neurology

Bloggerwave

2008-04-07T00:09:00.000-07:00

News Release Bloggerwave

News Release

Copenhagen , May 4, 2007

Gaining popularity, growing strong- Bloggerwave is
Bloggerwave.com has proven to be the desired destination for bloggers from around the world. A multi tier offering for bloggers, advertisers and agencies has caused this site to create an explosion of e-activity in this sector. Their concept of commercial blogging to enhance brand image, product sales and public relations, has really paid off! The site has done IQ Division Company proud by bringing together hundreds of bloggers who are keen to get their opinions on screen while getting paid to do so.

Here info Link
bloggerwave

JOIN US, YOU WILL BE FIND HOW TO BE A GREAT WEBMASTER

1. What should we do

Contact Us

Office Location
Contact With : Bloggerwave
Fruebjergvej 3
2100-Copenhagen
Denmark
Tel : +45 3696 4530
So .. dont worry about your PRIVATION we will kept to protect it

2. Join us

You have time to join us with Bloggers or advertisers

a. Click ">Bloggers or advertisers">

b. Login With Blogger or advertisers

3 . How about advertisers

Advertiser is Pathner with blogger. Thy have twin bussines from bloggerwave to make money on internet market.
Be Bloggerwave Pathner

Since their effective launch, Bloggerwave.com has certainly caused waves in the industry. Having seen exponential growth and concept acceptance from the word ‘go’, they are now revving up their operations to sustain the premature success. To start with, they have set up a dedicated server to handle the traffic and to strengthen the back office.
Ulrik S. Thomsen, Managing Director with Bloggerwave Ltd. was quoted saying “Since we now have proven the concept and have already recruited several thousands of bloggers, we have decided to focus even more on clients, partnerships and getting more opportunities and assignments to our bloggers”.
With more effective servers and improvement to other finer details the site is back with a vengeance. Next on the agenda, they intend to tag each commercial blog to give it a ring of authenticity. So don’t be surprised if you see ‘Sponsored by Bloggerwave’ next to a posting. As pioneers in commercially sponsored blogs, the website hopes to reign in top clients and maintain their loyalty for years to come.

you wil be find sponsor link here

There’s also good news for bloggers. The site commits to making payment at the end of every month for successful blog postings even on the first assignment. They understand that credibility is key in this business. A safe and dedicated site, bloggerwave.com honours their payment commitments.
With better offerings, improved services and a passionate game plan, bloggerwave.com will be something to watch out for. Propelled by success they aim to push ahead to offer best-in-class services to both bloggers and organisations alike. This drive will certainly take them places.

Here Links Popular Pathnership

2008-01-29T22:22:00.000-08:00

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http://www.healtycenter.com/2007/12/

Anisocoria

2007-11-22T20:04:00.000-08:00

Background: Anisocoria, or unequal pupil sizes, is a common condition. The varied causes have implications ranging from life threatening to completely benign.

Pathophysiology: Various pathophysiological processes can cause anisocoria. However, pupil size depends upon the effects of the autonomic nervous system and the iris muscle.

The parasympathetic system constricts the iris, while sympathetic channels dilate the iris. The sympathetic system begins in the hypothalamus, descends through the brain stem (including the lateral medulla) and into the cervical cord to synapse in the ciliospinal center of Budge-Waller at the C8-T1 level. The second-order neuron then exits the C8-T1 nerve root, travels over the lung apex, and ascends to the superior cervical ganglia with the carotid artery. The third-order neuron leaves the superior cervical ganglia to ascend with the internal carotid artery through the cavernous sinus, where fibers destined for the pupil dilator and the Mueller muscle of the eyelid travel with the trigeminal nerve. Fibers destined to modulate sweating of the face travel with the external carotid artery. The parasympathetic fibers begin in the Edinger-Westphal subnucleus of cranial nerve III in the midbrain. Parasympathetic fibers destined for the iris sphincter travel with the oculomotor (cranial III) nerve.

Frequency:

In the US: Anisocoria is common, although no overall prevalence statistics are available. The incidence and prevalence data for anisocoria depend on the specific pathophysiology.

Mortality/Morbidity: Mortality and morbidity rates associated with anisocoria depend entirely upon the specific pathophysiology.

Several causes of anisocoria are life threatening, including Horner syndrome with carotid dissection or third nerve palsy due to aneurysmal expansion or rupture.

Other causes of anisocoria are completely benign (eg, simple or physiologic anisocoria), although the evaluation of these disorders may produce morbidity inadvertently.

Treatment
Medical Care: Depends upon the underlying pathophysiology

Surgical Care: Depends upon the specific etiology

Consultations: Depends upon the underlying cause. Compressive third nerve palsies may require neurosurgical intervention, while ophthalmologists may be helpful in other causes of anisocoria.

Activity: Depends upon the specific etiology

Medication
Drugs used in the diagnosis of anisocoria include cocaine, hydroxyamphetamine, and pilocarpine (0.1-1%).
Drug Category: Topical anesthetic agents -- This agent is used for diagnostic testing to detect Horner syndrome.

Drug Name	Cocaine 4-10% (ophthalmic solution) -- Prevents norepinephrine reuptake and accordingly dilates eye with intact sympathetic nervous system supply. Decreases membrane permeability to sodium ions, which, in turn, inhibits depolarization and blocks conduction of nerve impulses.
Adult Dose	1-2 gtt 4-10% OU
Pediatric Dose	1 gtt 4% OU
Contraindications	Documented hypersensitivity
Interactions	Increases toxicity of MAOIs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hypertension, severe cardiovascular disease, thyrotoxicosis; avoid use in traumatized mucosa and sepsis at region of intended application; do not inject; corneal toxicity may result from overuse; urine drug screen will be positive for cocaine at least 24 h after use

<Drug Category: Cholinergic agents -- This agent is used for diagnostic testing related to tonic pupil (0.1% concentration) or pharmacologic dilation-induced anisocoria (1% concentration).

Drug Name	Pilocarpine 0.1 % (Isopto) -- Does not normally constrict pupil; however, with tonic pupil, produces miosis due to cholinergic supersensitivity. Constricts normal pupil or mydriatic pupil due to oculomotor palsy; however, after pharmacologic dilation (eg, atropinelike agents), pilocarpine has no miotic effects.
Adult Dose	1-2 gtt OU
Pediatric Dose	1 gtt OU
Contraindications	Documented hypersensitivity; acute inflammatory disease of anterior chamber; acute iritis; pupillary block glaucoma
Interactions	May be ineffective when used concomitantly with NSAIDs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in acute cardiac failure, peptic ulcer, hyperthyroidism, GI spasm, bronchial asthma, Parkinson disease, recent MI, urinary tract obstruction, and hypertension or hypotension; miosis may cause difficulty with dark adaptation and night driving

<Drug Category: Sympathomimetic agents -- Hydroxyamphetamine is useful diagnostically to test integrity of the third-order sympathetic neuron.

Drug Name	Hydroxyamphetamine (Paredrine) -- Dilates pupil if third-order sympathetic neuron intact, and fails to dilate pupil if third-order neuron impaired.
Adult Dose	1-2 gtt OU
Pediatric Dose	1 gtt OU
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; anatomically narrow (occludable) angle without glaucoma
Interactions	Beta-blockers may cause systemic adverse effects; exaggerated adrenergic effects may result as long as 21 d after MAOIs (supervise and adjust dosage carefully)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hypertension, diabetes, hyperthyroidism, cardiovascular abnormalities, arteriosclerosis; rebound congestion may occur with frequent or extended use; rebound miosis may occur in older persons 1 day after phenylephrine treatment; reinstillation may produce reduction in mydriasis

Amyotrophic Lateral Sclerosis

2007-11-22T20:02:00.000-08:00

Background: Anencephaly is a serious developmental defect of the central nervous system in which the brain and cranial vault are grossly malformed. The cerebrum and cerebellum are reduced or absent, but the hindbrain is present. Anencephaly is a part of the neural tube defect (NTD) spectrum. This defect results when the neural tube fails to close during the third to fourth weeks of development, leading to fetal loss, stillbirth, or neonatal death.

Pathophysiology: In the normal human embryo, the neural plate arises approximately 18 days after fertilization. During the fourth week of development, the neural plate invaginates along the embryonic midline to form the neural groove. The neural tube is formed as closure of the neural groove progresses from the middle toward the ends in both directions, with completion between day 24 for the cranial end and day 26 for the caudal end. Disruptions of the normal closure process give rise to NTDs. Anencephaly results from failure of neural tube closure at the cranial end of the developing embryo. Absence of the brain and calvaria may be partial or complete.

MTHFR) has been shown to be associated with the risk of NTDs; however, the overall effect is relatively weak. A variety of environmental factors appears to be influential in the closure of the neural tube. Most notably, folic acid and other naturally occurring folates have a strong preventive effect. Folate antimetabolites, maternal diabetes, maternal obesity, and hyperthermia in early development have been identified as stressors that increase the risk of NTDs, including anencephaly.

Frequency:

<In the US: Average birth prevalence of anencephaly is approximately 1.2 per 10,000 births, with a gradient of increasing frequency from the West Coast to the East Coast. The frequency during pregnancy is considerably higher than the birth prevalence, with estimates as high as 1 case per 1000 pregnancies. Such pregnancies often end in early pregnancy loss, spontaneous abortion, fetal death, or pregnancy termination. Within the United States, South Carolina has historically reported the highest birth prevalence of NTDs, with a rate that has been approximately double that of the national average. The rate of NTDs in South Carolina has fallen dramatically over the past decade following the introduction of aggressive campaigning for periconceptional folic acid supplementation, fortification of wheat flour, and increased periconceptional vitamin supplementation. The reason for a higher occurrence of NTDs in South Carolina compared with other areas of the country is not known.

Internationally: Considerable geographical variation in NTD rates exists, with noted hotspots in Guatemala, northern China, Mexico, and parts of the United Kingdom.

Race: Hispanic and non-Hispanic whites are affected more frequently than women of African descent.

Sex: Females are affected more frequently than males.

Age: Anencephaly is determined by the 28th day of conception and is therefore invariably present at the time of birth.

Treatment
Medical Care: Because anencephaly is a lethal condition, heroic measures to extend the life of the infant are contraindicated. The physician and medical care team should focus on providing a supportive environment in which the family can come to terms with the diagnosis and make preparations for their loss.

Families not aware of the diagnosis of anencephaly prior to birth or for whom the diagnosis is still fresh probably will need extra emotional support and possibly grief counseling. Families who have had some time to adjust to the diagnosis prior to delivery and who have had an opportunity to begin the grieving process ahead of time may seem well prepared, but they also will need adequate time to grieve and come to closure. The presence of family, friends, or clergy may be helpful in many cases.

Families often want to hold the baby after delivery, even if the baby is stillborn, and families wanting photographs of the baby with the family are not unusual. A cap or head covering of some sort is useful to minimize the visual impact of the malformation. Some families want to see the lesion, and this may help to dispel mental pictures, which are often worse than the actual malformations. In most cases, direct personal contact with the baby may help the parents to actualize the medical information they have been given and may help in the process of grief resolution.

If parents have chosen a name for the baby, they may be comforted if the doctor refers to the baby by name.

Feelings of guilt are normal responses of parents of a baby with serious birth defects. The involvement of genetic counselors, if available, may be particularly useful to parents in this situation because of their experience in dealing with a wide range of birth defects.

With timely prenatal diagnosis of this lethal disorder, the option of pregnancy termination should be presented to the couple. For couples who elect to continue the pregnancy, the possibilities of preterm labor, oligohydramnios, failure to progress, and delayed onset of labor beyond term also should be discussed.

Families commonly inquire about organ donation after the diagnosis of anencephaly. This cannot practically be arranged without crossing the lines of ethical care. Patients should be affirmed in their desires to see something meaningful come from the tragedy of having a pregnancy affected with anencephaly.

Consultations: Every couple with a child who has anencephaly should consult with a geneticist and/or a genetic counselor in order to obtain information regarding recurrence risks, prevention, screening, and diagnostic testing options for future pregnancies and to assess the family history. Ideally, a genetic counselor should be consulted prenatally and should remain involved, as needed, until the family comes to closure after the conclusion of the pregnancy.

Diet: Folic acid supplementation and/or a folate-enriched diet prior to and during future pregnancies are recommended. Obtaining enough folates from diet alone to effectively prevent recurrences in future pregnancies is extremely difficult.

Medication
Pharmaceutical interventions are not used in cases of anencephaly.

Amyotrophic Lateral Sclerosis

2007-11-22T20:00:00.001-08:00

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the anterior horn cells of the spinal cord and the motor cranial nuclei that leads to progressive muscle weakness and atrophy. Although major recent advances have shed light on its etiology, the key mechanisms in both familial and sporadic ALS remain unknown. No cure is known. This article reviews the major breakthroughs in ALS research, the clinical aspects of the disease, and current therapeutic options. An outline of new and promising technology and its application to the understanding of ALS is presented.

Pathophysiology: ALS primarily involves anterior horn cells in the spinal cord and cranial motor nerves. Patients may have weakness of bulbar muscles or of single or multiple limb muscle groups. Presentation is not always bilateral or symmetrical. A predominantly bulbar form usually leads to more rapid deterioration and death. Limb weakness is predominantly distal. Weakness and atrophy of the intrinsic hand muscles are prominent. Weakness progresses to involve the forearms and shoulder girdle muscles and the lower extremities.

Involvement of both upper and lower motor neurons is characteristic. Patients develop variable hyperreflexia, clonus, spasticity, extensor plantar responses, and limb or tongue fasciculations. Wallerian degeneration of corticospinal and corticobulbar tracts may be demonstrated by MRI (high-intensity T2 lesions in frontal lobes) or in postmortem examination. Extraocular muscles and bladder and anal sphincter muscles typically are spared.

ALS rarely affects cognitive functions. Electromyogram (EMG) shows signs of diffuse denervation with generally preserved nerve conduction velocities. Although an inflammatory process may be present, new evidence points toward multiple mechanisms that promote neuronal cell death in the CNS as the underlying basis for ALS. The recent demonstration of superoxide dismutase 1 (SOD1) mutations in human familial ALS and in murine ALS models supports the view that oxidative stress, mitochondrial dysfunction, and excitotoxicity pathways may be involved in the process of neuronal cell death.

A lack of trophic factor support has been hypothesized, as some authors have reported decreased insulin-like growth factor 1 (IGF-1) in patients with ALS. Aberrant RNA processing in sporadic ALS is thought to lead to abnormal expression of glutamate transporter (EAAT2) variants in the spinal cord. Despite multiple searches for infectious causative agents, no definitive viral or bacterial etiology has been identified.

ALS can be part of a complex with parkinsonism and dementia (ALS/PDC complex). This variant can be seen in patients from southern Guam. An ALS-like motor neuron disease also can be seen as a paraneoplastic syndrome in patients with cancer.

The complexity of ALS pathogenesis is highlighted by the recent discovery that alsin, a molecule putatively involved in cell-signaling, may be affected in a subset of familial ALS cases.

Autoimmunity may play a role in ALS. T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction. Supporting this hypothesis, IgG derived from ALS patient sera may affect the conductance of neuronal voltage-activated calcium channels and may induce an excessive release of glutamate from nerve endings. The presence of immune complex formation in spinal cords of patients with ALS also has been demonstrated.

The El Escorial World Federation of Neurology criteria are helpful in diagnosis. Careful clinical history-taking is essential in making the correct diagnosis. For instance, Lyme neuroborreliosis on rare occasions may mimic an ALS-like syndrome.

Intravenous cyclophosphamide treatment has resulted in only temporary and mild amelioration of symptoms.

Patients with ALS may benefit from riluzole, a glutamate antagonist medication that modestly prolongs tracheostomy-free survival. Techniques that aim to elucidate altered pathways of gene expression (ie, gene chip technology) or protein expression (proteomics) may give clues to ALS pathogenesis in animal models. These may also expedite the identification of abnormal pathway-modifying pharmaceutical agents.

Frequency:

In the US: Taking into account the most comprehensive studies (by Kurtzke), the frequency is approximately 5 cases per 100,000 population.

Mortality/Morbidity:

ALS leads to death within a decade. In most cases, death occurs within 5 years.

Some patients with familial, juvenile-onset ALS have been reported to survive for longer periods (2-3 decades).

Race: In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.

Sex: The ratio of ALS-affected males to females is 1.5:1.

Age: Onset occurs in the fourth to seventh decades of life. However, exceptions to this do exist.

Treatment
Medical Care:

Medical care in ALS is primarily palliative.

Patients should be involved in regular exercise and a physical therapy program.

Medications such as baclofen and tizanidine may be used to relieve severe spasticity.

Riluzone is an FDA-approved medication for prolonging tracheostomy-free survival.

Surgical Care:

Early consideration for elective tracheostomy should be considered in patients with early signs of respiratory difficulty.

Home health aides can be helpful in managing secretions and feeding.

Computerized aids for writing and communication also can be helpful.

Consultations:

Surgeon or gastroenterologist - To perform elective tracheostomy or G-tube placement

Pulmonologist and respiratory therapist - For ventilator assistance and management of intercurrent infections and tracheostomy

Physical and respiratory therapists - To enhance muscle function and manage spasticity

Secretion management - For chest percussion therapy and suctioning

Diet:

Evaluate swallowing to quantify any dysphagia.

Modify the patient's diet to prevent aspiration.

Consider a gastrostomy tube when patient cannot swallow fluids or soft foods.

Activity: No activity restriction is necessary. Patients should maintain a regular exercise regimen if the degree of weakness allows

Medication
Riluzole is the only medication that has shown treatment efficacy for ALS. That it prolongs tracheostomy-free survival compared to placebo has been shown in 2 randomized trials. No statistically significant difference in mortality rates was revealed at the end of these studies, however. In other clinical trials, creatine, human recombinant IGF-1, and ciliary neurotrophic factor (CNTF) also have shown promise, but none are expected to lead to dramatic benefits.
Drug Category: Glutamate pathway antagonist -- Riluzole is thought to counteract the excitatory amino acid (glutaminergic) pathways, but its exact mechanism of action in ALS is unknown.

Drug Name	Riluzole (Rilutek) -- Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 h; steady state reached within 5 d with multiple dose administration; metabolism occurs in liver (P 450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites produced.
Adult Dose	50 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, liver disease with elevations in liver function tests
Interactions	Metabolized primarily by liver isoenzyme CYP₁A₂; other agents also metabolized via this enzymatic pathway (ie, theophylline, caffeine) may affect rate of elimination
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use caution in patients with concomitant liver or renal insufficiency

<Drug Category: Antispastic agents -- These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Drug Name	Baclofen (Lioresal) -- Metabolized in liver and excreted primarily in urine; not a DEA-controlled substance.
Adult Dose	5 mg PO tid; not to exceed 80 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with caution in patients with seizure disorder or impaired renal function; serious reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression; common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, increased perspiration; exercise caution in prescribing to patients already experiencing such symptoms; excessive dosing may lead to weakness

Drug Name	Tizanidine (Zanaflex) -- Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces; used in patients with predominantly UMN involvement; not a DEA-controlled substance.
Adult Dose	4-8 mg PO q8h prn; not to exceed 36 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance); can increase hypotensive effects when administered concurrently with diuretics
Pregnancy	A - Safe in pregnancy
Precautions	Use with caution in elderly patients and in patients with impaired renal function; serious reactions include hallucinations, severe bradycardia, and liver toxicity; more common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension

Amyotrophic Lateral Sclerosis

2007-11-22T19:57:00.000-08:00

The complexity of ALS pathogenesis is highlighted by the recent discovery that alsin, a molecule putatively involved in cell-signaling, may be affected in a subset of familial ALS cases.

