Ventriculoperitoneal shunt, as guided by lumbar perfusion test and/or tap test results
Aggressive control of vascular risk factors (see Sect. 6.6).
Cholinesterase inhibitors may be tried in the event of combined AD and vascular lesions.
Dementia associated with PD/DLB
l-dopa and dopaminergic agonists can be tried to improve motor symptoms but may increase hallucinations and confusion.
Cholinesterase inhibitors may be tried (for dosing see above).
Wernicke’s encephalopathy, and Korsakoff’s syndrome.
See Sect. 6.1.
Inflammatory encephalopathies (e.g., paraneoplastic and non-paraneoplastic limbic encephalitis, Hashimoto encephalitis).
See Sect. 6.1.
6.4.1 General Aspects
AED that can be used as initial monotherapy (in alphabetical order, “*” denotes level A evidence as suggested by the “Updated ILAE Evidence Review for Initial Monotherapy”) (Glauser et al. 2013):
Adults with partial–onset seizures: carbamazepine*, gabapentin, lamotrigine, levetiracetam*, oxcarbazepine, phenobarbital, phenytoin*, topiramate, valproate, and zonisamide*
Children with partial–onset seizures: carbamazepine, clobazam, clonazepam, lamotrigine, oxcarbazepine*, phenobarbital, phenytoin, topiramate, valproate, and zonisamide
Adults with generalized onset tonic–clonic seizures: carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate
Children with generalized onset tonic–clonic seizures: carbamazepine, phenobarbital, phenytoin, topiramate, valproate, and oxcarbazepine
Children with absence seizures: ethosuximide*, lamotrigine, and valproate*
JME: clonazepam, lamotrigine (may occasionally worsen myoclonus), levetiracetam, phenobarbital, piracetam, topiramate, and valproate
Infantile spasms: adrenocorticotropic hormone (ACTH), pyridoxine, valproate, and vigabatrin
Benign partial epilepsy syndromes in childhood (e.g., benign partial epilepsy of childhood with centrotemporal spikes (BECTS)): if necessary, valproate and carbamazepine
New AED approved for the use as adjunctive treatment of partial–onset seizures
Eslicarbazepine, lacosamide, retigabine, zonisamide, and rufinamide (Lennox-Gastaut syndrome)
Alcohol withdrawal period
Many different regimens have been proposed for the treatment and prevention of alcohol withdrawal seizures, including carbamazepine (200 mg three times daily for 5 days), clomethiazole (300 mg as needed), and phenobarbital (100 mg as needed). However, a task force group of the European Federation of Neurological Societies (EFNS) concluded in their guidelines on the diagnosis and management of alcohol-related seizures that “benzodiazepines are efficacious and safe for primary and secondary seizure prevention; diazepam or, if available, lorazepam, is recommended. The efficacy of other drugs is insufficiently documented […] Benzodiazepines should be chosen for the treatment and prevention of recurrent alcohol withdrawal seizures” (Bråthen et al. 2005).
Phenobarbital, phenytoin, and valproate
Clonazepam, e.g., 2–3 mg IV or p.o. ×3 daily (however, if the patient is in coma following cardiac arrest and has myoclonic status epilepticus, the prognosis is usually very poor)
Magnesium sulfate 4 g IV and 10 mg IM, then 5 mg every 4 h as required
Decreased effects of oral contraceptive pill with hepatic enzyme inducers (e.g., barbiturates, carbamazepine, oxcarbazepine, phenytoin, primidone).
Some data indicate that topiramate and lamotrigine may also decrease contraceptive efficacy to a certain degree via different mechanisms.
Injectable contraceptives have usually no interactions with AEDs.
Rescue contraception: First dose of the usual rescue pill should be doubled and a second single dose given 12 h later.
Folic acid (5 mg/day) should be provided to all women of childbearing age to decrease the risk of neural tube defects.
Aim for monotherapy!
Generally, valproate is not recommended for fertile women due to its teratogenic effects and evidence that valproate during pregnancy can result in learning disabilities and decreased intelligence of the child.
Contraceptive pills and pregnancy decrease serum levels of lamotrigine. Monitoring serum lamotrigine levels before, during, and after pregnancy (and adjusting the dosage) or initiation of contraception is useful.
Only ethosuximide, lamotrigine, levetiracetam, and phenobarbital are significantly released into breast milk; barbiturates and lamotrigine may lead to sedation of the infant.
As a rule, the steady state is reached after four to five half lives following initiation or change of antiepileptic drug therapy. Monitoring of serum levels can be useful in patients with signs of toxicity or lack of treatment response and if noncompliance is suspected.