Intravenous cyclophosphamide treatment has resulted in only temporary and mild amelioration of symptoms.

Frequency:

In the US: Taking into account the most comprehensive studies (by Kurtzke), the frequency is approximately 5 cases per 100,000 population.

Mortality/Morbidity:

ALS leads to death within a decade. In most cases, death occurs within 5 years.

Some patients with familial, juvenile-onset ALS have been reported to survive for longer periods (2-3 decades).

Race: In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.

Sex: The ratio of ALS-affected males to females is 1.5:1.

Age: Onset occurs in the fourth to seventh decades of life. However, exceptions to this do exist.

Treatment
Medical Care:

Medical care in ALS is primarily palliative.

Patients should be involved in regular exercise and a physical therapy program.

Medications such as baclofen and tizanidine may be used to relieve severe spasticity.

Riluzone is an FDA-approved medication for prolonging tracheostomy-free survival.

Surgical Care:

Early consideration for elective tracheostomy should be considered in patients with early signs of respiratory difficulty.

Home health aides can be helpful in managing secretions and feeding.

Computerized aids for writing and communication also can be helpful.

Consultations:

Surgeon or gastroenterologist - To perform elective tracheostomy or G-tube placement

Pulmonologist and respiratory therapist - For ventilator assistance and management of intercurrent infections and tracheostomy

Physical and respiratory therapists - To enhance muscle function and manage spasticity

Secretion management - For chest percussion therapy and suctioning

Diet:

Evaluate swallowing to quantify any dysphagia.

Modify the patient's diet to prevent aspiration.

Consider a gastrostomy tube when patient cannot swallow fluids or soft foods.

Drug Name	Riluzole (Rilutek) -- Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 h; steady state reached within 5 d with multiple dose administration; metabolism occurs in liver (P 450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites produced.
Adult Dose	50 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, liver disease with elevations in liver function tests
Interactions	Metabolized primarily by liver isoenzyme CYP₁A₂; other agents also metabolized via this enzymatic pathway (ie, theophylline, caffeine) may affect rate of elimination
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use caution in patients with concomitant liver or renal insufficiency

Drug Category: Antispastic agents -- These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Drug Name	Baclofen (Lioresal) -- Metabolized in liver and excreted primarily in urine; not a DEA-controlled substance.
Adult Dose	5 mg PO tid; not to exceed 80 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with caution in patients with seizure disorder or impaired renal function; serious reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression; common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, increased perspiration; exercise caution in prescribing to patients already experiencing such symptoms; excessive dosing may lead to weakness

Drug Name	Tizanidine (Zanaflex) -- Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces; used in patients with predominantly UMN involvement; not a DEA-controlled substance.
Adult Dose	4-8 mg PO q8h prn; not to exceed 36 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance); can increase hypotensive effects when administered concurrently with diuretics
Pregnancy	A - Safe in pregnancy
Precautions	Use with caution in elderly patients and in patients with impaired renal function; serious reactions include hallucinations, severe bradycardia, and liver toxicity; more common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension

Amyloid Angiopathy

2007-11-22T19:52:00.000-08:00

Background: Cerebral amyloid angiopathy (CAA) refers to the deposition of b-amyloid in the media and adventitia of small- and mid-sized arteries (and less frequently, veins) of the cerebral cortex and the leptomeninges. It is a component of any disorder in which amyloid is deposited in the brain, and it is not associated with systemic amyloidosis. CAA has been recognized as one of the morphologic hallmarks of Alzheimer disease (AD), but it also is found often in the brains of elderly patients who are neurologically healthy. While often asymptomatic, CAA can present as intracranial hemorrhage (ICH), dementia, or transient neurologic events. ICH is the most consistent effect of CAA. Although the vast majority of cases are sporadic, 2 familial forms exist (ie, hereditary cerebral hemorrhage with amyloidosis [HCHWA]-Dutch type and HCHWA-Icelandic type).

Pathophysiology: Deposition of amyloid damages the media and adventitia of cortical and leptomeningeal vessels, leading to thickening of the basal membrane, stenosis of the vessel lumen, and fragmentation of the internal elastic lamina. This can result in fibrinoid necrosis and microaneurysm formation, predisposing to hemorrhage. Some evidence suggests that the amyloid is produced in the smooth muscle cells of the tunica media as a response to damage of the vessel wall (perhaps by arteriosclerosis or hypertension). Impaired elimination and accumulation of soluble and insoluble b-amyloid peptide may underlie the pathogenesis of CAA and may explain the link between CAA and AD.

Frequency:

In the US: The true incidence and prevalence are hard to specify, as definite CAA can be diagnosed only at postmortem. However, estimates can be made based on autopsy series and the incidence of lobar ICH. A series of 400 autopsies found evidence of CAA in the brains of 18.3% of men and 28% of women aged 40-90 years. In a series of 117 brains of patients with confirmed AD, 83% had evidence of CAA. The prevalence of CAA increases with advancing age; in some autopsy series it has been found in 5% of individuals in the seventh decade but in 50% of those older than 90 years.

Sex: Although CAA may be found more commonly in women than men at autopsy, the incidence of ICH is the same in women and men. Hemorrhage occurs at the same age in men and women.

Treatment
Medical Care:

CAA is largely untreatable at this time.

The management of CAA-related ICH is identical to the standard management of ICH. Pay special attention to reversing anticoagulation, managing intracranial pressure, and preventing complications.

If coexisting vasculitis is found on angiography and brain biopsy, long-term treatment (up to 1 y) with steroids and cyclophosphamide is indicated.

A syndrome of subacute cognitive decline, seizures, and white matter changes on MRI with perivascular inflammatory changes on biopsy was recently described. Some patients improved clinically (but not to baseline) when given corticosteroids or cyclophosphamide.

Surgical Care:

Hematoma evacuation can be life saving when the hematoma causes significant mass effect and predisposes to herniation, particularly when there has been no response to medical management of increased intracranial pressure. The goal of therapy is to lower intracranial pressure.

No evidence is available from well-designed, randomized clinical trials that can help determine which patients benefit from evacuation of the hematoma. However, that the intervention should be considered in patients with intermediate-sized hematomas (20-60 cc) who have a progressive deterioration in their level of consciousness is agreed.

Surgery should be performed before coma develops.

Surgery is not beneficial for small or very large hematomas. Patients with small (<20>60 cc) and the patient is lethargic or comatose, the prognosis is poor despite surgical evacuation.

Early concerns about the safety of hematoma evacuation in patients with CAA-related ICH were unfounded. Several recent series have reported low rates of mortality and postoperative hematoma; surgical evacuation of the hematoma should be performed when clinically indicated.

No evidence supports the belief that evacuation leads to an increased rate of recurrence. A recent large series that evaluated 50 neurosurgical procedures in 37 patients with CAA-related ICH found a mortality rate of 11% and a 5% rate of postoperative hematoma that required intervention. Risk factors associated with an adverse postoperative outcome were age >75 years and the presence of a parietal hematoma.

Although transoperative oozing from the walls of the hematoma was a common occurrence, it could be controlled easily with an absorbable hemostat (eg, oxidized cellulose, gelatin sponge) or fibrin glue.

When determining whether evacuation of the hematoma is appropriate, consider the patient's cognitive status.

Consultations:

Neurosurgical consultation in cases of ICH

Neuropsychological assessment for cognitive impairment

Diet: No special diet

Activity: Activities should not be restricted. However, patients should avoid head trauma of any degree.

Ambulatory Electroencephalography (EEG)

2007-11-22T19:46:00.000-08:00

Background Continuous cardiac monitoring was first described by Holter in 1962. The development of portable EEG recording proved more problematic than the Holter monitor because of the need for signal amplification and multichannel recording. A multichannel portable recorder was developed in the early 1970s. This technology was later adapted to EEG recording, and miniature preamplifiers that could be worn on the head were developed.

Early clinical investigations documented the ability of AEEG to record identifiable focal and generalized epileptiform activity. In 1982, Ives introduced a 16-channel AEEG that utilized signal multiplexing. The 16 channels allowed improved spatial resolution and localization but recorded discrete samples rather than continuous EEG. In 1983, a cassette tape AEEG system was introduced; it used off-head preamplifiers that had continuous 8-channel recording capability, real-time identification, and gain and filter adjustments.

In the past decade, computer technology has enabled portable recording of up to 36 channels with sampling rates of up to 400 Hz. Currently, numerous AEEG systems are available commercially.

TECHNICAL ASPECTS

Disk electrodes should be applied with collodion to ensure stability during the 24-hour recording period. Electrode gel may need to be reapplied by syringe beneath the electrodes.

The patient's scalp may be wrapped in gauze and the lead wires gathered and tacked to reduce traction on the electrodes. New batteries should be provided every 24 hours.

Calibration is recorded using a 50-µV square wave or pulse; each electrode should be tapped sequentially. This part of the recording should be reviewed while the patient is in the laboratory to verify the integrity of the system and the appropriate connection of electrode leads to the preamplifier.

Patients should be instructed to record activity in a diary. Documenting physiological artifacts, such as eye movements, chewing, speaking, and swallowing, is useful. Patients should not chew gum, which could produce prolonged artifact. In addition, they should not bathe with the device.

When the patient returns to the laboratory for removal of the device, the end of the recording should be reviewed to ensure that signal recording was maintained.

In the past, when utilizing 4- and 8-channel AEEG, montage design was of paramount importance in capturing and attempting to localize a suspected discharge. Because abnormalities were recorded most often in the anterior temporal regions and frequently in the frontal regions, montages were designed to optimize coverage of these regions and to maximize yield. With the newer digital 16- to 36-channel AEEG systems, standard EEG montages are adequate, since digital reformatting is always an option.

AEEG REVIEW
Because AEEG records a vast amount of data, scanning techniques are necessary to decrease review time. Cassette 8-channel systems allow scanning at speeds of 20, 40, and 60X. They also allow audio output monitoring. While perceiving isolated, single discharges may be difficult at these speeds, seizures are less likely to be missed because of longer onscreen time, recognition of rhythmic or evolving patterns, and rhythmic audio bursts (usually of declining frequency).

Review of a 24-hour digital study would be prohibitively time-consuming without the benefit of computer-aided analysis. Newer digital AEEG models reduce reviewing time by sampling (which has the risk of missing infrequent discharges) and with automated spike and seizure detection programs. Pioneered by Gotman, these computer techniques identify epileptiform discharges on the basis of changes in amplitude, frequency, and rhythmicity. Further refinements have reduced the incidence of false positives due to physiological artifacts and sleep patterns. Neural network modeling techniques may offer additional advantages in the future.

Because the AEEG is recorded outside of the controlled confines of the EEG laboratory and the patient performs customary daily activities, it is susceptible to a variety of physiological and environmental artifacts. Such artifacts may be difficult to recognize in AEEG, especially if using a limited number of channels. Artifacts from sustained blinking, chewing, or movement may obscure the underlying EEG. Additionally, rhythmic artifacts due to repetitive activities (eg, teeth brushing, scratching, or bicycle pedaling) may mimic seizure activity. Ideally, the patient diary will document these occurrences. Judicious use of filters, gain, and reformatting may further clarify these waveforms and assist in distinguishing seizure activity from artifact.

Electrographic seizures usually demonstrate evolution of amplitude and frequency, may spread to involve neighboring electrodes, and may be followed by postictal slowing or suppression. If doubt exists as to whether a discharge is artifactual or epileptic, a conservative interpretation should be made.

CLINICAL APPLICATIONS
AEEG has several important clinical applications. Depending on the clinical suspicion, other diagnostic tests (eg, ambulatory cardiac monitor, polysomnogram, or inpatient video/EEG monitoring) may be more appropriate in a given situation.

Confirm clinical suspicion of epilepsy

A clinical suspicion of epilepsy can be confirmed by recording a seizure on AEEG. This is most likely to occur when the patient is experiencing daily or almost daily spells. Studies looking at the diagnostic yield of AEEG indicate that 6-15% of AEEGs record seizures. Higher yields have been reported from 16-channel AEEG with computer-assisted seizure detection than from older 4- or 8-channel systems without seizure-detection algorithms. A 2001 study by Tatum et al of 502 patients with computer-assisted 16-channel AEEG demonstrated that 8.5% of patients had a seizure during the recording period (mean, 28.5 h).

In patients with intractable epilepsy, AEEG has been used to localize seizure onset as part of presurgical evaluation. However, inpatient video/EEG monitoring remains the criterion standard for presurgical evaluation.

Evaluate interictal epileptiform activity

Detection of interictal epileptiform abnormalities in the absence of recorded seizures can provide supporting evidence for a clinical diagnosis of epilepsy. Studies have demonstrated that 34.9% of patients with known seizures had a positive AEEG, while 15.3% of 216 patients in whom the diagnosis of seizures was considered (ie, patients with episodic alterations of behavior, perception, sensation, or motor functioning) had interictal epileptiform abnormalities on 4-channel AEEG. When a 16-channel recorder was used, 38% of patients who were referred for AEEG had some type of epileptiform abnormality.

AEEG is highly specific; spikes were found on overnight AEEG in only 0.7% of asymptomatic adults without history of migraine or family history of epilepsy. In patients with a history of migraine headaches or a family history of epilepsy, the incidence of spikes on AEEG was 12.5% and 13.3%, respectively.

Some patients in whom epilepsy is suspected have a normal routine or sleep-deprived EEG. In these patients, AEEG can increase the chance of detecting an epileptiform abnormality. Of patients who have a prior normal or nondiagnostic routine EEG, 12-25% have epileptiform activity on AEEG.

A study comparing the usefulness of sleep-deprived EEG and computer-assisted 16-channel AEEG in patients with suspected epilepsy (but a nondiagnostic initial routine EEG) found that sleep-deprived EEG improved detection of epileptiform discharges by 24%, while AEEG improved detection by 33%. Of the 46 patients studied, 15% had actual seizures recorded on AEEG, while none had seizures during the sleep-deprived recording.

Document seizures of which patients are unaware

For a patient to have seizures and yet be unaware of them is not uncommon. Brief alterations of awareness occur in both absence and complex partial seizures. AEEG is helpful at identifying seizures that are unrecognized or unreported by the patient.

Absence seizures may be so brief that the patient is unaware of them. A study using AEEG to evaluate absence seizures in pediatric patients found that most paroxysms of generalized spike and wave discharges were asymptomatic.

Patients with complex partial epilepsy are often amnestic for their seizures. The sequelae of a nocturnal generalized convulsive seizure, if present at all, may be so subtle (eg, fatigue, muscle soreness) that the patient is unsure whether a seizure actually occurred.

A study of patients in an epilepsy-monitoring unit found that 63% of all seizures were unrecognized by the patients. This difficulty in identifying the occurrence of seizures impedes seizure diagnosis and assessment of treatment adequacy. Liporace et al found that the AEEGs of 3 patients (of 46) demonstrated seizures that were not designated as events by the patients. Tatum et al found that more than one third of AEEGs with ictal activity contained at least one seizure that was unreported by the patient. These studies demonstrate the utility of AEEG at capturing unsuspected events.

Evaluate response to therapy

A significant number of patients are unaware of their seizures, making their responses to treatment difficult to gauge. Patients with mental retardation or other forms of encephalopathy may be unable to report seizures accurately. In such cases, AEEG can have a significant impact on clinical management.

AEEG is particularly useful in quantitating response to the treatment of absence seizures. Untreated, they typically occur numerous times per day; adequate treatment usually normalizes the EEG.

Evaluate nocturnal or sleep-related events

Certain diagnoses are difficult to confirm using the typical 20-minute outpatient EEG. The interictal epileptiform discharges of benign rolandic epilepsy, for example, are highly activated by sleep and may not always be achieved adequately in a laboratory. Continuous spike and wave activity during slow-wave sleep is another entity that may demonstrate a relatively normal EEG during waking hours and a strikingly abnormal EEG during deep sleep. Because of its capacity to record an entire night of sleep, AEEG is invaluable in assessing these clinical situations. Another advantage is that children can be monitored at home.

If a nonepileptic sleep disorder is suspected, a polysomnogram is the preferred study because of the added information from monitoring electromyography (EMG), eye movements, ECG, and respiration.

The history may not differentiate clearly between a sleep disorder and epilepsy. AEEG may record frequent arousals (suggesting sleep apnea) or decreased rapid eye movements (REM) sleep latency (suggesting narcolepsy). In 500 patients who had AEEG, the study suggested narcolepsy in 6 patients, including 3 patients in whom narcolepsy had not been suspected.

Evaluate suspected pseudoseizures

Pseudoseizures, also known as psychogenic seizures or nonepileptic events, are clinical events in which patients perceive altered movement, emotion, sensation, or experience similar to those due to epilepsy but without an electrographic ictal correlate. They are surprisingly frequent, occurring in up to 20% of patients at epilepsy referral centers and in 5-20% of outpatient populations. Some patients have both pseudoseizures and epileptic seizures; coincident events occur in an estimated 10-60% of epilepsy patients.

AEEG can be a useful screening tool in identifying patients who have nonepileptic paroxysmal events. In one study, 36% of patients had event marker activations without associated electrographic changes.

Potential problems exist in using AEEG to definitively diagnose nonepileptic seizures. A 24-hour recording without associated video does not allow evaluation of clinical stereotypy, which is valuable when evaluating patients with unusual seizure manifestations and minimal EEG changes. Scalp EEG may not show electrographic ictal abnormality during some frontal lobe seizures or only subtle abnormalities that would be difficult to interpret without associated video. Kanner et al found that 25% of their group of 12 patients with supplementary motor seizures demonstrated no electrographic ictal pattern during seizures.

Seizures and nonepileptic seizures may be associated with movement and muscle artifact that may obscure the underlying EEG. While AEEG may be a useful initial screening tool for nonepileptic events, inpatient video/EEG monitoring remains the criterion standard in evaluating nonepileptic seizures.

Evaluate syncope

AEEG may be helpful in evaluating syncope or near syncope if an ECG lead replaces 1 of the EEG channels. If cardiogenic syncope is suspected, a Holter monitor or prolonged cardiac event monitor may be more useful clinically. While arrhythmias have been diagnosed with continuous ambulatory EEG/ECG recording, a study of epileptiform abnormalities in AEEG found that only 1 of 67 patients with syncope, near syncope, or episodic dizziness had an epileptiform abnormality.

Future applications

Seizure anticipation methods are under development to identify EEG changes prior to seizure onset, allowing ongoing assessment of the probability of seizure occurrence. With further characterization of EEG changes in the preictal state, future AEEG recording may be coupled with a seizure anticipation device, providing a time window for therapeutic intervention to prevent a seizure.

Alzheimer Disease in Individuals With Down Syndrome

2007-11-22T19:45:00.000-08:00

Background: Alzheimer disease (AD) is the most common form of dementia. It is a progressive degenerative disease of the brain, strongly associated with advanced age. However, it should not be considered a part of the normal aging process. AD is characterized by a relentless progression of symptoms associated with defined neuropathologic changes.

Individuals with trisomy 21, or Down syndrome (DS), develop a clinical syndrome of dementia that has the same clinical and neuropathologic characteristics of AD as described in individuals without DS. The only difference is the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.