Carbamazepine (target level 20–40 μmol/L)
Ethosuximide (300–700 μmol/L)
Lamotrigine (10–60 μmol/L)
Levetiracetam (35–120 μmol/L)
Phenobarbital (60–120 μmol/L)
Phenytoin (40–80 μmol/L or higher in case of status epilepticus)
Valproate (300–700 μmol/L)
Pharmacokinetic drug interactions
Relevant drug interactions with another antiepileptic drug: carbamazepine, ethosuximide, lamotrigine, oxcarbazepine, phenytoin, phenobarbital, topiramate, valproate, and zonisamide
Interactions with non–AED: antibiotics, antidepressives, antifungal drugs, antihypertensive drugs, antipsychotics, cardiovascular drugs, theophylline, and warfarin
No clinically relevant drug interactions: gabapentin, levetiracetam, and pregabalin
6.4.2 Status Epilepticus
Lorazepam 4 mg IV (may be repeated once), diazepam 5–10 mg IV (may be repeated), and clonazepam 1–3 mg IV (may be repeated).3
Fosphenytoin 15–20 mg PE/kg (not exceeding 100 mg PE/min); check serum phenytoin level after 2 h and, if necessary, give more (target level 80–100 μmol/L, do not forget to prescribe maintenance therapy); alternatively, valproate 1000–2000 mg IV, levetiracetam 2000 mg IV, or lacosamide 200–400 mg IV.
General anesthesia (propofol, midazolam, thiopental); aim for burst suppression on EEG monitoring; when seizures have been controlled for 12–24 h, withdraw sedation slowly (over 12 h); if seizures reoccur, another cycle of 12 h general anesthesia should be provided; and so on. Beware of the propofol infusion syndrome.4
6.4.3 Antiepileptic Drugs (AED)
The following AED are listed in alphabetical order:
Start with 100 mg twice daily, then 200 mg twice daily; if necessary, increase with 200 mg/week until seizure control (target 200–400 mg twice daily, max. 800–1200 mg twice daily)
Emergency loading 300–400 mg twice daily
Carbamazepine extended release
The extended-release formulation is preferred for long-term treatment because of more stable serum levels, thereby avoiding “high peak” concentrations.
Initially 100 mg twice daily, then 200 mg twice daily, then increase with 200 mg/week until seizure control (target 400–600 mg twice daily)
Start with 0.5 mg at night, increase by 1–2 mg/week, maintenance 0.5–6 mg/day (occasionally, up to 8 mg daily), divided into two to three doses/day
Gabapentin is the only AED that should be given three times a day because of the short half-life:
First day 300 mg once daily, second day twice daily, and third day three times daily
Increase by 300 mg/day until seizure control (target dose 900–1200 mg, max. 3600 mg)
25 mg once daily during first 2 weeks, followed by 50 mg once daily during the next 2 weeks
Then increase with 50 mg every week or every second week until seizure control (target 50–100 mg twice daily, max. 500 mg/day)
In combination with valproate:
Valproate prolongs lamotrigine clearance by roughly 100%:
25 mg once daily every other day (!) for 2 weeks, followed by 25 mg once daily for next 2 weeks.
Then increase with 25 mg every week or every second week until seizure control (target 50–100 mg twice daily, max. 500 mg/day).
In combination with carbamazepine, phenytoin, phenobarbital, primidone, or other inducing drugs:
50 mg once daily for 2 weeks, followed by 50 mg twice daily for next 2 weeks
Then increase with 100 mg every or every second week until seizure control (target 100–200 mg twice daily, max. 500 mg/day)
250 mg twice daily for 1–2 weeks (or less), then 500 mg twice daily (target dose; if required, faster titration is usually well tolerated)
If necessary, increase with 500 mg every few days until seizure control (max. 3000 mg/day)
In combination with other AEDs:
500 mg twice daily (target level)
If necessary, increase with 1000 mg every few days until seizure control (max. 3000 mg/day)
300 mg twice daily (target dose 600–1200 mg/day)
If necessary, increase with 600 mg every week until seizure control (max. 2400 mg/day)
75 mg twice daily for 1 week
If necessary, increase to 150 mg twice daily
If necessary, increase to 300 mg twice daily after another week (target dose 150–600 mg/day)
25 mg once daily in the evening for 1 week
Then 25 mg twice daily, increase with 25 mg every week
Target dose 50 mg twice daily (max. 500 mg/day)
In combination with other AEDs:
50 mg once daily (evening) for 1 week
Then 50 mg twice daily, increase with 50 mg every or every other week
Target dose 100 mg–200 mg twice daily (max. 1000 mg/day)
Start with 300 mg twice daily
Fast increase possible, maintenance 600–3000 mg/day
Valproate extended release
Extended-release formulation is preferred for long-term treatment because of more stable serum levels:
Initially 600 mg/day–1500 mg/day, e.g., 300 mg twice daily or 500 mg twice daily
Fast increase possible, maintenance 1200–3000 mg/day
Rational polytherapy is the combined use of two or more AEDs with favorable pharmacokinetic interactions and/or different mechanisms, e.g., a sodium channel blocker and a drug with GABAergic properties.