Pathophysiology: The reason AD is more frequent in individuals with DS is not known. All recognized mutations and some risk factors (age, head trauma) for AD are associated with increased production of amyloid beta. Amyloid beta-42, a neurotoxic fragment of the amyloid precursor protein (APP), is released when APP is catabolized. This accumulation results in selective and progressive loss of neurons due to poorly understood mechanisms. The hippocampus, amygdala, and mesotemporal regions are affected most frequently, followed by other neocortical areas.

Cells that produce neurotransmitters in the nucleus basalis of Meynert (acetylcholine), locus ceruleus (epinephrine), and midbrain raphe nuclei (serotonin) also are affected. This is consistent with the clinical presentation. This process involves a certain degree of asymmetry, which explains the protean clinical characteristics. Individuals with greater frontal and temporal lobe damage may experience increased agitation and psychiatric disorders. Individuals with greater damage in the left hemisphere may experience language disturbances. Neuronal death is followed by disease of related neurons, probably due to lack of neurotrophic factors. A certain degree of neuronal plasticity provides a limited balance, keeping the individual functioning at a normal level for a period of time, although the disease process is active.

A complementary hypothesis suggests that different thresholds exist for the presentation of clinical symptoms, depending on the cognitive reserve of the individual. Greater brain weight, larger number of neurons, and higher educational level may increase cognitive reserve.

ased on these 2 interrelated hypotheses, DS individuals develop symptoms earlier in life because of their increased production of amyloid beta-42 and their smaller cognitive reserve.

Frequency:

In the US: Several studies document that most if not all individuals with DS develop AD. This is unrelated to the degree of mental retardation; AD is not more prominent in individuals with mental retardation from other causes. Due to better clinical management, most persons with DS now reach the age of 40 years. Thus, the frequency of AD is likely to increase.
he percentage of people with DS and AD varies in some of the epidemiologic studies presented. A review of these studies showed that 10-25% of patients had AD when aged 40-49 years, 20-50% had AD when aged 50-59 years, and 60-75% had AD when older than 60 years.

Internationally: No particular geographic distribution exists. A similar clinical picture has been described in other countries.

Mortality/Morbidity: The disease is responsible for the sharp decline in survival in DS patients older than 45 years.

Race: No documentation exists that race influences prevalence.

Sex: Few studies have evaluated the influence of sex, and some of the results are contradictory. For example, sex was not associated with earlier onset in some studies, while other studies found that women were at increased risk of earlier onset than men. Some earlier conclusions are presented below.

Women with DS who are aged 40-65 years are at a higher risk for AD than men with DS who are of comparable age.

Women with DS and menopause at age 46 years or younger had earlier onset and increased risk of AD than those with menopause after age 46 years.

Age:

Age and the presence of trisomy 21 are the most important factors in disease development.

The neuropathologic findings related to AD have been described in all DS individuals older than 35 years.

Early clinical signs and symptoms are observed at the end of the fifth decade to the beginning of the sixth decade of life. Mean age at the time of clinical diagnosis is 51 ± 6 years.

Treatment
Medical Care: The following medications have been used or found to be useful in AD. Only one (donepezil) was evaluated in individuals with DS.

Cholinesterase inhibitors - Tacrine, donepezil, rivastigmine, galantamine.

Antioxidants - Alpha-tocopherol (vitamin E) and selegiline

Estrogen replacement therapy

NSAIDs and COX-2 inhibitors

N-methyl-D-aspartate antagonists (NMDA)

Surgical Care:

Some patients may require placement of a feeding tube.

Some patients may need a tracheostomy.

Consultations:

Consult a neurologist and/or gerontologist for diagnosis, advice, and follow-up care.

Consult rehabilitation specialists.

In advanced stages, consult an ethics specialist regarding decisions for resuscitation and/or hospice care.

Diet:

No particular diet is required. As the disease progresses, dysphagia may become a prominent feature and changes in food texture usually are recommended. A dietitian's help may be needed at this stage.

n advanced stages, limited intake may be associated with severe weight loss. At this point, consider a feeding tube.

Activity: A good comprehensive plan for individuals with AD should include a variety of physical and social activities.

Medication

The following medications have been recommended or used in individuals with AD. The cholinesterase inhibitor donepezil is the only drug investigated in individuals with DS. A few studies in persons with DS and AD have reported that donepezil slowed down the progression of the disorder and/or improved the condition somewhat. Some studies reported adverse effects, such as urinary incontinence; however, other studies found tolerance to be very good.
Drug Category: Cholinesterase inhibitors -- The nucleus basalis of Meynert degenerates in AD, leading to a deficiency in CAT that results in deficient production of ACh in the cerebral cortex. This cholinergic deficiency is associated with behavioral changes, mainly memory dysfunction, observed in AD. Inhibitors of AChE, the enzyme that metabolizes ACh, may improve symptoms of AD. These drugs do not have clinically significant drug-drug interactions. These drugs can exacerbate stomach ulcers, asthma, and cardiac arrhythmias.

Drug Name	Tacrine (Cognex) -- Indicated in early stages of dementia; centrally acting, reversible cholinesterase inhibitor that slows degradation of ACh produced by remaining cholinergic neurons; these effects in turn increase ACh concentrations in cerebral cortex. Use is very limited because of adverse effects.
Adult Dose	10 mg PO qid; increase by 40 mg/d with adjustments q6wk; not to exceed 160 mg/d
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity; history of jaundice (>3 mg/dL bilirubin) associated with tacrine
Interactions	Inhibits hepatic microsomal enzyme CYP450 and potentiates theophylline and cimetidine effects; increases toxicity of cholinesterase inhibitors, succinylcholine, or cholinergic agonists; antagonized by cigarette smoke; concomitant administration of NSAIDs may cause GI bleeding
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in bladder outlet obstruction, sick sinus syndrome, cardiovascular disease, peptic ulcer, and asthma; increased serum transaminases may occur

Drug Name	Donepezil (Aricept) -- Noncompetitively inhibits centrally active AChE, which in turn may increase concentrations of ACh available for synaptic transmission in CNS; indicated in mild forms of AD. The only drug with clinical trials in persons with DS.
Adult Dose	Initially 5 mg/d PO hs; may increase up to 10 mg qhs after 4-6 wk
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	Agents that affect CYP450, CYP2D6, and CYP3A4 enzymes may affect rate of elimination; antagonizes anticholinergic medications; effects of succinylcholine, cholinesterase inhibitors, or cholinergic agonists are increased when administered concurrently; monitor for GI bleeding when using concomitantly with NSAIDs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in sick sinus syndrome, other supraventricular cardiac conduction disorders, or asthma

Drug Name	Rivastigmine (Exelon) -- Indicated in mild-to-moderate dementia. Competitive and reversible inhibitor of acetylcholinesterase. While mechanism of action unknown, may reversibly inhibit cholinesterase, which may in turn increase concentrations of ACh available for synaptic transmission in CNS and enhance cholinergic function. Effect may lessen as disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that acetylcholinesterase inhibitors alter the course of underlying dementia.
Adult Dose	Initially 1.5 mg bid; if tolerated, increase by 1.5 mg bid q2wk; usual range, 6-12 mg; not to exceed 12 mg/d; take with meals
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of anticholinergics; increases effects of cholinergic agonists and neuromuscular blockers; risk of bradycardia increases when administered concurrently with beta-blockers without ISA, calcium channel blockers diltiazem or verapamil, or digoxin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause significant nausea, vomiting, anorexia, and weight loss (occurs frequently during titration phase, and in women); if significant adverse effects occur, patient should discontinue treatment for several doses, then restart at same or next lower dose; if treatment stopped for several days, initiate treatment at lowest daily dose; caution in history of peptic ulcer disease, concurrent NSAID use, sick sinus syndrome, urinary obstruction, pulmonary conditions such as COPD or asthma, and bradycardia or supraventricular conduction conditions

Drug Name	Galantamine (Reminyl) -- Indicated in AD. Recent studies showed some benefits in vascular dementia and vascular dementia combined with AD.
Adult Dose	Initially, 4 mg bid for 1 mo; if well tolerated, increase by 4 mg bid qmo; not to exceed 12 mg bid; take with meals
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity; severe renal dysfunction (ie, <10>
Interactions	Coadministration with other cholinesterase inhibitors (eg, succinylcholine) may increase toxicity; CYP450-2D6 or -3A4 inhibitors (eg, cimetidine, ketoconazole, ritonavir, paroxetine, erythromycin) may decrease elimination and increase serum levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Decrease dose in moderate renal insufficiency or moderate-to-severe hepatic impairment; caution in asthma; may cause bradycardia or AV block; syncope may occur with doses >24 mg/d; cholinergic adverse effects are dose related

Drug Category: Anti-Parkinson agents -- These agents increase availability of dopamine and extend its duration of action.

Drug Name	Selegiline (Eldepryl) -- An irreversible MAOI that has been used experimentally in treating AD; acts as a "suicide" substrate for the enzyme where MAO converts it to an active moiety that combines irreversibly with active site or enzyme's essential FAD cofactor; blocks breakdown of dopamine; in parkinsonism, extends duration of action from each dose of L-dopa; often allows for L-dopa dose reduction; because of greater affinity for type B than for type A active sites, can serve as a selective inhibitor of MAO type B at recommended dose; however, at doses >10 mg/d, significant MAO-A inhibition may occur; no evidence that additional benefit is obtained from doses >10 mg/d. A large double-blind placebo-control study failed to showed any benefit in slowing the progression of the disease. No studies in DS have been reported.
Adult Dose	Initially 5 mg PO qd, increased gradually up to 10 mg/d
Pediatric Dose	Disease state not seen in children
Contraindications	Concomitant use of opioids (eg, meperidine); concurrent administration of SSRIs; antidepressants can probably be used, although concerns exist regarding rare interactions
Interactions	At least 3-5 wk should lapse between discontinuation of fluoxetine and initiation of MAOIs to prevent fatal interactions that have been reported with MAO type A inhibitors; in general, avoid administering MAOIs concomitantly with opioids; severe agitation, hallucinations, and death have occurred with concomitant administration with meperidine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects include nausea, dizziness, and syncope

Drug Category: Antioxidants -- Free radicals, which may damage cell membranes and tissues, are natural byproducts of metabolic processes, especially oxidative metabolism. Eliminating free radicals is hypothesized to prevent neuronal damage.

Drug Name	Alpha-tocopherol (vitamin E, Vita-Plus E, E-Complex-600) -- Protects polyunsaturated fatty acids in cell membranes from attack by free radicals. No studies published using vitamin E in DS. One study involving persons with DS is in progress. A double-blind, placebo-controlled trial with 2000 IU of vitamin E suggested that vitamin E delayed admission to nursing home, functional decline, and death but did not affect cognitive decline in persons with moderate-to-severe AD. Vitamin E 2000 IU/d is considered standard therapy for persons with AD; however, a government panel recommended a lower dose of no more than 1000 IU because of the possibility of coagulation disorders.
Adult Dose	2000 IU PO qd has been used in the treatment of AD (daily requirement is 10-30 mg/d)
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	Increases effect of PO anticoagulants; mineral oil decreases absorption when used concomitantly; delays absorption of iron
Pregnancy	A - Safe in pregnancy
Precautions	May induce vitamin K deficiency; large doses have been associated with necrotizing enterocolitis

Drug Category: N-methyl-D-aspartate antagonists -- Newest class of agents indicated for AD. May be used alone or combined with acetylcholinesterase inhibitors. Glutamate stimulates 70% of excitatory synapses. The dysfunction of this excitatory system may result in continuous excitation in the neurons and may result in neuronal damage and death. This excitatory neuronal death may be related to the stimulation of the glutamate receptor N-methyl-D-aspartate (NMDA). Blocking this receptor may prevent the excitatory damage that results from excessive glutamate release.

Drug Name	Memantine (Namenda, Axura) -- Indicated for moderate-to-severe Alzheimer disease. NNMDA antagonist. NMDA receptor stimulation in the CNS by glutamate (an excitatory amino acid) is hypothesized to contribute to Alzheimer symptoms.
Adult Dose	5 mg PO qd initially; gradually titrate to a 20-mg/d target dose using following dosage regimen (allow >1 wk between each dosage increase): 5 mg PO bid; then, 5 mg PO every am and 10 mg PO every pm; then, 10 mg PO bid
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	Coadministration with drugs causing alkaline urine (eg, sodium bicarbonate, carbonic anhydrase inhibitors) may decrease clearance by 80%; thus, accumulation and toxicity may occur; coadministration with other NMDA antagonists (eg, amantadine, ketamine, dextromethorphan) may increase toxicity risk; concurrent use with other drugs renally eliminated via tubular secretion (eg, hydrochlorothiazide, triamterene, cimetidine, ranitidine, quinidine, nicotine) may alter plasma levels of either drug
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Common adverse effects include dizziness (7%), headache (6%), and constipation (5%); predominantly excreted renally; no data support use in severe renal impairment

Alzheimer Disease

2007-11-22T19:43:00.000-08:00

Background: Alzheimer disease (AD) is the most common cause of dementia, which is an acquired cognitive and behavioral impairment of sufficient severity to markedly interfere with social and occupational functioning.

AD affects approximately 5 million people in the United States and more than 30 million people worldwide. A larger number of individuals have decreased levels of cognitive impairment (eg, minimal cognitive impairment), which frequently evolves into a full-blown dementia, thereby increasing the number of affected persons. The prevalence of AD is expected to substantially increase in this century because it preferentially affects the elderly, who constitute the fastest growing age group in many, especially industrialized, countries. Statistical projections indicate that the number of persons affected by the disorder in the United States will nearly triple by the year 2050.

AD is also a major public health problem from the economic perspective. In the United States, the cost of caring for patients with AD was more than $110 billion per year in the early 1990s, and the average yearly cost per patient is about $45,000. Because methods for assessing the economic effects of neurodegenerative disorders are still in their infancy, these figures must be interpreted as underestimates.

Many excellent treatises on AD have reviewed important aspects of the disorder in considerable detail. This article is intended to be a comprehensive but not necessarily exhaustive review of AD.

Pathophysiology: The anatomic pathology of AD includes neurofibrillary tangles (NFTs); senile plaques (SPs) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. In his original report on the disorder, Alois Alzheimer described the co-occurrence of NFTs and SPs, which is now universally accepted as a hallmark of the disease.

Although NFTs and SPs are characteristic of AD, they are not pathognomonic. In fact many other neurodegenerative conditions distinct from AD are characterized by NFTs (eg, progressive supranuclear palsy, dementia pugilistica) or SPs (eg, normal aging). Therefore, the mere presence of these lesions is not sufficient to diagnose AD. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD.

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer's original papers were published. These include (1) the granulovacuolar degeneration of Shimkowicz; (2) the neuropil threads of Braak et al; and (3) neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

Some authorities believed that NFTs, when present in low densities and essentially confined to the hippocampus, were part of normal aging. However, the histologic stages for AD that Braak et al formulated includes an early stage in which a low density of NFTs is present in the entorhinal and perirhinal (ie, transentorhinal) cortices. Therefore, even small numbers of NFTs in these areas of the medial temporal lobe should be considered abnormal. The issue of whether these early changes should be considered part of minimal cognitive impairment (Kuljis, 1997) or the early stages of AD instead remains to be settled experimentally.

In contrast, the presence of even low numbers of NFTs in the cerebral neocortex is considered abnormal and indicates AD if associated with SPs in that location, with a specific topographic pattern. Granulovacuolar degeneration occurs almost exclusively in the hippocampus and has received less attention than neuropil threads, which are an array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion suggests neuropil alterations beyond those merely due to NFTs and SPs and indicates an even more widespread insult to the cortical circuitry than that visualized by studying only plaques and tangles.

Despite the wide distribution of these lesions in the cerebral cortex, the increasing consensus is that most patients with AD have a relatively consistent topographic pattern. NFTs are initially and most densely distributed in the medial aspect and in the pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most severely. As AD progresses, NFTs accumulate in most other cortical regions, beginning in high-order association regions and less frequently in the primary motor and sensory regions. SPs also accumulate primarily in association cortices and in the hippocampus. Plaques and tangles have relatively discrete and stereotypical patterns of laminar distribution in the cerebral cortex, which indicate predominant involvement of corticocortical connections, as many investigators have observed.

According to this formulation, the pathophysiologic mechanism underlying the clinical manifestations of AD is corticocortical disconnection due to the loss of medium-sized pyramidal neurons effecting such connections. However, multiple lines of evidence suggest that several classes of local circuit neurons are selectively lost throughout the cerebral cortex as well; these data demonstrate that the corticocortical disconnection is not the only alteration in cortical circuitry that mediates the symptoms of AD.

Frequency:

In the US: The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

Internationally: Prevalences similar to those in the United States have been reported in industrialized nations. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States.

Mortality/Morbidity:

Second to only certain cancers and cardiovascular disease, AD is frequently considered a leading cause of death in the United States.

The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has experienced the debilitating effects of AD for many years.

Race: Some claim that AD affects certain ethnic and racial groups more severely than others, but more study is needed before reliable statements about racial predilections can be made.

Sex: AD affects both men and women. Many studies indicate that the risk of AD is significantly higher in women than in men. Some authorities have postulated that this difference is due to the loss of the neurotrophic effect of estrogen in postmenopausal women. Other factors may also influence this relative difference.

Age: The prevalence of AD increases with age.

AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of AD.

More than 90% of cases of AD are sporadic and occur in individuals older than 60 years.

Of interest, results of some studies of nonagenarians and centenarians suggest that the risk decreases in individuals older than 80 or 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed.

Treatment
Medical Care: Therapeutic approaches to AD are based on developing theories of its pathogenesis and on the need to alleviate its cognitive and behavioral manifestations. The predominantly symptomatic approach preceded, by many decades, the more recent interventions based on our improving understanding of the pathogenesis and pathophysiology of AD.

To date, no interventions have been shown to convincingly prevent AD or slow its progression. Medical treatments for AD include psychotropic medications and behavioral interventions, cholinesterase inhibitors (ChEIs) and the avoidance of centrally acting anticholinergic medications, N-methyl-D-aspartate (NMDA) antagonists, and other and new therapeutic interventions.

Psychotropic medications and behavioral interventions
- A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior, which are best approached symptomatically. These interventions are useful in managing AD, though their effectiveness is often modest and temporary, and they do not prevent the eventual deterioration of the patient's condition.
- Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).
- No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the US Food and Drug Administration (FDA) has not approved any agent for the treatment of AD. However, medications that many practitioners prefer are haloperidol, risperidone, olanzapine, and (more recently) quetiapine. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients.
- Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations of dementia with cortical Lewy bodies (DCLB), also known as Lewy body dementia (LBD), because patients with DCLB may be extremely sensitive to these agents. Adverse reactions to conventional neuroleptics have fueled the search for new agents that alleviate disruptive behavior while minimizing the occurrence of extrapyramidal manifestations and worsening of motor and behavioral performance, which is frequently observed in DCLB. This is the basis for the recent trend to use new-generation agents to alleviate the behavioral manifestations of AD, with therapy usually extending into the more advanced stages of the disorder.
- Results of several studies indicate that anticonvulsants (eg, gabapentin) may have a role in the treatment of behavioral problems in patients with AD.

Cholinesterase inhibitors
- A strategy widely used to address the symptoms of AD is palliating the deficiency in cholinergic innervation to the cerebral cortex. Numerous lines of evidence indicate that the corticipetal cholinergic system is targeted relatively early and more or less selectively in AD. For over 2 decades, AD has been characterized by substantial loss of acetylcholine (ACh) in the cerebral cortex, progressive decline in cortical levels of choline acetyltransferase (biosynthetic enzyme necessary for the synthesis of ACh), and severe loss of neurons in the subcortical cholinergic nuclei that project to the cerebral neocortex (ie, basal nucleus of Meynert) and hippocampus (ie, medial septal nuclei).
- These observations have led to the theory that some of the clinical manifestations of AD are due to loss of the cholinergic innervation to the cerebral cortex. In turn, this theory led to development of an increasing number of compounds capable of palliating the cholinergic defect by interfering with the degradation of ACh by acetylcholinesterase (AChE), the synaptic, or specific, form of cholinesterase. More recent compounds include substances capable of blocking the nonsynaptic, or nonspecific, cholinesterases; these are frequently called butyrylcholinesterases (BuChEs).

An often neglected aspect of palliation of cholinergic deficits is the avoidance of centrally acting anticholinergic medications. Patients not uncommonly receive both ChEIs and anticholinergic agents, which negate or at least counteracting the effects of the former. Therefore, a careful listing of the patient's medications is important to reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents.

N-methyl-D-aspartate antagonists: A relatively new category of drugs, NMDA antagonists, is based on an entirely different mechanism of action. Memantine is the first NMDA antagonist approved in the United States. This agent is approved for treating the advanced stages of AD, in contrast with ChEIs, which are approved for only the early and intermediate stages. Of interest, memantine may also be helpful in other neurodegenerative conditions, such as Huntington disease, AIDS-related dementia, and vascular dementia.
Antidepressants: The role of antidepressants in the treatment of mood disorders, and especially depression, cannot be overemphasized. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition can considerably improve their cognitive and noncognitive performance. Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have.

Other and new therapeutic interventions: Other agents proposed for the treatment of AD and new drugs being developed are free-radical scavengers, and estrogen- or selective estrogen-receptor agonists, anti-inflammatories, and clioquinoline and other drugs.

The proposal that oxidative stress causes AD and evidence suggesting that estrogen has a trophic effect on certain neuronal populations that is lost after menopause were the bases for previous recommendations to give high doses of tocopherol (1000 IU PO bid) to all patients and estrogen replacement therapy to postmenopausal women with AD. Federal and institutional policies do not mandate use of these agents; their common use reflects the widespread belief that they may be beneficial. Because findings show that estrogen supplementation may be associated with cognitive impairment and that high-dose tocopherol may cause adverse cardiovascular events, the entire body of evidence is being re-evaluated, and few (if any) now recommend these treatments. Results to date indicate that patients with clinical dementia do not benefit from estrogen replacement therapy.
An additional treatment, the use of anti-inflammatory agents, is based on the postulation that inflammation is needed for many AD lesions, especially SPs, to develop and progress through the theoretical stages of increasing severity. This theory has received considerable support, and many studies purportedly show improvement or a lack of progression of the manifestations of AD over relatively short periods of anti-inflammatory therapy. No present recommendations require the use of anti-inflammatories in AD; results of large-scale trials still underway have not been published.
New drugs under development include clioquinoline, an antibiotic that may help reduce brain amyloid deposition in patients with AD. Other, unrelated compounds under development and are also expected to reduce or eliminate cerebral amyloid deposition and possibly NFTs.

Surgical Care: No accepted surgical treatments exist for AD. One unconfirmed postulate was that omental transposition to the brain may be beneficial in AD, but most experts remain highly skeptical of this claim. Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD. Studies are also underway to evaluate a claim that ventriculoperitoneal shunting of CSF may be beneficial in AD.

Diet: No special dietary considerations exist for AD.

Activity:

Both physical and mental activities are recommended for patients with AD. Many experts recommend mentally challenging activities, such as doing crossword puzzles and brainteasers, both to prevent deterioration and to slow its rate.

The mental activities should be kept within a reasonable level of difficulty for the patient, they should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes.

Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently.

Unfortunately, little standardization and rigorous testing has been done to validate this treatment modality.

Some investigators have attempted various forms of cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a substantial experimental study must still be performed to determine if it is useful in AD.

Medication
The mainstay of therapy is the use of centrally acting cholinesterase inhibitors to palliate the depletion of ACh in the cerebral cortex and hippocampus. Because the clinical manifestations of AD are believed to be partly due to a loss of the cholinergic innervation to the cerebral cortex, compounds have been developed to palliate the cholinergic defect by interfering with the degradation of ACh by AChE, the synaptic (or specific) form of cholinesterase. Some of the more recently available compounds are substances that inhibit also the nonsynaptic (or nonspecific) cholinesterases, which are frequently called BuChE.

AChE inhibitors approved by the FDA for use in the early and intermediate stages of AD are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy because BuChE levels increase during the course of AD and are present in some AD lesions, including senile plaques. At present, tacrine, is used seldom if at all because it has been superseded by the other 3. To date, the ChEIs is the only class of drugs that has been formally approved for use in AD.

An increasing number of clinical studies demonstrate that cholinesterase inhibition can have modest but detectable effects, such as improvement in cognitive performance, as measured by tools such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). More recent evidence indicates that ChEIs may also alleviate the noncognitive manifestations of AD. For example, they can ameliorate behavioral manifestations, as assessed by using tools such as the Neuropsychiatric Inventory, and they may improve the performance of activities of daily living, as evaluated by using the Progressive Deterioration Scale.

In general, the benefits are temporary because ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. Although the increasingly large family of ChEIs was originally expected to help in only the early and intermediate stages of AD, results indicate that (1) they improve cognitive performance in advanced stages; (2) they significantly improve behavioral manifestations (eg, wandering, agitation, socially inappropriate behavior associated with advanced stages); and (3) they help in patients with presumed vascular components added to dementia due to AD, as well as in patients with the DLB, which often co-occurs or overlaps with AD (Lewy body variant of AD).

Therefore, the modest benefits of ChEIs seem to extend beyond the low-level cognitive impairment in the early stages of AD. This phenomenon has not been fully explained. Interesting speculations, which remain to be tested experimentally, include the possibility that some of the newly recognized benefits in advanced behavioral and cognitive performance may be associated with the inhibition of BuChE, in addition to AChE, a characteristic of only some ChEIs currently in use.

The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow uptitration to the desired maintenance dose. Use of drugs whose absorption peaks are blunted by food (eg, rivastigmine) can further mitigate adverse effects and improve the tolerability of ChEI treatment.

It may be reasonable to perform serial trials of different individual ChEIs when effectiveness of 1 medication decreases or if adverse effects are not tolerable. A new agent in this class should be tapered up when one switches among ChEIs, with the understanding that cognition and/or behavior may temporarily worsen during this period. No current evidence supports the use of more than 1 ChEI at a time. Another important clinical caveat is that, once a ChEI is started, it should be continued indefinitely. Stopping the medication may precipitate an acute, and possibly severe, cognitive and behavioral decline that may not be resolved by restarting the ChEI. The cause for this potentially catastrophic decline is not known.

Drug Category: Centrally acting AChE inhibitors -- These agents are used to palliate cholinergic deficiency.

Drug Name	Rivastigmine (Exelon) -- Centrally acting AChE and BuChE inhibitor.
Adult Dose	1.5 mg PO bid for 1 mo, 3 mg PO bid for 1 mo, 4.5 mg PO for 1 mo, then 6 mg PO bid thereafter
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported; metabolized by cholinesterases (no significant hepatic metabolism)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer with large meals to minimize adverse effects; titrate up slowly

Drug Name	Donepezil (Aricept) -- Centrally acting AchE but not BuChE inhibitor
Adult Dose	5 mg PO qd for 3-4 wk, the 10 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; sick sinus syndrome, other supraventricular cardiac conduction abnormalities; peptic ulcer disease; bladder outflow obstruction
Interactions	Increases effects of succinylcholine, ChEIs, or cholinergic agonists; may increase fluvoxamine levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with seizures, asthma, sick sinus syndrome, or other supraventricular conduction abnormalities

Drug Name	Galantamine (Reminyl) -- Enhances central cholinergic function; likely to inhibit AChE.
Adult Dose	16-24 mg PO qd bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Can interfere with effect of anticholinergics; synergistic effect if given with other ChEIs, succinylcholine, or other neuromuscular blocking agents
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Most frequent adverse events are nausea, vomiting, diarrhea, anorexia, and weight loss; dose titration needed in patients with hepatic and/or renal dysfunction; can cause bladder outflow obstruction; prescribe with care in patients with lung disease; could potentiate tendency for seizures

Drug Category: NMDA antagonists -- The newest class of agents indicated for the treatment of AD. As of October 2003, the only approved drug in this class is memantine. These agents may be used alone or combined with AChE inhibitors. Most believe that combination therapy offers superior benefits compared with results of either category of agent alone.

Drug Name	Memantine (Namenda, Axura) -- NMDA antagonist indicated for all stages of AD. NMDA-receptor overstimulation in CNS by glutamate (excitatory amino acid) may contribute to symptoms; no evidence confirms glutamatergic deficit in AD.
Adult Dose	5 mg PO qd, gradually titrate to 20-mg/d target dose as follows (allow >1 wk between increases): 5 mg PO bid, 5 mg PO q am, 10 mg PO q pm, 10 mg PO bid
Pediatric Dose	Not indicated
Contraindications	Documented hypersensitivity
Interactions	Coadministration with drugs causing alkaline urine (eg, sodium bicarbonate, carbonic anhydrase inhibitors) may decrease clearance by 80%, leading to accumulation and toxicity; coadministration with other NMDA antagonists (eg, amantadine, ketamine, dextromethorphan) may increase toxicity; concurrent use with another drug eliminated via renal tubular secretion (eg, hydrochlorothiazide, triamterene, cimetidine, ranitidine, quinidine, nicotine) may alter plasma levels of both
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Common adverse effects are dizziness (7%), headache (6%), and constipation (5%); predominantly excreted renally, no data support use in severe renal impairment

span >Drug Category: Free-radical scavengers -- These agents are used to palliate postulated oxidative damage as a cause or contributor to AD. Recent results indicate that high-dose tocopherol supplementation increases risk of adverse cardiovascular outcomes. Therefore, use of these agents is not currently recommended, and most practitioners have abandoned their use.

Drug Name	Tocopherol (Vitamin E) -- Nutritional supplement with antioxidant properties
Adult Dose	1000 IU PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Increases hypoprothrombinemic response to oral anticoagulants
Pregnancy	X - Contraindicated in pregnancy
Precautions	May cause fatigue, headaches, and blurred vision

Alcohol (Ethanol) Related Neuropathy

2007-11-22T19:37:00.000-08:00

Background: The clinical symptoms of alcoholic peripheral neuropathy were described more than 200 years ago. The descriptions by Lettsom (1787) and Jackson (1822) have led to the recognition and association of peripheral nerve disease with excessive ethanol use. Several terms connote alcohol neuropathy, including neuritic beriberi, neuropathic beriberi, and alcoholic neuritis. In patients with alcoholic neuropathy, nutritional deficiency goes hand in hand with alcohol abuse.

The similarity between beriberi and alcoholic neuropathy had long been noted, but Shattuck in 1928 was the first to seriously discuss the relationship. He suggested that "polyneuritis of chronic alcoholism" was caused chiefly by failure to take or assimilate food containing a sufficient quantity of vitamin Bx and might properly be regarded as true beriberi. However, this theory may be only partly true.

Pathophysiology: The precise pathogenesis of alcohol neuropathy remains unclear. Separating ethanol use from nutritional and vitamin deficiencies, especially thiamine, has always been difficult and a source of long-standing debate. Nutritional deficiency (frequently associated with alcohol neuropathy) and/or the direct toxic effect of alcohol or both have been implicated and studied. In Wernicke-Korsakoff syndrome, a clear association between reduction of thiamine levels or thiamine-mediated enzyme activity (transketolase) has been established, though this has not been conclusively established in the case of peripheral neuropathy.

In their comparison of alcoholics and nonalcoholic control subjects, Behse and Buchthal concluded that nutritional deficiencies alone did not produce the neuropathy.

Monforte et al concluded that alcohol appears to be toxic to autonomic and peripheral nerves in a dose-dependent manner, on the basis of heart rate, blood pressure, and electrophysiologic examination.

In a study of macaque monkeys, Hallet et al failed to produce clinical and electrophysiologic signs of neuropathy in monkeys that were given a certain amount of alcohol for 3-5 years.

Studies in rats also failed to demonstrate a direct toxic effect of alcohol on the peripheral nerves.

Most studies of peripheral neuropathy in humans and animals implicate nutritional deficiency as an etiology as opposed to the direct toxic effect of alcohol.

Frequency:

Internationally: Depending on criteria and patient selection, incidence of peripheral neuropathy ranging from 10-50% has been reported. These studies included alcoholics hospitalized for other reasons or for detoxification. Neuropathy is more prevalent in frequent, heavy, and continuous drinkers compared to more episodic drinkers (Monforte, 1995). When electrodiagnostic criteria are added, neuropathy detection increases to 25-90% (Vittadini, 2001).

Mortality/Morbidity: Johnson and Robinson studied the mortality rate of alcoholics with autonomic neuropathy.

Their findings suggested that evidence of vagal neuropathy in long-term alcoholics is associated with a significantly higher mortality rate than in the general population (a reported 88% survival rate at 7 years in alcoholics with autonomic neuropathy as compared to 94% in the general population).

Deaths due to cardiovascular disease are a major factor.

Many deaths were attributed to strokes, since heavy alcohol consumption is a significant risk factor for stroke.

Sex:

A high incidence of alcoholic polyneuropathy has been observed in women.

Treatment
Medical Care: Treatment is directed toward stopping further damage to the peripheral nerves and returning to normal functioning. These can be achieved by alcohol abstinence, a nutritionally balanced diet supplemented by all B vitamins, and rehabilitation. However, in the setting of ongoing ethanol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients.

Acute Stroke Management

2007-11-22T19:32:00.000-08:00

Background

Stroke is the clinical term for acute loss of perfusion to vascular territory of the brain, resulting in ischemia and a corresponding loss of neurologic function. Classified as either hemorrhagic or ischemic, strokes typically manifest with the sudden onset of focal neurologic deficits, such as weakness, sensory deficit, or difficulties with language. Ischemic strokes have a heterogeneous group of causes, including thrombosis, embolism, and hypoperfusion, whereas hemorrhagic strokes can be either intraparenchymal or subarachnoid.

Only in recent years have advances been made that enable physicians to significantly improve the outcome of this devastating disease. A new era in acute stroke care began in 1995, when the National Institute of Neurologic Disorders and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Study Group first presented data indicating that early administration of t-PA benefited a carefully selected patient group with acute ischemic stroke (AIS). Currently, t-PA is the only approved therapy for AIS, and despite proven efficacy, utilization rates of rt-PA remain low.

Pathophysiology

The brain is the most metabolically active organ in the body. While representing only 2% of the body's mass, it requires 15-20% of the total resting cardiac output to provide the necessary glucose and oxygen for its metabolism. Ischemic strokes result from events that limit or stop blood flow, such as embolism, thrombosis in situ, or relative hypoperfusion. As blood flow decreases, neurons cease functioning, and irreversible neuronal ischemia and injury begin at blood flow rates of less than 18 mL/100 mg/min.

Ischemic cascade

The processes involved in stroke injury at the cellular level are referred to as the ischemic cascade. Many factors are thought to result in cell death and dysfunction, and others are being discovered at a rapid rate. Within seconds to minutes of the loss of glucose and oxygen delivery to neurons, the cellular ischemic cascade begins. This is a complex process that begins with cessation of the normal electrophysiologic function of the cells. The resultant neuronal and glial injury produces edema in the ensuing hours to days after stroke, causing further injury to the surrounding tissues.

Ischemic penumbra

An acute vascular occlusion produces heterogeneous regions of ischemia in the dependent vascular territory. The quantity of local blood flow is comprised of any residual flow in the major arterial source and the collateral supply, if any. Regions of the brain without significant flow are referred to collectively as the core, and these cells are presumed to die within minutes of stroke onset. Zones of decreased or marginal perfusion are collectively called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours because of marginal tissue perfusion, and currently studied pharmacologic interventions for preservation of neuronal tissue target this penumbra.

Administration of t-PA to the patient with an acute stroke attempts to establish revascularization so that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. Neuroprotective strategies are intended to preserve the penumbral tissues and extend the time window for revascularization techniques. While none to date have shown broad benefit in clinical trials, several trials are underway.

Mechanisms of stroke

Embolic strokes

Emboli may either be of cardiac or arterial origin. Cardiac sources include atrial fibrillation, recent myocardial infarction, prosthetic valves, native valvular disease, endocarditis, mural thrombi, dilated cardiomyopathy, or patent foramen ovale allowing passage of venous circulation emboli. Arterial sources are atherothrombolic or cholesterol emboli that develop in the arch of the aorta and in the extracranial arteries (ie, carotid and vertebral arteries). Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or calcific emboli.

Thrombotic strokes

Thrombotic strokes include large-vessel strokes and small-vessel or lacunar strokes. They are due to in situ occlusions on atherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches. Thrombogenic factors may include injury to and loss of endothelial cells exposing the subendothelium and platelet activation by the subendothelium, activation of the clotting cascade, inhibition of fibrinolysis, and blood stasis. Thrombotic strokes are generally thought to originate on ruptured atherosclerotic plaques. Intracranial atherosclerosis may be the cause in patients with widespread atherosclerosis. In other patients, especially younger patients, other causes should be considered, including hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency), sickle cell disease, fibromuscular dysplasia, arterial dissections, and vasoconstriction associated with substance abuse.

Lacunar stroke

Lacunar strokes represent 20% of all ischemic strokes. They occur when the penetrating branches of the middle cerebral artery (MCA), the lenticulostriate arteries, or the penetrating branches of the circle of Willis, vertebral artery, or basilar artery become occluded. Causes of lacunar infarcts include microatheroma, lipohyalinosis, fibrinoid necrosis secondary to hypertension or vasculitis, hyaline arteriosclerosis, and amyloid angiopathy. The great majority are related to hypertension.

Watershed infarcts

These infarcts, also known as border zone infarcts, develop from relative hypoperfusion in the most distal arterial territories and can produce bilateral symptoms. Frequently, these occur perioperatively or in situations of prolonged hypotension.

Frequency

United States

Approximately 705,000 strokes occur each year, including both new and recurrent cases. Of these strokes, approximately 625,000 are ischemic strokes. By the year 2025, the annual number of strokes is expected to reach 1 million. Currently, more than 4.4 million people in the United States are stroke survivors.

International

As in the United States, stroke is the third leading cause of death in the industrialized countries of Europe and the leading cause of adult disability. The global incidence of stroke will only increase, since the population older than 65 years will rise from 390 million now to 800 million by 2025, representing 10% of the total population.

Mortality/Morbidity

Stroke is the third leading cause of death in the United States (60.2 per 100,000), following cardiac and cancer-related deaths. Approximately 29% of patients die within 1 year following a stroke; this percentage rises in patients older than 65 years. Worldwide in 1990, more than 4.3 million people died of cerebrovascular disorders.
Stroke is the leading cause of disability in the United States; 31% of stroke survivors assistance with daily living, 20% need some type of assistance for walking, and 16% require admission to a long-term care facility. Furthermore, at least one third of stroke survivors have depression as well as many of their care providers.

The direct costs (ie, treatment) and indirect costs (ie, lost productivity) of stroke in the United States are approximately $43 billion/year.

Race

In the United States, stroke has a higher incidence in the black population than in the white population.