Valproate with lamotrigine for partial-onset and generalized seizures.
Valproate with ethosuximide for absence seizures.
Lamotrigine with topiramate for a range of seizure types.
Levetiracetam, which has a unique mechanism and no known drug interactions, can theoretically be combined with any AED.
6.4.4 Epilepsy and Mood Disorders
Depression and related depressive disorders are highly prevalent in patients with epilepsy. The lifetime incidence of depression among patients with chronic epilepsy is 30%, and its prevalence in patients admitted to a tertiary epilepsy center may be as high as 50% (Kanner 2003; Boylan et al. 2004). Yet depression in these patients remains underdiagnosed and undertreated. This is particularly worrisome as depression is associated with poor seizure control, and the risk of suicide in patients with epilepsy is greatly increased (Baker 2006; Pompili et al. 2006). Reluctance to treat depression results from the traditional belief that antidepressants decrease seizure threshold. However, there is growing evidence that many antidepressants have anticonvulsant effects instead and that modern antidepressants may indeed reduce seizure frequency in patients with pharmacoresistant epilepsy. When adhering to the usual precautions, treatment with selective reuptake inhibitors of serotonin (SSRI, e.g., citalopram 20 mg once daily, escitalopram 10 mg once daily, sertralin 50 mg once daily) in patients with epilepsy and depression is safe and should not be withheld.
6.4.5 Options for Patients with Medically Refractory Seizures
Despite the continuous introduction of new AEDs, approximately one-third of patients with epilepsy do not become seizure-free. Options for these patients include:
Vagus nerve stimulation
Deep brain stimulation (DBS); see below
22.214.171.124 Epilepsy Surgery
Resection of epileptogenic tissue can have a tremendous effect both in regard to seizure control and quality of life. As a rule, a patient should be referred to a tertiary epilepsy clinic if two proper antiepileptic drug trials have failed. The following criteria have to be fulfilled prior to epilepsy surgery:
The diagnosis of epilepsy is verified.
A focal epileptogenic area is identified (by using MRI, video-EEG monitoring, and perhaps invasive EEG recording, ictal and interictal SPECT, magnetoencephalography, and neuropsychological testing).
It is reasonably certain that resection of the epileptogenic area will not lead to unacceptable neurological deficits.
Temporal lobe resection is the most commonly performed epilepsy surgery and is generally associated with the best results. However, if seizure control cannot be obtained by medical treatment, resection of epileptogenic areas outside the temporal lobe can lead to satisfactory seizure control as well. Occasionally, callosotomy or hemispherectomy may be necessary.
126.96.36.199 Vagus Nerve Stimulation
Vagus nerve stimulation is another option for some patients with refractory epilepsy, especially those who are not suitable for epilepsy surgery or who have had insufficient benefit from surgery. Vagus nerve stimulation reduces seizure frequency with ≥50% in one-third of patients. It has few side effects and may have antidepressive properties.
188.8.131.52 Ketogenic Diet
Several studies have shown beneficial effects of the ketogenic diet in patients with pharmacoresistant epilepsy, especially in children. In a recent study on ketogenic diet for treatment of childhood epilepsy, after 3 months of ketogenic diet, the mean percentage of baseline seizures had decreased by 75% in the diet group compared to the controls (Neal et al. 2008). Energy from a ketogenic diet is largely derived from fat. The composition is traditionally 80% fat and 20% proteins and carbohydrates, but some studies have shown similar success with the modified Atkins diet.
184.108.40.206 Deep Brain Stimulation (DBS)
DBS has not yet been widely used for the treatment of epilepsy, although some data suggest that, e.g., bilateral stimulation of the anterior nucleus of the thalamus may have beneficial effects for patients with partial seizures with or without secondary generalization.
6.5 Sleep Disorders
Obstructive sleep apnea
Lifestyle adjustments, weight loss
Continuous positive airway pressure treatment at night
Modafinil during daytime for excessive sleepiness
Lifestyle adjustments (e.g., short naps during daytime, avoidance of heavy meals)
Start with 100 mg twice daily (morning and lunchtime).
Increase to 200 mg twice daily if necessary.
5–10 mg ×3 daily (duration of action roughly 2 h).
Increase up to 15–20 mg ×3 daily if necessary.
Start with 5–10 mg once daily.
Increase by 10 mg/week, two or three doses per day, max. 60 mg/day.
Switch to extended-release form (same daily dose, once daily, e.g., methylphenidate 10 mg twice daily = methylphenidate extended release 20 mg once daily).