In black males, the incidence is approximately 93 per 100,000, with a death rate of approximately 51%. In black females, incidence is 79 per 100,000 with a death rate of 39.2%. Young blacks have a 2-5 times greater risk of ischemic stroke than the white population of the same age, and they are 2.5 times more likely to die of stroke. Blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites.

White males have a stroke incidence of 62.8 per 100,000, with death being the final outcome in 26.3% of cases, compared with women who have a stroke incidence of 59 per 100,000 and a death rate of 39.2%.

Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent lacunar strokes and stroke at an earlier age.

Sex

In patients younger than 60 years, the incidence of stroke is greater in males (3:2 ratio).

Age

Stroke can occur in patients of all ages, including children.

Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur.

Treatment

Medical Care

Medical care for AIS occurs on a continuum, beginning in the prehospital setting and ending at home after discharge. Stroke centers and organized protocols for the acute and in-house treatment of stroke patients have been shown to decrease morbidity and mortality associated with stroke.

Prehospital care personnel are critical elements in the AIS chain of survival. Emergency medical services (EMS) personnel should begin with the ABCs and, once the patient's condition is stable, should perform a more directed assessment and administer supportive treatment.
- Prehospital stroke assessment tools, such as the Cincinnati Prehospital Stroke Scale or Los Angeles Prehospital Stroke Scale, identify patients with potential stroke. Providing supplemental oxygen when indicated, establishing intravenous lines, measuring serum glucose, and administering glucose in hypoglycemic patients are elements of prehospital stroke care.
- Equally important is prehospital triage and notification of a potential stroke patient. This allows for early mobilization of necessary resources, such as a stroke team, radiology, and pharmacy.
- With the creation and certification of primary stroke centers, regional health care systems should determine the best triage policy for potential stroke patients in their area.
The goal of acute stroke management in the emergency department is rapid and efficient care. Continuing from the assessment of the ABCs, stroke patient evaluation and, if eligible, fibrinolytic therapy should be administered within 1 hour from presentation as shown below.
Table 2. NINDS Recommended Stroke Evaluation Time Benchmarks for Potential Thrombolysis Candidate
Time Interval Time Target
Door to doctor

Access to neurologic expertise

Door to CT scan completion

Door to CT scan interpretation

Door to treatment

Admission to monitored bed
10 min

15 min

25 min

45 min

60 min

3 h

Time Interval	Time Target
Door to doctor Access to neurologic expertise Door to CT scan completion Door to CT scan interpretation Door to treatment Admission to monitored bed	10 min 15 min 25 min 45 min 60 min 3 h

Again, general stroke management is a team effort with the nursing and medical staff working closely together. General stroke care issues are outlined in the table below.

Table 3. General Management of Patients With Acute Stroke

Blood glucose	Treat hypoglycemia with D50 Treat hyperglycemia with insulin if serum glucose >200 mg/dL
Blood pressure	See recommendations for thrombolysis candidates and noncandidates.
Cardiac monitor	Continuous monitoring for ischemic changes or atrial fibrillation
Intravenous fluids	Avoid D5W and excessive fluid administration IV isotonic sodium chloride solution at 50 mL/h unless otherwise indicated
Oral intake	NPO initially; aspiration risk is great, avoid oral intake until swallowing assessed
Oxygen	Supplement if indicated (Sa0₂ <90%,>
Temperature	Avoid hyperthermia, oral or rectal acetaminophen as needed

Hypoglycemia and hyperglycemia need to be identified and treated early in the evaluation. Not only can both produce symptoms that mimic ischemic stroke, but both also can aggravate ongoing neuronal ischemia. Administration of glucose in hypoglycemia produces profound and prompt improvement, while insulin should be started for patients with stroke and hyperglycemia. Ongoing studies will help determine the optimal level of glycemic control.
Hyperthermia is infrequently associated with stroke but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is indicated in the presence of fever (temperature >100.4°F).

Supplemental oxygen is recommended when the patient has a documented oxygen requirement. To date, conflicting evidence exists that supernormal oxygenation improves outcome.
Optimal blood pressure targets remain to be determined. Many patients are hypertensive on arrival. Recent American Stroke Association guidelines have reinforced the need for caution in lowering blood pressures acutely. Table 4 shows current recommendations for both candidates and noncandidates for thrombolytic therapy.

In the small proportion of patients with stroke who are relatively hypotensive, pharmacologically increasing blood pressure may improve flow through critical stenoses.

Table 4. Blood Pressure Management in Patients With Stroke*

	Blood Pressure	Treatment
Candidates for fibrinolysis	Pretreatment SBP >185 or DBP >110 mm Hg	Labetalol 10-20 mg IVP 1-2 doses or Enalapril 1.25 mg IVP
	Posttreatment DBP >140 mm Hg SBP >230 mm Hg or DBP 121-140 mm Hg SBP 180-230 mm Hg or DBP 105-120 mm Hg	Sodium nitroprusside (0.5 mcg/kg/min) Labetalol 10-20 mg IVP and consider labetalol infusion at 1-2 mg/min or nicardipine 5 mg/h IV infusion and titrate Labetalol 10 mg IVP, may repeat and double every 10 min up to maximum dose of 150 mg
Noncandidates for fibrinolysis	DBP >140 mm Hg SBP >220 or DBP 121-140 mm Hg or MAP >130 mm Hg SBP <220 mm Hg or DBP 105-120 mm Hg or MAP <130>	Sodium nitroprusside 0.5 mcg/kg/min; may reduce approximately 10-20% Labetalol 10-20 mg IVP over 1-2 min; may repeat and double every 10 min up to maximum dose of 150 mg or nicardipine 5 mg/h IV infusion and titrate Antihypertensive therapy indicated only if AMI, aortic dissection, severe CHF, or hypertensive encephalopathy present

Blood Pressure

Treatment

Candidates for fibrinolysis

Pretreatment
SBP >185 or DBP >110 mm Hg

Labetalol 10-20 mg IVP 1-2 doses or
Enalapril 1.25 mg IVP

Posttreatment
DBP >140 mm Hg

SBP >230 mm Hg or
DBP 121-140 mm Hg

SBP 180-230 mm Hg or
DBP 105-120 mm Hg

Sodium nitroprusside (0.5 mcg/kg/min)

Labetalol 10-20 mg IVP and consider labetalol infusion at 1-2 mg/min or nicardipine 5 mg/h IV infusion and titrate

Labetalol 10 mg IVP, may repeat and double every 10 min up to maximum dose of 150 mg

Noncandidates for fibrinolysis

DBP >140 mm Hg

SBP >220 or
DBP 121-140 mm Hg or
MAP >130 mm Hg

SBP <220 mm Hg or
DBP 105-120 mm Hg or
MAP <130>

Sodium nitroprusside 0.5 mcg/kg/min; may reduce approximately 10-20%

Labetalol 10-20 mg IVP over 1-2 min; may repeat and double every 10 min up to maximum dose of 150 mg or nicardipine 5 mg/h IV infusion and titrate

Antihypertensive therapy indicated only if AMI, aortic dissection, severe CHF, or hypertensive encephalopathy present

*Adopted from 2005 Advanced Cardiac Life Support (ACLS) guidelines and 2003 American Stroke Association Scientific Statement
Abbreviations: SBP - systolic blood pressure; DBP - diastolic blood pressure; IVP - intravenous push; MAP - mean arterial pressure

Fibrinolytic therapy: Intravenous t-PA for appropriate patients within 3 hours from symptom onset remains a Class I recommendation by the American Stroke Association. A recent re-analysis of the original NINDS data reaffirmed the original findings. Similarly, a meta-analysis of published t-PA use demonstrated efficacy and safety comparable to that of the original NINDS trial.

Surgical Care

Surgical intervention is rarely required urgently in AIS; however, current recommendations suggest that neurosurgical care should be available within 2 hours when needed, eg, to evaluate surgical options in hemorrhagic transformation following t-PA or in the management of life-threatening elevations of ICP.

Increased ICP is a life-threatening event occurring in as many as 20% of all strokes; it is more common in large, hemispheric strokes. Edema and herniation are the most common causes of early death in patients with hemispheric stroke.
- Patient position, hyperventilation, hyperosmolar therapy, and rarely, barbiturate coma may be used, as in patients with increased ICP secondary to closed head injury.
- Recent reports of hemicraniectomy to treat life-threatening ICP have suggested that these patients have shorter ICU stays and a lower mortality rate if surgery is performed before clinical deterioration. One randomized clinical trial did not confirm these benefits.
Selected patients with either hemorrhagic transformation or intracerebral hemorrhage after thrombolytic therapy may benefit from surgical evacuation of the hematoma.
If neurosurgical care is not available in house, a transfer policy is encouraged to expedite patient transfer when neurosurgical expertise is needed.

Consultations

Consultations are tailored to individual patient needs.

In the first hours of acute stroke, an experienced professional sufficiently familiar with stroke or a stroke team should be available within 15 minutes of the patient's arrival in the emergency department.
Often, physical medicine and rehabilitation (PM&R), occupational therapy, physical therapy, and speech therapy experts are consulted within the first day of hospitalization.
Consultation of cardiology and vascular surgery or neurosurgery may be warranted based on the results of TTE/TEE, carotid duplex scanning, neuroimaging, and clinical course.
During hospitalization, additional useful consultations include home health care coordinator, rehabilitation coordinator, social worker, psychiatrist (commonly for depression), and dietitian.

Diet

Patients with acute stroke are at great risk of aspiration. All patients should remain NPO until a swallowing assessment is performed.
Because of dysphagia, a temporary feeding tube may be required.
If the patient remains at a significant aspiration risk for the foreseeable future, a percutaneous endoscopic gastrostomy (PEG) feeding tube may be required.
A dietitian can help identify a diet that not only addresses the aspiration risk but also ensures adequate caloric intake to help prevent poststroke malnutrition.
The dietitian also must consider special dietary needs of patients with hypertension, diabetes mellitus, and hyperlipidemia.

Activity

Activity is tailored to the severity of stroke.

Aspiration precautions, with the head of the bed elevated to 30°, need to be observed.
Physical therapy will test and suggest level of activity. This should be performed within the first 24 hours of hospitalization.
Increase activity if tolerated as per the suggestions of the rehabilitation coordinator, with the goal of mobilizing the patient as early as possible. At discharge, encourage patients to increase activity as tolerated.

Medication

While only one drug, t-PA, has demonstrated efficacy and effectiveness in treating AIS and is approved by the US Food and Drug Administration (FDA), other medications are equally important. National consensus panels have included antihypertensives, anticonvulsants, and osmotic agents in their recommendations. Additional agents may be required for comorbid illnesses in many patients with stroke.

Drug Category: Antihypertensives

Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters largely depend on whether the patient is a candidate for thrombolytic therapy. While the target blood pressures may differ, the therapeutic agents are largely the same.

Drug Name	Labetalol (Normodyne)
Description	Adrenergic receptor-blocking agent with both nonselective beta-adrenergic and selective alpha1 competitive receptor-blocking actions. Produces dose-related decreases in blood pressure without inducing reflex tachycardia.
Adult Dose	10-20 mg IV over 1-2 min; may repeat or double q10min; total dose not to exceed 150 mg May initiate IV drip at 1-2 mg/min and increase to 2-8 mg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bronchial asthma; heart block; cardiac failure; cardiogenic shock; symptomatic bradycardia; hypotension
Interactions	Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia resulting from nitroglycerin use without interfering with hypotensive effects; cimetidine may increase blood levels; glutethimide may decrease effects by inducing microsomal enzymes
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired hepatic function; discontinue therapy if signs of liver dysfunction; in elderly patients, response rate may be lower and incidence of toxicity higher

Drug Name	Enalapril (Vasotec)
Description	Angiotensin-converting enzyme (ACE) inhibitor. By inhibiting ACE, decreases circulating angiotensin II levels and suppresses renin-angiotensin-aldosterone system, lowering overall blood pressure.
Adult Dose	0.625-1.25 mg IV; may repeat if inadequate response
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of ACE-induced angioedema or idiopathic or hereditary angioedema; acute renal failure; hyperkalemia
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; diuretics may increase hypotensive effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment, valvular stenosis, or severe CHF

Drug Name	Nicardipine (Cardene)
Description	A calcium channel blocker, inhibiting calcium ion influx into vascular smooth muscle and myocardium.
Adult Dose	Start 5 mg/h IV, increase by 2.5 mg/h q5-15min to a maximum of 15 mg/h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90>
Interactions	May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when administered with beta-blockers, may increase cardiac depression; cimetidine may increase levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired renal or hepatic function; may increase LFTs, and hepatic injury may occur.

Drug Name	Sodium nitroprusside (Nitropress)
Description	Vasodilator that decreases peripheral vascular resistance by direct action of arteriolar smooth muscle. Also decreases venous return through venous dilation.
Adult Dose	0.5 mcg/kg/min IV; slowly titrate within range of 0.5-10 mcg/kg/min; not to exceed 3.5 mg/kg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypertension secondary to arteriovenous shunts or coarctation of aorta
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in increased ICP, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, levels may increase and can cause cyanide toxicity; has ability to lower blood pressure and thus should be used only in those patients with mean arterial pressures >70 mm Hg

Drug Category: Antiplatelet agents

Besides thrombolytics, aspirin is the only other therapeutic agent shown to improve outcome in acute stroke. This class of medications is well known to decrease the risk of stroke recurrence.

Drug Name	Aspirin (Anacin, Bayer Aspirin, Ecotrin, Ascriptin)
Description	Add to treatment if not t-PA candidate. Produces irreversible antiplatelet activity by inhibiting cyclooxygenase, which produces thromboxane A2, a potent platelet activator. Studies have shown that aspirin, started within 48 h of stroke onset and in doses of 50-325 mg/d, reduces risk of early recurrent stroke.
Adult Dose	50-325 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bleeding disorders; liver damage; hypoprothrombinemia; vitamin K deficiency; asthma Because of association with Reye syndrome, do not use in children ( <16 y) with flu Do not administer in first 24 h in patients with stroke who received thrombolytic therapy, though administration of aspirin prior to t-PA is not contraindication
Interactions	Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels; with anticoagulants, additive hypoprothrombinemic effects and increased bleeding time may occur; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, history of blood coagulation defects, or taking anticoagulants

Drug Category: Anticonvulsant agents

While seizures associated with stroke are relatively uncommon, recurrent seizures may be life threatening. Generally, agents used for treating recurrent convulsive seizures are also used in patients with seizures after stroke. Benzodiazepines, typically diazepam and lorazepam, are the first-line drugs for ongoing seizures.

Drug Name	Diazepam (Valium)
Description	Act on GABA receptor complex in limbic system and thalamus, producing calming effect. Useful in controlling active seizures and should be augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital.
Adult Dose	5 mg IV q5-10min; total dose not to exceed 20 mg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute narrow-angle glaucoma or open-angle glaucoma
Interactions	Phenothiazines, barbiturates, alcohols, and MAOIs increase CNS toxicity; drugs that impair hepatic function, such as cimetidine, may increase risk of sedation
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause significant sedation and obscure neurologic examination findings; caution in impaired hepatic function; caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Drug Name	Lorazepam (Ativan)
Description	Short-acting benzodiazepine with moderately long half-life. Has become drug of choice in many centers for treating active seizures.
Adult Dose	1-4 mg IV over 2-10 min; may repeat q10-15min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute narrow-angle glaucoma
Interactions	Alcohol, phenothiazines, barbiturates, and MAOIs increase CNS toxicity; valproate or probenecid may increase serum concentrations
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal, pulmonary, or hepatic impairment, myasthenia gravis, organic brain syndrome, altered mental status, alcohol intoxication, or Parkinson disease

Drug Category: Antipyretic agents

Hyperthermia in acute stroke is potentially harmful and should be treated. Agents with potential bleeding risk should be avoided if possible.

Drug Name	Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)
Description	Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body-heat via vasodilation and sweating.
Adult Dose	325-1000 mg PO/PR q4-6h; not to exceed 4 g/24 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; known G-6-P deficiency; significantly impaired liver function
Interactions	Rifampin can reduce analgesic effects; barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; acetaminophen contained in many OTC products and, combined, these products may result in cumulative acetaminophen doses exceeding recommended maximum dose

Drug Category: Fibrinolytic agents

Tissue plasminogen activator is a fibrinolytic protein that is produced normally by the endothelial lining of blood vessels. It is an enzyme (serine protease) that converts plasminogen to plasmin in the presence of fibrin but produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, it binds to fibrin in the thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis.

While several new fibrinolytic agents have been introduced for AMI, only alteplase has received FDA approval in treating AIS.

Drug Name	Alteplase (Activase)
Description	Commercially manufactured recombinant DNA fibrinolytic protein approved for treatment of AMI, AIS, and acute massive pulmonary embolism.
Adult Dose	0.9 mg/kg IV; not to exceed 90 mg/dose; infuse over 60 min with 10% of total dose administered as initial IV bolus over 1 min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active internal bleeding; stroke within last 3 mo; recent intracranial or intraspinal surgery or trauma; intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm; bleeding diathesis; severe uncontrolled hypertension
Interactions	Drugs that alter platelet function (eg, aspirin, dipyridamole, clopidogrel, abciximab) may increase risk of bleeding prior to, during, or after alteplase therapy Note that criteria for use of IV t-PA preclude use of antiplatelet or antithrombotic agents for 24 h following t-PA infusion
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Noncompressible arterial punctures and internal jugular and subclavian venous punctures must be avoided to minimize bleeding from noncompressible sites; in event of serious bleeding, immediately discontinue alteplase; monitor patients for allergic-type reactions, such as anaphylactoid reaction, laryngeal edema, rash, and urticaria

Acute Inflammatory Demyelinating Polyradiculoneuropathy

2007-11-22T19:31:00.000-08:00

Background: Acute inflammatory demyelinating polyneuropathy (AIDP) is an autoimmune process that is characterized by progressive areflexic weakness and mild sensory changes. Sensory symptoms often precede motor weakness. About 20% of patients end up with respiratory failure. Many variants exist. In the West, the most common presentation is a subacute ascending paralysis. This is associated with distal paresthesias and loss of deep tendon reflexes. Progression is often maximal by the end of 4 weeks, then the condition usually plateaus before slowly improving. In 1859, Landry described 10 cases characterized by ascending paralysis and sensory changes.

During World War I, Guillain, Barré, and Strohl described a series of patients with a similar presentation and decreased or absent deep tendon reflexes. They also described albuminocytologic dissociation in the cerebrospinal fluid (CSF), ie, increased CSF protein in the absence of increased WBCs. This allowed them to differentiate AIDP from poliomyelitis, the most common acute paralytic syndrome of that era. (AIDP often is referred to as Guillain-Barré syndrome [GBS]).

Myelin breakdown and axonal degeneration were observed in nerve biopsies from patients with AIDP by Haymaker and Kernohan in 1949. An allergic etiology was suggested by Krucke in 1955 after he observed lymphocytic infiltrates within biopsy specimens. An autoimmune process was supported by Waksman and Adams when they created the experimental allergic neuritis model by injecting peripheral nerve tissue into rodents.

Pathophysiology: AIDP is believed to be caused by an immunologic attack that is directed against myelin components. This results in a demyelinating polyneuropathy. Both cellular and humoral immune mechanisms appear to play a role. Early inflammatory lesions consist of a lymphocytic infiltrate that is adjacent to segmental demyelination. Macrophages are more prominent several days later.

The peripheral nerve changes consist of varying degrees of perivascular edema, accumulations of mononuclear cells, and paranodal and less commonly, segmental demyelination. They are often multifocal with some predilection for the nerve roots, sites of entrapment, and distal ends. In the axonal variant of GBS, axonal degeneration often predominates. Severe GBS is often associated with axonal degeneration as well, which results in wallerian degeneration. Axonal degeneration occurs either as a primarily axonal process or as a bystander-type axonal degeneration, associated with demyelination. Rarely, the pathologic process extends into the central nervous system.

As the regeneration occurs, nerve sprouting and increased scarring often results.

With electron microscopy, macrophages are observed stripping off the myelin sheath. Humoral molecules such as antimyelin antibodies and complement likely contribute to the process by directing macrophages to Schwann cells by opsonization. Indeed, complement and antibodies have been found to coat the myelin sheath. The changes are observed in nerve roots, peripheral nerves, and cranial nerves. In acute motor axonal neuropathy (AMAN, an AIDP variant), deposited complement is found at the nodes of Ranvier, while myelin often is left undamaged.

Damage to the myelin sheath leads to segmental demyelination. This results in decreased nerve conduction velocity and, at times, conduction block. In this current review, AIDP refers to the more common demyelinating form unless otherwise specified.

Frequency:

In the US: AIDP is the most common acquired demyelinating polyneuropathy. The incidence is 0.6-1.7 cases per 100,000 per year. No significant seasonal variation has been noted.

Internationally: Frequency is not well documented. In rural China, the AMAN variant occurs in clusters during the late summer. Similar outbreaks have been reported in Mexico, Spain, and Jordan.

Mortality/Morbidity: In 3 recent large studies, mortality rate ranged from 2-6%.

In general, death is due to complications of ventilation. Causes include cardiac arrest, pulmonary embolus, sepsis, bronchospasm, pneumothorax, adult respiratory distress syndrome (ARDS), and dysautonomia.

More than 75% of patients have complete or near-complete recovery with no deficit or only mild residual fatigue and distal weakness.

Other patients, almost all of whom required ventilation, report severe dysesthesias or moderately severe distal weakness as residual symptoms. About 15% of patients end up with significant neurological residuals.

Race: AIDP occurs in all races and in all regions of the world.

Sex: The male-to-female ratio is 1.1-1.7:1.

Age: Patients have ranged in age from 2 months to 95 years.

In the United States, age distribution is apparently bimodal, with most patients presenting from 15-35 years or 50-75 years.

In China (and other countries), frequent outbreaks in children aged 2-12 years have been reported.

Treatment
Medical Care: Advances in supportive medical care have resulted in improved survival rates in AIDP.

Mechanical ventilatory assistance is required in about one third of patients with AIDP and lasts for an average of 49 days. Intubation should be performed when FVC drops to less than 15 mL/kg or negative inspiratory pressure is worse than -25 cm H₂O. Tracheostomy is usually recommended if mechanical ventilation will be required for more than 2-3 weeks. Bedridden patients need prophylaxis against thromboembolism. Subcutaneous heparin is the most common agent. Some may also need GI prophylaxis with an H2-blocker (or similar agent).

Enteric nutrition is necessary for patients on mechanical ventilation. Nasogastric tubes or Dubhoff tubes can be used initially. Those requiring more than 2 or 3 weeks or enteric nutrition may require gastrostomy or jejunostomy tube feedings.

Cardiac monitoring is necessary. Chronic sinus tachycardia often responds to beta-blockers or calcium channel blockers. Bradycardia requires atropine treatment, if symptomatic. Heart block may require temporary pacing. Hypertension responds well to beta-blockers. These treatments should be administered cautiously under the direction of a cardiologist or critical care specialist, since one of the main causes of death is iatrogenic hypotension, especially in patients with autonomic failure.

Constipation is common in intubated patients with AIDP, and a bowel regimen is usually necessary. Some patients may also require enemas. Ileus is rare. If it occurs, bowel rest is usually necessary and parenteral nutrition can be used during that time.

Skilled nursing care of intubated patients is necessary to avoid skin breakdown. Special mattresses are available in most intensive care or step-down units. Communication difficulties can lead to frustration and exacerbate depression. Involvement of speech therapy, physical therapy, and occupational therapy is highly recommended. Many patients may require a rehabilitation unit after being weaned off a ventilator.

Conventional immunosuppressant treatments with corticosteroids have failed to show benefit. But immunomodulation with IVIg and plasmapheresis has led to faster recovery, relatively mild disability, and shorter hospital stays. IV steroid therapy alone is not indicated for the treatment of AIDP. Treatment is less likely to be effective if initiated more than 2 weeks after the onset of symptoms. Some patients with mild weakness, especially those presenting during the plateau, may not require immunomodulatory therapy. Plasmapheresis had shown to cut the respirator time and time to independent ambulation, by about half when treatment was given during the first week of the disease.

Surgical Care: Tracheostomy is necessary in many intubated patients. Those requiring long-term enteral nutrition typically require a gastrostomy or jejunostomy.

Consultations:

Neurology: For patients on general medicine or other services, neurological consultation is indicated to manage diagnostic studies and to help determine appropriate treatment.

Critical care: About one third of patients require mechanical ventilation. Any intubated patient or patient who is transferred to an ICU for monitoring should be monitored by a critical care or pulmonary specialist.

Surgery: Some patients may require tracheostomy or a feeding tube for parenteral nutrition.

Cardiology: Patients with arrhythmias in addition to sinus tachycardia or major cardiac rhythm abnormalities should be evaluated by a cardiologist.

Physical medicine and rehabilitation

Diet: No special diet is required.

Activity: Keep patients ambulatory if they are able to walk without assistance. Most patients who are admitted to the hospital require bedrest.

Medication
Immunomodulatory therapy with either IVIg or plasmapheresis has been demonstrated to result in more rapid recovery of AIDP than other treatments or no treatment. Recent large studies have demonstrated that the 2 treatments are equal in efficacy. Bedridden and critically ill patients also require treatment to prevent complications.

The mechanism of action of plasma exchange is not known. Suggested mechanisms include the removal of antibody, complement components, immune complexes, lymphokines, and acute-phase reactants. The generally recommended regimen includes every other day plasma exchange, totaling 6 exchanges in 2 weeks, with 3-3.5 L exchanged per treatment. If venous access is not of sufficient quality to ensure rapid blood withdrawal, a central line should be a consideration (in about 20% of cases).

Plasmapheresis (PE) is more frequently associated with severe adverse effects requiring cessation of therapy, including a bleeding diathesis. In addition, PE requires special, appropriate equipment and trained personnel. Also, younger children may be at risk for bleeding after insertion of wide catheters. Transient hypotension, which might occur, is corrected by adjusting the inflow-to-outflow ratio. Other common side effects include paresthesias, and rarely hypersensitivity reactions and hypocalcemia.

Drug Category: Immunomodulatory agents -- AIDP is believed to be caused by immune dysregulation resulting from an attack against myelin. Therapy directed at the immune system can result in more rapid recovery. IVIG is especially proven highly effective in children.

Drug Name	IV Immunoglobulin (IVIg) or gamma globulin (many manufacturers) -- IVIg is prepared from serum pooled from many donors by fractionation and purification. Most manufacturers include a detergent step to help prevent spread of viruses. Mechanism of action is poorly understood. However, it is believed to act by down-regulating antibody and cytokine production and by neutralizing antibodies specific for myelin. Also appears to down-regulate pro-inflammatory cytokines, such as IL-1 and gamma-IFN. Other proposed mechanisms are Fc receptor blockade and interference with complement cascade (ie, interfering with opsonization).
Adult Dose	0.4 g/kg/d for 5 d has been used most often Alternative regimen is 1-2 g/kg/d for 2 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; IgA immunodeficiency (if present, low-IgA preparations available) Severe congestive heart disease is relative contraindication
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Common adverse effects include headache and itching—pretreatment with acetaminophen and diphenhydramine help prevent these effects Patients with prior cardiac history are at risk for pulmonary edema—if it occurs, furosemide is drug of first choice Rarer adverse effects include aseptic meningitis, stroke, skin rashes, renal tubular necrosis; hepatitis C has been transmitted by IVIg in past, but current preparations include detergent step Can artificially decrease serum sodium and elevate ESR

Drug Name	Plasmapheresis or plasma exchange -- This treatment entails removing blood from body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. Can be performed using either 2 large-bore peripheral IV sites or multiple lumen central line. May not be effective if started more than 2 wk after onset of symptoms.
Adult Dose	Typical protocol: 200-250 mL/kg for each of 4 or 5 exchanges during an 8- to 10-d period
Pediatric Dose	Administer as in adults
Contraindications	Recent myocardial infarction; coronary artery disease; arrhythmias; severe renal failure; severe hepatic failure; bleeding disorder
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Back-to-back plasmapheresis sessions may remove clotting factors and can alter coagulation test results Common adverse effects include headaches Rare cases of myocardial infarction and stroke have been reported

Drug Category: Anticoagulant agents -- Bedridden patients are at risk for deep venous thrombosis. This risk can be reduced by mild anticoagulation.

Drug Name	Heparin -- Given subcutaneously, interacts with antithrombin III to decrease clot proliferation. This can result in decreased incidence of deep venous thrombosis.
Adult Dose	5000 U SC tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Some preparations contain benzyl alcohol as preservative and, when used in large amounts, may be associated with fetal toxicity (ie, gasping syndrome); preservative-free heparin recommended in neonates Use with caution in patients with shock or severe hypotension

Acute Disseminated Encephalomyelitis

2007-11-22T19:29:00.000-08:00

Background: Acute disseminated encephalomyelitis (ADEM) is a nonvasculitic inflammatory demyelinating condition that bears a striking clinical and pathological resemblance to multiple sclerosis (MS). However, in most instances, ADEM and MS cases occurring in children are readily distinguishable on the basis of clinical features and findings on laboratory investigations. MS is typically a chronic relapsing and remitting disease of young adults, while ADEM is typically a monophasic disease of prepubertal children. Abnormalities of findings on cerebrospinal fluid (CSF) immunoglobulin studies are likely in MS but are much less common in ADEM. The onset of ADEM usually occurs in the wake of a clearly identifiable febrile prodromal illness or immunization and in association with prominent constitutional signs and encephalopathy of varied degree, features that are uncommon in MS.

However, the division between these processes is indistinct, which is suggestive of a clinical continuum. Moreover, other conditions along the suggested continuum include optic neuritis, transverse myelitis, and Devic syndrome, clinical entities that may occur as manifestations of either MS or ADEM. Other boundaries of ADEM merge indistinctly with a wide variety of inflammatory encephalitic and vasculitic illnesses as well as monosymptomatic postinfectious illnesses that should remain distinct from ADEM, such as acute cerebellar ataxia (ACA). A further indistinct boundary is shared by ADEM and Guillain-Barré syndrome and is manifested in cases of Miller-Fisher syndrome and encephalomyeloradiculoneuropathy (EMRN).

Susceptibility to either condition is likely the product of multiple factors, including a complex interrelationship of genetics and exposure to infectious agents and possibly other environmental factors. Of particular interest are the indications that susceptibility to either condition is in part age related. Most cases of either MS or of ADEM possibly occur as the result of an inflammatory response provoked by prepubertal infection with a virus, viral vaccine, or other infectious agent. Typically, the manifestations of ADEM occur quickly after this prepubertal febrile systemic illness and are monophasic. In a minority of cases, patients with ADEM experience 1 or 2 prepubertal recurrences followed by remission.

MS, on the other hand, typically manifests as a relapsing-remitting illness in ensuing adolescence or young adulthood, a significant and unexplained latency of effect with apparent permanency of immunodysregulation. Bouts of MS occur without febrile prodrome. Uncommonly, MS develops in prepubertal individuals and ADEM develops in postpubertal individuals, and some cases of adolescent-onset MS may go into remission. In very rare instances, individuals manifest prepubertal ADEM and, after long latency, MS in adolescence.

Pathophysiology: MS and ADEM bear a close pathological resemblance, each resembling the pathology of experimental allergic encephalomyelitis (EAE). The prominence of perivenular round cell inflammation in either illness is a feature that is shared with many forms of encephalitis, but patchy demyelination with preservation of axon cylinders and the prominence of microglial cells in the inflammatory exudate are not.

The pathology of various developmental stages of the MS plaque is more fully characterized than the pathology of the lesions of ADEM. This is because most patients with ADEM recover completely and without apparent pathological residua. Few biopsies have been obtained or submitted to postmortem analysis. MS plaques are known to exhibit organization features, especially in the margins of active plaques, that are not found in cases of ADEM. On the other hand, the general pathological similarities suggest but do not confirm the possibility that ADEM is a forme fruste of MS that is somehow effectively and permanently controlled after one, or possibly a few, demyelinative bouts.

Patients with large tumorlike demyelinating lesions may exhibit a combination of pathological features consistent with both MS and ADEM. The possible relationship between these illnesses is further supported by the similarity of clinical manifestations in either illness and the development of MS during adolescence in a small minority of patients who have had typical ADEM bouts in the first decade of life.

The pathophysiological similarities of these illnesses suggest that the immunologic constitution of susceptible individuals is in some fashion permissive of ADEM, MS, or both and that the degree of susceptibility may describe a gradient with regard to severity and risk for recurrence. The threshold for an initial bout of demyelinative illness may be determined by the combination of this immunologic constitution and the nature of a given antigenic stimulus; the likelihood of recurrence may be determined by the fertility of that constitution for persistence of immuno-dysregulation. Immuno-dysregulation in MS or ADEM may consist of responses that are inadequate, too exuberant, or the combination of both.

If a pathophysiological continuum between MS and ADEM exists, achieving better understanding of the manner in which susceptible individuals with ADEM are able to bring a monophasic or temporarily recurrent immuno-dysregulative response under permanent control is of obvious importance. Cases with characteristics that fall in the indeterminate area of this continuum, such as those that might be labeled recurrent ADEM, represent an important challenge for accurate classification. In some of these cases, appropriately crediting the immune system with tardy but permanent compensation may be important, thus avoiding inappropriate diagnosis of MS, fraught as that is with psychosocial consequences.

The mechanisms of these demyelinative illnesses remain incompletely understood despite the extraordinary richness and complexity of immunologic abnormalities that have been identified after more than a century of clinical, pathological, and laboratory studies. Experimental observations have depended greatly on EAE, a research model that may be more pertinent to ADEM than MS.

However, the possibility of provoking spontaneously recurrent demyelination with this model further supports the concept that ADEM and MS represent a continuum. Basic studies have shown that, in the earliest stages of inflammation, both MS and ADEM are likely to be mediated by stimulated clones of T-helper cells sensitized to autoantigens such as myelin proteins. The complex ensuing inflammatory cascade entails the local action of cytokines and chemokines as well as lymphokine-induced chemotaxis of other cellular mediators of inflammation (eg, other T cell lines, B cells, microglia, phagocytes).

Pathogenic differences of MS and ADEM are likely to arise in part because of differences in details concerning proinflammatory and anti-inflammatory cytokines and chemokines. Interleukin (IL)–1beta, Il-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon (IFN)–gamma, tumor necrosis factor-alpha, and macrophage inflammatory protein-1beta are significantly elevated in CSF compared with the CSF of controls. Granulocyte colony-stimulating factor shows a particularly striking elevation at as much as 38-fold greater concentration than is found in the CSF from control subjects. Elevations of IFN-gamma, IL-6, and IL-8 have been significantly correlated with CSF cell counts and protein concentration in individuals with ADEM. The pattern of cytokine elevation suggests that ADEM involves activation of macrophages, microglial cells, and various Th (T helper)–1 and Th2 cells (Ishizu, 2006).

Additionally, in 2006, Franciotta et al demonstrated that adults with ADEM have higher CSF concentrations of chemokines that recruit or activate neutrophils (CXL1 and CXL7), monocytes (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL17, and CCL22) than healthy normal controls. Moreover, ADEM-associated concentrations of certain of these neutrophils (CXL7 neutrophil activator and the CL1, CCL17, and CCL22 Th2 activators) are higher in the CSF from individuals with ADEM than those with MS. On the other hand, CSF concentrations of the chemokine CCL11 is lower in adults with MS than in the CSF from adults with ADEM or in normal controls.

CSF Th1/Th2 cytokine concentrations were not significantly different in adults with MS, those with ADEM, or in normal healthy controls. No significant differences in serum concentrations of cytokines or chemokines were noted in the 3 adult groups. These findings raise the possibility that elevated chemokine concentrations might serve as biomarkers for ADEM and that they may provide keys to understanding of the nature of and differences in the pathogenesis of ADEM and MS.

Disturbance of the blood-brain barrier is likely to be an important event. The elaboration of antibodies occurs but remains of uncertain significance. Recent evidence in studies of the brains of individuals with MS suggest that gray matter degeneration, especially of descending subcortical fibers, may participate in the progression of MS. Gray matter involvement also occurs in ADEM. Discerning how these inflammatory changes differ in MS or ADEM and how the reactions in either illness are distinguishable from those in other inflammatory and infectious illnesses are among the important subjects of current research.

Frequency:

In the US: In the authors' personal series of more than 150 cases grouped under the general heading ADEM, the ratio of ADEM cases in the first decade of life to adolescent MS cases is approximately 3:1. If the incidence of MS in the second decade of life in the United States is presumed to be approximately 1 case per 100,000, the incidence of first-decade ADEM may be approximately 3 cases per 100,000. Incidence of second-decade ADEM could be estimated, by similarly imprecise methods, at 1.5 cases per 100,000.
Whether the increasing incidence of MS at increasing distance from the equator is also true of ADEM is unknown. Occurrences of both ADEM and MS bouts describe sine wave plots of seasonal incidence in North America, with peak incidence in February to March in North America and lowest incidence in July to August. Some severe forms of ADEM, such as those that occur in the wake of measles and the severe hemorrhagic variant called acute hemorrhagic leukoencephalopathy (AHLE) are probably less commonly encountered than they were prior to widespread immunization against measles and other formerly common and potentially serious illnesses that may serve as triggers for ADEM/AHLE.
On the other hand, the prevalence of some forms of ADEM is possibly increasing in developed nations, rather than merely being diagnosed more frequently because of the increased use of MRI. No direct evidence supports increased prevalence, but concern is raised by evidence that MS prevalence has increased in the women of such nations during the past 4 decades and that the prevalence of childhood or adolescent autoimmune diseases such as juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile-onset diabetes mellitus is also increasing.

Internationally: Little is known about occurrence throughout the world, except that cases are likely to occur in all regions of the world. Genetic factors, prevalence of infectious pathogens, immunization status, degree of skin pigmentation, diet, and other factors may influence risk. Of particular importance is immunization because immunization to pathogens known to provoke ADEM has reduced the incidence of severe forms of ADEM such as those that may follow cases of measles and other viral illnesses. On the other hand, early forms of the Pasteur rabies vaccine may also provoke severe ADEM, a problem that has been resolved by improvement of rabies vaccines. The role of other vaccines in ADEM remains controversial. Areas of the world where malaria is prevalent produce cases of cerebral malaria, likely to be an ADEM variant.

Mortality/Morbidity: Although older studies suggest a 10% mortality rate, the data upon which such estimates were based were obtained in epochs during which measles was prevalent, techniques for intensive care were comparatively primitive, and anti-inflammatory therapies were inadequate. Formerly, deaths occurred in patients with AHLE, a severe ADEM variant, which has become less common since children have received immunization to many common childhood illnesses.