Selegiline (5–10 mg twice daily, morning and lunchtime)
Gamma-hydroxybutyrate liquid preparation, e.g., taken before bed and second dose 4 h after initial sleep (4.5–9 g per night)
Fluoxetine 20–60 mg once daily
Clomipramine 25–50 mg once daily, increase to 50 mg twice daily if necessary during first week
Venlafaxine 75 mg once daily, increase by 75 mg/week if necessary, max. 300 mg/day
Gamma-hydroxybutyrate (see above)
Good sleep hygiene is crucial. Avoid heavy meals, alcohol, coffee, and other stimulating beverages before bedtimes as well as a large fluid intake during evening hours; a regular daily schedule is important; no sleeping in on weekends and daytime naps should be avoided; optimization of bedroom temperature, air quality, darkness, and sound; no reading or watching television in bed; a short walk and other forms of light (in contrast to exhaustive) exercise in the evening can be beneficial; consider psychotherapeutical measures, e.g., writing a diary before going to bed, and if unable to sleep, leave the bedroom but avoid stimulating activities and try again after a while.
Zopiclone 3.75 mg once at bedtime (may be increased to 7.5 mg).
Jet lag, delayed sleep phase syndrome, night shift, and others
Melatonin 2 mg 1–2 h before sleep
REM sleep behavior disorder
Clonazepam 0.25–1 mg at bedtime
Melatonin 2 mg once before sleep, may be increased to 6 mg
Anecdotal success with levodopa, carbamazepine, and gabapentin
6.6 Cerebrovascular Disorders
Patients with acute stroke or TIA should be evaluated and treated as soon as possible in dedicated stroke units. One out of 12 patients is saved from death or disability simply by being cared for in a stroke unit as compared to a general medical ward or mobile stroke teams. This effect is irrespective of age, gender, and stroke severity. (In comparison, the simple administration of aspirin within 48 h after stroke prevents death or disability in just 1 out of 100 patients.) Perhaps even more impressive is the fact that emergent diagnostic evaluation and initiation of secondary prevention in TIA patients at specialist stroke centers is associated with an 80% risk reduction for a new cerebral ischemic event (Lavallée et al. 2007). Also, dedicated stroke centers allow for early initiation of multidisciplinary rehabilitation.
6.6.1 Intravenous Thrombolysis (IVT)
IVT, using alteplase (a recombinant tissue plasminogen activator, rt.-PA), is the first treatment with documented effect in acute ischemic stroke. It was approved in the USA in 1996 and has been widely adapted in Europe since 2003. For every eight patients, IVT increases the number of stroke survivors who are neurologically intact after 3 months from two to three. Of course, also patients without complete resolution of neurological deficits can benefit from IVT. The number needed to treat for significant neurological improvement is 3.6 for patients treated within 90 min, 4.3 for treatment within 91 and 180 min, and 5.9 for treatment within 181 and 270 min. The number needed to harm (i.e., to induce a significant intracranial and/or extracranial hemorrhage) is 65, 38, and 30 for the corresponding time intervals. This translates into a net benefit of IVT of 1 in 3.8 patients, if treatment can be initiated within 90 min, 4.9 between 91 and 180 min, and 7.4 between 181 and 270 min (Lansberg et al. 2009). Thus, the earlier IVT is initiated, the more effective and safer it is.
Indications and inclusion criteria for IVT comprise the following:
Ischemic cerebral infarction, if treatment can be initiated within the time window of 4.5 h from symptom onset (at the time of writing, IVT given after 3 h is off-label in the USA).
Neurological deficits as measured by the NIHSS ≤25. Higher NIHSS values indicate a larger volume of ischemic tissue with possibly reduced effect of IVT and higher risk of secondary hemorrhage. IVT can also be given for subtle neurological deficits if there is risk for significant handicap (e.g., a patient with isolated dysphasia only has an NIHSS score of ≤3).
CT of the brain has excluded intracranial hemorrhage and extensive infarction (≥1/3 of MCA territory, ≥1/2 of ACA territory).
Age ≥18 years. IVT can be administered with or without reduced dosage in adolescents and children but is then off-label.
Contraindications (absolute or relative) to IVT include:
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Inclusion criteria are not fulfilled, e.g., CT of the brain shows intracranial hemorrhage or an established infarction of >1/3 of MCA territory, or the patient is outside the time window.
Large stroke volume with stroke-related impairment of consciousness.
Uncontrolled arterial hypertension (systolic ≥185 mmHg, diastolic ≥110 mmHg).
Increased bleeding risk. The beneficial effects of IVT must always be weighed against the risks for an intracranial or systemic hemorrhage in patients prone to bleeding.
Intracranial bleeding risk, e.g.:
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