Current acute mortality rates are probably less than 2%, involving cases with fulminant cervical transverse myelitis or brain swelling. Children younger than 2 years are particularly subject to such severe presentations.

Morbidity chiefly includes visual, motor, autonomic, and intellectual deficits and epilepsy. Overall, these problems persist after the first few weeks of illness in only about 35% of cases, and in most of these patients, the deficits resolve within 1 year of onset. Intellectual deficits (varying from attention problems to mental retardation) and epilepsy arise most often in children whose bout of ADEM occurs before the second birthday. Visual and motor deficits and problems with bowel or bladder function may persist for varying periods of time (months to permanently) in some cases, particularly in those with transverse myelitis, optic neuritis, and the combination Devic syndrome.

At particular risk for long-term consequences are patients whose ADEM becomes steroid dependent and frequently recurrent with onset before age 6 years, a condition the authors have termed steroid-dependent encephalomyelitis. Another group at significant risk are those whose much less frequent recurrences are diagnosed as MS (usually when the patient is >10 y).

Race: The scientifically imprecise concept of race does not lend itself readily to discussions of ADEM. In the authors' series of more than 150 cases, the ratio of light-skinned to dark-skinned individuals who have some contribution of genetic material from individuals who have left Africa in the past 5 centuries is approximately 6:1. In the former group, the element of African heritage from the past 5 centuries is presumed small but is in fact unknown. ADEM is found in all ethnic groups and races; referral bias complicates any assessment of relative prevalence.

Degree of skin pigmentation (irrespective of racial background) may influence risk for ADEM, as it may for MS, if recent theories concerning vitamin D metabolism and autoimmune diseases advanced by Hector DeLuca and others prove valid.

Sex: In the authors' series of more than 150 cases, the ratio of boys to girls is 1.3:1. No other substantial data are available.

Age: More than 80% of childhood cases occur in patients younger than 10 years; somewhat less than 20% of cases occur in the second decade of life. Incidence in adulthood is unclear, accounting for less than 3% of the reported cases. However, diagnostic overlap with MS may lead to underestimation of the prevalence in adults.

Treatment
Medical Care: ADEM is often treated with high-dose intravenous corticosteroids, to which it appears to be responsive (Pasternak, 1980). One common protocol is 20 mg/kg/d of methylprednisolone (maximum dose of 1 g/d) for 3-5 days. Improvement may be observed within hours but usually requires several days. An oral taper for 3 weeks or some other interval is sometimes appended. The chief alternative therapy is intravenous immune globulin (IVIG) (Kleiman, 1995; Hahn, 1996; Nishikawa, 1999). It is administered as 2 g/kg intravenously for 2-3 days. IVIG may be preferable in instances where meningo-encephalitis cannot be excluded based upon the hypothesis that corticosteroids might worsen the course of infection (Nishikawa, 1999).

Available published information concerning efficacy is inadequate to accurately assess much concerning the impact of either form of therapy, although it appears likely that both forms of therapy increase the pace of initial recovery. Whether these forms of therapy influence times to final outcome or extent of final recovery is not known.

Theoretically, very high-dose corticosteroids (30-50 mg/kg) administered intravenously at presentation to patients with transverse myelitis may be advantageous from the vantage point of its capacity to close the blood-brain barrier and limit swelling. Marked cord swelling may account for poor outcome in some cases of transverse myelitis because of circulatory impairment and cord infarction. The same argument may hold true for severe cerebral ADEM such as tends to arise in some young children (<3>

There is as yet no convincing evidence that treatment with the combination of intravenous corticosteroids and IVIG confers any advantage in such cases, although this approach is employed by some clinicians.

Severe ADEM has also been treated, apparently successfully, with such alternative approaches as (1) combination of intravenous corticosteroids and IVIG, (2) cyclosporin, (3) cyclophosphamide, or (4) plasma exchange/plasmapheresis (Stricker, 1992; Kanter, 1995). Greater understanding of trimolecular complex regulation, adhesion molecules, and inflammatory cytokines may permit development of more specific and effective ADEM therapies. The polymorphism of the human major histocompatibility complex and apparent heterogeneity of T cell response to autoantigens render this a daunting project (Miller, 1991), although anticytokines represent an intriguing avenue of therapeutic research (Sugita, 1993).

Surgical Care: Surgical treatment for severely elevated intracranial pressure has been undertaken for cases of AHLE, hemorrhagic brain purpura, and non-Reye syndrome, examples of what have been termed obscure encephalopathies of infancy. Some of these cases were likely examples of hyperacute ADEM. Surgical interventions have ranged from placement of pressure bolts to decompression of the intracranial fossae by unroofing of the cranium. Outcome of such interventions was mixed.

Although such severe cases were regularly noted in the medical literature from the 1920s until the mid 1970s, few examples have been noted since that time. Prevalence clearly has dramatically decreased. Because these severe cases often followed measles, mumps, and other diseases for which effective vaccines have been developed and because the disappearance of such cases has followed the availability and use of such vaccines (earlier disappearance in the United States and Western Europe, subsequent disappearance in Asia and the Middle East), this change in prevalence likely reflects the removal of pathogens that are provocative of such severe forms of ADEM.

Consultations: Consultations with infectious disease specialists are occasionally warranted to consider alternative diagnoses. Pediatric intensivists generally become involved in severe cases for management of airway, breathing, and circulation.

Activity: No clear restrictions on activity exist except as indicated by the severity of disease. The possible exceptions are ADEM-related postinfectious demyelinative syndromes, sometimes in association with the development of brain edema, that arise in the wake of illnesses such as brucellosis or malaria. In the case of acute brucellosis, recovery is clearly more rapid and relapse is less likely if patients are treated with enforced bedrest. This rule may also be true of the relapsing neurobrucellotic illnesses, including the types that closely resemble or are examples of ADEM. Although somewhat less clear in the case of cerebral malaria, little doubt exists that enforced bedrest with appropriate positioning (because of elevation of intracranial pressure) is of importance. In the case of cerebral malaria and in cases of the more severe varieties of neurobrucellosis, bedrest is often necessary because of the low mental status and weakness of such individuals.

Medication
The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Drug Category: Anti-inflammatory Agents -- These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Both corticosteroids and intravenous IVIG modify the body's immune response to diverse stimuli.

Drug Name	Methylprednisolone (Adlone, Medrol, Solu-Medrol, Depo-Medrol) -- Considerable experience has accumulated in the use of various corticosteroids in the treatment of ADEM. No conclusive evidence exists that this form of therapy is effective. The weight of evidence at present supports the view that corticosteroids may shorten the time to onset of improvement. Whether this form of therapy shortens time to maximal recovery is unclear, and whether deleterious effects, such as enhancement of tendency to recurrence, exist is unknown. Generally, however, this form of therapy appears, within the considerable limits of present knowledge, to be safe. The usual approach is administration of methylprednisolone for 3-5 d IV (or the equivalent dose of some other anti-inflammatory corticosteroid). The initial dose should be administered under close supervision because rare instances of anaphylaxis after initial dose have been reported.
Adult Dose	1 g IV qam for 3-5 d; this may be followed, where deemed appropriate, by 2 mg/kg PO (maximal dose 80 mg/d), followed with taper over 3-5 wk
Pediatric Dose	20 mg/kg IV for 3-5 d initially; this may be followed, where deemed appropriate, by 2 mg/kg/d PO (maximum 80 mg/d), followed with taper over 3-5 wk
Contraindications	Documented hypersensitivity; systemic fungal infection; use in some patients receiving amphotericin B; concomitant cerebral malaria; latent or active amoebiasis; active chickenpox or measles; active tuberculosis; recent myocardial infarction; ulcerative colitis; active or latent peptic ulcer disease; impending gastrointestinal perforation; enteric abscess
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Human immune globulin (Gammagard, Gamimune, Sandoglobulin, IVIg) -- Believed to treat conditions associated with inflammation and immune dysregulation by neutralizing circulating myelin antibodies through anti-idiotypic antibodies. May down-regulate proinflammatory cytokines, including IFN-gamma. Blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells; blocks complement cascade. May promote remyelination. May increase CSF IgG modestly.
Adult Dose	2 g/kg IV administered over 2-5 d
Pediatric Dose	Not established, adult dosage is usually employed, administered IV
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before administering IVIg (use an IgA-depleted product, eg, Gammagard S/D); may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes mellitus, volume depletion, or preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Absence Seizures

2007-11-22T19:27:00.001-08:00

Background: Absence seizures are a type of generalized seizures. They were first described Poupart in 1705, and later by Tissot in 1770, who used the term petit access. In 1824, Calmeil used the term absence. In 1935, Gibbs, Davis, and Lennox described the association of impaired consciousness and 3-Hz spike-and-slow-wave complexes on electroencephalograms (EEGs).

Absence seizures occur in both idiopathic and symptomatic generalized epilepsies. Among the idiopathic, or primary, generalized epilepsies (ie, with age-related onset), absence seizures are seen in childhood absence epilepsy (CAE, or pyknolepsy), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME, or impulsive petit mal seizures). The seizures in these conditions are called typical absence seizures and usually associated with 3-Hz spike-and-slow-wave complexes on EEG. In CAE, seizures are frequent and brief, lasting just a few seconds (pyknoleptic). Some children can have hundreds of such seizures per day. In other epilepsies, particularly those with an older age of onset, the seizures can last several seconds to minutes and may occur only a few times a day (called nonpyknoleptic or spanioleptic absence seizures). Myoclonic and tonic-clonic seizures may also be present, especially in syndromes with an older age of onset. In these syndromes, the discharge frequency may be faster than 3 Hz.

In the symptomatic generalized epilepsies, absence seizures are often associated with slow spike-wave complexes of 1.5-2.5 Hz; these are also called sharp-and-slow-wave complexes. These seizures are termed atypical absence seizures.

Pathophysiology: The etiology of idiopathic epilepsies with age-related onset is genetic. About 15-40% of patients with these epilepsies have a family history of epilepsy; concordance in monozygotic twins is 75%. Family members may have other forms of idiopathic or genetic epilepsy (eg, febrile convulsions, generalized tonic-clonic [GTC] seizures).

Several animal models demonstrate the genetic basis for absence seizures. A strain of Wistar rat, ie, genetic absence epilepsy rats from Strasbourg (GAERS), is a polygenetic model in which all animals have clinical seizures consisting of a behavioral arrest with twitching of facial muscles. This is associated with bilateral synchronous spike-wave discharges. Several single-gene loci in mice, when mutated, result in generalized spike-wave epilepsy. The tottering (chromosome 8), lethargic (chromosome 2), stargazer (chromosome 15), mocha (chromosome 10), and ducky (chromosome 9) loci all have generalized 6-per-second spike-wave EEG paroxysms that are associated with clinical seizures consisting of behavioral arrest. All types respond to ethosuximide (ETX), but the underlying cellular mechanisms for the generation of the discharges are not identical.

Several mutations of genes which encode protein subunits in various ion channels have been found in patients and family members with idiopathic epilepsies. Some forms of JME and absence epilepsy have been shown to result from mutations in Ca⁺⁺ channels.

In symptomatic generalized epilepsies, absence seizures are due to a wide variety of causes that, at an early stage of neural development, result in diffuse or multifocal brain damage. The causes of secondary generalized epilepsies and the other seizure types that accompany them, and their management, are not discussed in this article.

The pathophysiology of absence seizures is not fully understood. In 1947, Jasper and Droogleever-Fortuyn electrically stimulated nuclei in the thalami of cats at 3 Hz and produced bilaterally synchronous spike-and-wave discharges on EEG. In 1953, bilaterally synchronous spike-and-wave discharges were recorded by using depth electrodes placed in the thalamus of a child with absence seizures.

In 1977, Gloor demonstrated that the bilaterally synchronous 3-Hz spike-wave discharges in the feline penicillin model of absence seizures were generated in the cortex. This led to the corticoreticular theory of primarily generalized seizures.

Abnormal oscillatory rhythms are believed to develop in thalamocortical pathways. This involves GABA-B–mediated inhibition alternating with glutamate-mediated excitation. The cellular mechanism is believed to involve T-type calcium currents. T channels of the GABAergic reticular thalamic nucleus neurons appear to play a major role in the spike-wave discharges of the GABAergic thalamic neurons. GABA-B inhibition appears to be altered in absence seizures, and potentiation of GABA-B inhibition with tiagabine (Gabitril), vigabatrin (Sabril), and possibly gabapentin (Neurontin) results in exacerbation of absence seizures. Enhanced burst firing in selected corticothalamic networks may increase GABAB receptor activation in the thalamus, leading to generalized spike-wave activity.

Frequency:

In the US: The incidence is 1.9-8 cases per 100,000 population.

Mortality/Morbidity:

No deaths result directly from absence seizures. Accidents from driving or operating dangerous machinery during absence may result in death. In children with absence seizures due to secondary generalized epilepsies, death is related to the underlying disease.

The morbidity from typical absence seizures is related to the frequency and duration of the seizures, as well as to the patient's activities; effective treatment ameliorates these factors. Educational problems and behavioral problems are sequelae of unrecognized, frequent seizures.

Race: No racial predilection is known.

Sex:

Absence seizures are generally believed to be more common in females and in males, with some studies showing a 2:1 female-to-male ratio. Other studies have shown no difference between the sexes.

Absence epilepsy with myoclonus has a male predominance.

Age: The generalized idiopathic epilepsies have age-related onset. Onset of absence seizures in children with symptomatic generalized epilepsies depends on the underlying disorder. While many of these disorders may have their onset at an early (prenatal, perinatal, or postnatal) age, absence seizures do not appear until later in childhood.

An example is the Lennox-Gastaut syndrome. The cause may be a genetic disorder or a perinatal insult, but the absence seizures do not present until age 1-8 years.

CAE onset is at age 4-8 years, with peak onset at age 6-7 years.

JAE onset is at age 7-14 years, with peak onset at age 10-12 years. Onset of JAE with myoclonus averages about age 7 years.

JME has a more varied age of onset (8-26 y), but 79% of patients have an onset at age 12-18 years. Because the absence and myoclonic seizures are brief, they often go unrecognized, and many patients do not present until they experience a tonic-clonic seizure.

Treatment

Medical Care: Treatment involves antiepileptic drugs (AEDs). Once the proper diagnosis (ie, of the specific epilepsy syndrome) is made, the likelihood of other coexistent seizure types, such as myoclonic or tonic-clonic, should be considered and an appropriate medication selected.

ETX (Zarontin) is effective only against absence seizures.

Valproic acid (VPA; Depakene, Depacon) and divalproex sodium (Depakote) is considered a broad-spectrum AED because it is effective against absence, myoclonic, and tonic-clonic (as well as partial) seizures.

Newer broad-spectrum medications, not yet approved by the US Food and Drug Administration (FDA) for treatment of absence seizures, include lamotrigine (LTG, Lamictal), topiramate (TPM, Topamax), zonisamide (ZNS, Zonegran), and levetiracetam (LEV, Keppra).

Symptomatic generalized epilepsies are often refractory to first-line AEDs. LTG is approved by the FDA as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (at least aged 2 y). Clonazepam (Klonopin, felbamate (Felbatol), TPM, and the ketogenic or medium-chain triglyceride diet have been attempted to reduce seizure frequency. However, these adjunctive therapies have limited efficacy.

Treatment with tiagabine (Gabitril), vigabatrin (Sabril), and possibly gabapentin (Neurontin) has been associated with the exacerbation of absence seizures. The use of carbamazepine (Tegretol) has also been associated with the exacerbation of absence seizures in some patients.

Consultations: All patients with suspected absence seizures should be examined by a neurologist who has expertise in diagnosing epileptic syndromes. Patients with refractory seizures, especially those with symptomatic epilepsies, may need to be referred to an epileptologist for prolonged EEG-video monitoring and medication adjustments.

Diet: Patients with medically intractable seizures may be tried on a ketogenic or medium-chain triglyceride diet. The results are often only temporary, and these diets are difficult to maintain. Children in whom such diets are being considered should be referred to a center with specialized dietary services.

Activity: Physical activity should not be restricted any more than necessary. Activities in which a seizure might pose a threat, such as swimming or rock climbing, may be allowed with appropriate supervision. A child with epilepsy should not be unnecessarily handicapped. Patients with uncontrolled absence seizures should not be allowed to drive. The situation may be unclear when the patient's clinical seizures are controlled but the EEG still shows some spike-wave activity.

Medication
Most AEDs are relatively toxic. Patients often take them every day, usually several times a day, for many years. Therefore, the decision to start such a medication is difficult. Once a patient has more than one unprovoked seizure, the decision to start medication is straightforward; EEG studies can help to confirm this decision.

Most AEDs are not effective against absence seizures. Also, many patients have both absence and generalized convulsive (myoclonic and GTC) seizures. Only 2 first-line AEDs are currently used for absence seizures.

Drug Category: Antiepileptics -- If the patient has only absence seizures, then ETX (Zarontin) is an appropriate medication. This may be the case for patients with CAE. ETX also may be used in conjunction with an anticonvulsive AED, such as phenytoin (PHT, Dilantin) for patients at risk of tonic-clonic seizures in whom VPA is contraindicated.

Drug Name	ETX (Zarontin) -- Succinimide AED effective only against absence seizures. No effect on GTC, myoclonic, atonic, or partial seizures. Mechanism of action based on reducing current in T-type calcium channels on thalamic neurons. Spike-and-wave pattern during petit mal seizures thought to be initiated in thalamocortical relays by activation of these channels. Available in large 250-my capsules, which may be difficult for some children to swallow, and as syrup (250 mg/5 mL).
Adult Dose	250 mg PO bid; increase by 250-mg increments q4-7d until seizures controlled or maximum daily dose reached; not to exceed 1.5 g/d
Pediatric Dose	<6> >6 years: Administer as in adults Maintenance dose: 15-40 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; blood dyscrasias; renal or hepatic disease
Interactions	Generally minimal; enzyme-inducing drugs (eg, PHT, carbamazepine, phenobarbital) may lower levels by 15-25%; valproic acid may elevate levels; has weak enzyme-inhibiting effect, usually insignificant with respect to metabolism of other drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Blood dyscrasias may occur and may be fatal (monitor CBC); caution in hepatic or renal disease; abrupt withdrawal may precipitate absence status

Drug Name	Valproic acid (Depakene, Depacon, Depakote, Depakote ER) -- DOC for patients who have absence and GTC and/or myoclonic seizures; aliphatic compound, carboxylic acid. Discovery was serendipitous; used as solvent potential AEDs, and all test compounds seemed to work. Mechanism of action not known but believed related to ability to increase brain GABA. May inhibit rapid opening of sodium channels and block T-type calcium channels. VPA (Depakene) available as syrup (250 mg/5 mL), 250- or 500-mg capsules, and IV preparation (100 mg/5 mL; Depacon). Divalproex sodium (Depakote) available as 250- or 500-mg tab and 125-mg capsule (Depakote Sprinkles), which can be opened and mixed with food. Syrup rapidly absorbed through stomach and produces gastric irritation. Rapidly produces high serum levels and may cause peak-dose toxicity. Must be given in 3-4 divided doses. Other oral preparations absorbed more slowly from GI tract and better tolerated. Because of slower absorption, some patients who have achieved control may be treated with bid dosing. Highly protein bound; protein binding is level dependent. At 40 mg/mL, 90% bound, but at 130 mg/mL, 80% bound. Therefore, as total level increases from 40 to 130 mg/mL, free level increases from 4 to 26 mg/mL. Therapeutic range originally 50-100 mg/mL; patients with hard-to-control seizures may require higher level. Depakote ER is extended-release product intended for once-a-day oral administration. When converting from Depakote to Depakote ER, dose 8-20% higher than total daily dose of Depakote is needed. IV Depacon may be given as maintenance therapy; amount mixed with at least 50 mL of compatible diluent and infused at rate not >20 mg/kg/min over at least 60 min; research ongoing concerning IV loading at more rapid rates.
Adult Dose	10-15 mg/kg/d PO initially; increase by 5-10 mg/kg/d weekly until seizures controlled or adverse effects develop; not to exceed 60 mg/kg/d divided tid/qid
Pediatric Dose	15 mg/kg/d PO initial dose, increasing by 5-10 mg/kg/d weekly until seizures controlled or adverse effects develop; maximum recommended dosage 60 mg/kg/d divided tid/qid; for select patients with complete control, bid dosing may be tried
Contraindications	Documented hypersensitivity; hepatic disease or dysfunction; because of teratogenicity, first trimester of pregnancy and in women of childbearing age who are not on adequate birth control, unless it is clearly the most effective drug for a woman planning pregnancy and aware of risks
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin, phenytoin, phenobarbital, and carbamazepine may significantly reduce levels; in children, salicylates decrease protein binding and metabolism; carbamazepine may result in variable changes of carbamazepine concentrations with possible toxicity or loss of seizure control; may increase diazepam and ETX toxicity (monitor closely); may increase phenobarbital and phenytoin levels; may displace warfarin from protein-binding sites (monitor coagulation tests) and can displace phenytoin, resulting in transient increase in free levels; may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Hepatic dysfunction may occur (more common in children taking multiple AEDs) during first 6 mo of therapy, and may be fatal; assess liver function test (LFT) results before therapy and at frequent intervals during first 6 mo; clinical symptoms (loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia, vomiting) may precede LFT abnormalities; hyperammonemia reported and may be occur despite normal LFTs; may cause lethargy or coma; when asymptomatic elevations of ammonia are present, more frequent monitoring indicated; carnitine supplementation may be beneficial in addition to platelet dysfunction, thrombocytopenia may occur and associated with high doses; pancreatitis may occur, even after several years of therapy; perform appropriate tests in patients with malabsorption, abdominal pain, or other GI symptoms; spina bifida in 1-2% of children born to women taking VPA during first 12 wk of pregnancy; women planning to become pregnant should take folic acid 1-5 mg/d, and consider crossing over to ETX before conception; for women with have GTC seizures, ETX and anticonvulsant AED can be used

Abnormal Neonatal EEG

2007-11-22T19:27:00.000-08:00

Background Over the past several decades, electroencephalography (EEG) in newborn infants has become valuable as a serial, noninvasive screening tool for infants at high risk of perinatal injuries. The brain dynamics and connectivity in different states (awake or asleep) can be defined, and a whole range of acute or chronic cerebral disorders can be identified. Such information often reveals presymptomatic or subclinical conditions.

The EEG prognostic value at the time of continuous development is often greater than at a later stage. EEG testing can provide reassurance to the physician and parents at a time of potential catastrophic damage.

The continuous changes that occur during early brain development are often associated with striking changes in EEG patterns over short periods. This makes it difficult to interpret EEG results, which can discourage the use of EEG testing.

Given the close relationships between certain morphological aspects of the developing brain and EEG results, gestational age (GA) can be reliably estimated (to ±1 wk) by EEG criteria. In fact, CNS development of the immature brain proceeds at about the same rate during fetal development as in the postnatal environment.

The physiological substrate for these early EEG patterns is unknown, but is probably derived from cortical generators that are strongly influenced by subcortical (primarily thalamic) afferent input. Rapid maturation of these structures (and not the corpus callosum) is most likely responsible for the interhemispheric synchrony that occurs close to full-term GA; in particular, rapid dendritic spine development and synaptogenesis are typical of the last month of fetal development. The complex development of cerebral sulci during this same period is probably responsible for the neonatal EEG results showing complex, more definitive patterns at term. At this age, easily recognizable and organized activity patterns appear. These continue with little change during the first month of life and are strictly characteristic of neonatal EEG.

There are several technical considerations when recording from a small (neonate) scalp. High skin resistance impedes low-resistance scalp-to-electrode contact. The state of activity (awake or quiet vs active sleep) can be selectively bound to certain aspects of pathology. It is important to annotate the tracing with particular attention to the presence and type of eye movements, facial movements, respiration (regular or irregular), sucking, crying, grimacing, and so on. Extracerebral monitors are needed in routine recordings, including at least electrooculogram (EOG), respiration rate measurement, and electrocardiogram (ECG). Only a reduced number of scalp electrodes, generally never more than the set in a 16-channel recording, are applicable. A low time constant (0.25-0.60 seconds) is preferable to record the low-frequency background activity. Slow paper speed maximizes the slow background and the degree of interhemispheric synchrony.

THE NORMAL NEONATAL EEG

In the full-term born infant (FTBI), ultradian sleep and waking cycles are well defined and easy to detect with polygraphic and behavioral criteria. On EEG, wakefulness characterized by eye opening, crying, and vigorous motor behavior accompanied by irregular vital signs on recordings (ECG, respiration) is marked by a low-amplitude activity and discontinuous 4-7 cps theta activity interspersed with low-voltage delta rhythms. Hence, the French name activité moyenne.

Active sleep (AS), the antecedent of rapid eye movement (REM) sleep, is usually indicated by irregular respiratory patterns with interspersed, brief apneic episodes that often precede clusters of eye movements. Contrary to adult physiology, prominent, subtle motor activity, especially of the face (eg, grimacing, smiling), accompanies this state. These results are often interpreted as seizure activity by the inexperienced reader. On EEG, 2 patterns are observable, as follows:

A continuous, low- to medium-voltage background with theta and delta activity and occasional anterior sharp-waves that occur primarily at sleep onset, or
A lower amplitude, more continuous theta background is mostly seen between periods of quiet sleep (QS). The latter non-REM sleep is marked by a discontinuous pattern (tracé alternante) that is characterized by bursts of high-amplitude (50-20 mV) synchronous delta activity and separated by intervals of lower mixed activity that resemble wake or AS activity.

Sleep state cyclicity is certainly achieved after 30 weeks' postconceptional age (PCA), with stability over multiple cycles only at 36 weeks' PCA.

Lately, the increased survival of extremely young premature babies has allowed to assess very early expression of sleep cyclicity by combining measures of REM and EEG discontinuity (Sher, 2005) between 25 and 30 weeks' PCA. Early forms of "transitional" sleep akin to "seismic sleep" in the rat represents an immature form of paradoxical sleep with mixed features of active and quiet sleep. It probably corresponds to a primitive form of brain activity characterized by a low level of inhibition progressively declining toward term (Biagioni, 2005).

Near the end of the first month, a more diffuse pattern usually appears, consisting of continuous, high-to-moderate amplitude, slow activity that is not seen in the preterm infant. A high degree of synchrony between burst and interburst activity is desirable at term. This usually confirms normal maturational patterns.

Several morphological figures may occur with variable frequency. Random sharp-waves, most commonly temporal or rolandic, are sporadically seen in QS. Nonrolandic, repetitive, highly focal spikes confined to a single location that occur during wakefulness usually indicate abnormalities. A burst of frontal delta and synchronous, frontal sharp waves are still abundant in the FTBI during AS. Spindle delta bursts (brushes) are seen with decreasing frequency in the FTBI and are usually confined to the central and temporal leads during QS. This state is the most vulnerable, being susceptible to various minor CNS insults that are only transiently apparent, depending on their expression. It is important to perform prolonged recordings, especially in stressed infants as they are likely to express less QS.

Several important milestones characterize EEG maturation patterns during the first months of life. The newborn progressively develops a circadian rhythm, resulting from the interaction of endogenous factors with external synchronizers such as light, eating, and sensory stimulation over the course of a day. At approximately the third month, sleep efficiently occurs in nocturnal intervals of at least 8 hours, reflecting mother-child interactions and the established activity of endogenous pacemakers.

With regard to EEG results, several important changes accompany this phase. From the second week of life, slow and continuous background activity (consisting of increasing amplitude delta waves whose frequency also decreases with the approaching first month of life) progressively replaces the discontinuous pattern (tracé alternante) that is typical of QS. Typical EEG characteristics disappear within the second month of life, including slow frontal biphasic spikes (encoches frontales) and negative rolandic spikes. The newborn still falls asleep in AS until the end of the third month. AS decreases from 50% to 40% by the end of the fourth month; likewise, QS progressively increases and becomes more defined due to the appearance of EEG hypnic features that are typical of adults. Vertex waves can be noted in the rolandic regions after the third month; sleep spindles appear earlier, at about the sixth week, over the central regions.

The first sleep spindling samples are slower in frequency and more anteriorly distributed in newborns compared with older infants. These infrequently appear at the beginning of QS as rudimentary, low-voltage (<25>

Around the sixth postnatal week, 75 mV occipital sharp waves characterize AS and increase in frequency from 2 to 4 Hz toward the end of the third month. At 3 months, a clearly defined 3-4 Hz, 50-75 mV occipital rhythm appears during wakefulness; this is interrupted by eye opening. It progressively evolves at about 5 months to a faster frequency of 6-7 Hz.

ABNORMAL NEONATAL EEG
Even more than in other epochs of life, in neonates the abnormal neonatal EEG has a prognostic value as opposed to a diagnostic value. Rarely, specific EEG patterns correspond to typical syndromes. Prognostic value can be increased with the following methods:

Early recordings, possibly within the first 48 hours of life - Markedly abnormal EEG patterns usually last for a relatively short time, followed by less abnormal or even normal patterns despite the absence of clinical resolution.
Prolonged recordings to include samples of different activity states - QS, for instance, is far more likely to show valuable maturation pattern abnormalities and yet is less likely to occur within short recording intervals in a compromised infant.
Serial EEGs obtained at short intervals to assess the rapid changes that are likely to occur in rapidly maturing, high-risk infants - Normalization of a previously abnormal pattern may indicate a minimal impact of a brain insult on maturation. Conversely, progressive deterioration of previously normal or moderately abnormal patterns favors the possibility of long-term neurological sequelae.

Because EEG abnormalities in neonates cover a broad spectrum, any classification is difficult and, in some cases, arbitrary. One possibility for classification would be to distinguish between diffuse and focal abnormalities and to categorize separately ictal and paroxysmal patterns in the presence of neonatal convulsions.

DIFFUSE EEG ABNORMALITIES
With regard to severity and prognosis, severe and irreversible abnormalities should be distinguished from moderate, reversible abnormalities. Severe abnormalities correspond to 2 main EEG patterns, inactive and paroxysmal, both of which are accompanied by a lack of sleep cycles and a lack of reactivity to internal or environmental stimuli.

The inactive or isoelectric pattern consists of cerebral activity below 10 mV that is continuously present throughout the record. Brief intervals of low-voltage activity, which are located over the posterior head regions, may occasionally be present. This pattern may occur in varying clinical conditions and often occurs with the following states:

Early severe asphyxia or massive hemorrhage
Severe inborn metabolic deficits
CNS bacterial or viral infections
Gross congenital malformations
Drug-induced state
Hypothermia
Postictal recording

In the absence of a drug-induced state, hypothermia, or postictal recording, the prognosis is poor but not necessarily fatal.

The paroxysmal or burst suppression EEG pattern is characterized by intervals of inactive background activity (<10-15 href="http://www.emedicine.com/neuro/topic545.htm#target3">Picture 3). This pattern, which carries a highly unfavorable prognosis, must be clearly distinguished from a full-term newborn's tracé alternante and a preterm infant's tracé discontinue (TD), both of which are normal patterns. Serial recordings are essential to reach a reliable prognosis. Certain conditions (eg, Aicardi syndrome or uncommon dysgenetic conditions that involve the corpus callosum) rarely present as hemihypsarrhythmia.

Severe but reversible diffuse abnormalities can occur and are exemplified by the so-called low-voltage pattern throughout the EEG record. QS and AS are only distinguishable by the slightly higher voltage in QS, where mixed frequencies under 10-50 mV are almost continuously recorded. This finding and a diffuse delta pattern with minimal theta rhythms throughout the entire EEG record hold an intermediate prognosis. When the abnormalities are compatible with these changes seen in sleep, they are generally considered moderate and reversible.

Diffuse EEG abnormalities can also be seen as irregularities in maturational indices and organizational states. In addition to the patterns of profound disruption to the ability to organize cyclic states (which are typical of the most severe abnormalities), several patterns of EEG dysmaturity can be recognized and identified. In newborns who are small for their gestational age, transient or persistent dysmaturity patterns can be distinguished by their duration. Quantification may include assessment of interhemispheric synchrony in tracé alternante, typical of QS, or the counting of premature features such as delta brushes.

Abnormalities of EEG patterns, noted in relation to sleep states and the instability of sleep-wake states during the newborn period, have some prognostic value. When different etiologies of the EEG pattern are considered, a few fundamental groups can be distinguished.

Transient metabolic disorders

Neonatal hypoglycemia can range from an asymptomatic state with a minimal EEG correlation to late-onset, idiopathic hypoglycemia accompanied by neurological symptoms and seizures. Toxemia and maternal diabetes are often encountered in high-risk pregnancies. These newborns usually present with decreased QS with a relative increase in AS. Transient hypocalcemia is often associated with barely abnormal interictal EEG and variable focal seizures (in 20% of patients).

Inborn errors of metabolism

Periodic EEG patterns in newborns with uneventful deliveries strongly suggest the possibility of an inborn error of metabolism. The most frequent neurological symptoms are early movement disorders, convulsions, and cognitive dysfunction. In 1977, Mises accurately described periodic EEG patterns in methylmalonic aminoacidopathy.

High interindividual variability characterizes a pattern of periodic frontal or occipital sharp waves that are interspersed with rapid rhythms. In maple syrup urine disease, EEG complexes are low-voltage and less periodic; background activity is less depressed. Comb-like rhythms during the second and third postnatal weeks are pathognomonic of this disorder.

The highly peculiar EEG pattern of non-ketotic hyperglycemia distinguishes it from other forms. During the first 10 postnatal days, these infants, who present with hypotonia, respiratory distress, and myoclonic seizures, have EEGs characterized by periodic, highly stereotyped 1-3 Hz complexes with 4- to 18-second interburst intervals. Frontal, high-voltage slow waves are associated with characteristic rolandic and occipital early alpha rhythms.

Pyridoxine dependence (not to be confused with pyridoxine deficiency) is inherited as an autosomal recessive trait and is accompanied by severely abnormal EEGs and refractory seizures that only respond to pyridoxal supplementation.

CNS INFECTIONS
An important distinction must be made between prenatal and postnatal infections. No specific or typical EEG patterns exist for the first group. Severity and extent of CNS involvement is more significant compared to noninfectious etiologies. Rubella and toxoplasmosis are the most common causative agents.

Infants with congenital rubella and cataracts present with the most consistent EEG abnormalities in this group (ie, prolonged subclinical seizures expressed as paroxysmal bursts without interburst intervals or alpha-like activity). In the occipital areas, there is marked asynchrony between burst and interburst intervals. Slow anterior dysrhythmia with excessive frontal sharp waves is present. Sleep states are not well defined, given the absence of recorded REM and the paucity of QS.

Fetal toxoplasmosis is less disruptive, at least in terms of ultradian sleep cycle organization. It is associated with more variable EEG patterns. In cytomegalovirus, the EEG is frequently inactive.

For postnatal infections (usually meningitis), the prognostic value of EEG is linked to the severity and extent of the abnormalities rather than their specificity. In most cases, they are associated with early status epilepticus (SE) or single seizures with a definite interval following birth that is unlike postanoxic SE. Consistently abnormal recordings (rather than merely an initial abnormal recording) are linked to an unfavorable prognosis. Three distinctive patterns are associated with type 1 and type 2 herpes simplex virus (HSV) encephalitis. For pregnant women in many countries, HSV is still the most common (and preventable in neonates by means of cesarean section) genital infection. HSV is easily transmitted to the newborn during vaginal delivery. One type of EEG abnormality consists of continuous, sharply contoured unifocal or multifocal delta activity with a typical asynchronous distribution across several foci (each with a specific rate). Foci are predominantly temporal, frontal, or central in distribution. In older infants, hemispheric, monomorphic slow waves appear interspersed on a low-voltage or suppressed background. They may recur as periodic lateralized epileptiform discharges (PLEDs) within several seconds. Typical electroencephalographic seizures are associated with positive, multifocal sharp waves on a background that is characterized by significant interhemispheric voltage asymmetries and asynchrony.

FOCAL ACUTE NEUROLOGICAL ABNORMALITIES
The following conditions may cause focal neurologic abnormalities: trauma, primary subarachnoid hemorrhage, intraventricular hemorrhage (IVH), intraparenchymal hemorrhage, and cerebral infarction. EEG abnormalities include an interhemispheric amplitude asymmetry pattern that is mainly seen with intraparenchymal hemorrhage or with a prenatal or postnatal ischemic insult. A wider criterion (>50%) is usually applied to preterm (PT) infants in whom significant hemispheric voltage alteration has been found to strongly correlate with contralateral hemiparesis. In 1984, Challamel reported that transient hemispheric asymmetries were a normal variant in infants with no CNS-related ailments who later resumed fully developed normal EEG patterns.

The focal attenuation pattern refers to a single scalp region with a persistent voltage attenuation. This pattern has an inconsistent association with neuropathological lesions; both false-positive and false-negative correlations have been observed. Focal slowing is highly unusual and may be a sign of ongoing seizures.

Nonictal paroxysmal patterns include the following:

Midline rhythmic bursts offer no diagnostic or prognostic clue when observed during non-REM sleep. These may represent the normal maturation ebouché of primitive sleep figures such as vertex waves.
Positive rolandic sharp waves (PRWs), first described by Cukier in 1972 as pathognomonic of IVH, were considered poor prognostic indicators. Later studies by Tharp and Lombroso were not as conclusive about the long-term clinical implications. Although PRWs are seen in 30-50% of PT infants with IVH, they also have been detected in infants with periventricular leukomalacia without hemorrhage as well as in intraparenchymal or subarachnoid bleeding. Therefore, PRWs are probably related to deep white matter lesions, although the underlying cause is still undetermined
Positive temporal sharp waves (PTWs) are noted in the records of infants with hypoxic-ischemic damage and are thought to carry a poor prognosis. As with PRWs, the implications of the presence PTWs are still inconclusive.
Although rarely associated with ictal discharges, occipital spikes/sharp waves, whether isolated or in unilateral brief runs, are usually found in a population of high-risk infants and considered to be abnormal regardless of age.

EEG IN NEONATAL SEIZURES

Seizures frequently occur in newborns (14 per 1000), often causing death or permanent neurological sequelae. The prognosis largely depends on etiologic factors and the duration of convulsive activity. It should be noted that generalized tonic-clonic seizures are not seen in the immature brain.

Seizure patterns can be distinguished into subtle, classic, tonic, and myoclonic types. Among these, some have a fairly consistent EEG correlation. For example, tonic spasms, unlike those that occur in older children, are often associated with rhythmic delta wave activity. Clonic seizures frequently correspond to repetitive spike discharges. Myoclonic seizures, which are often erratic or fragmented and which should be distinguished from fragmentary neonatal sleep myoclonus, are often associated with other seizure types (eg, tonic or clonic) and with a burst suppression pattern with or without ictal correlation.

Ictal intervals, apnea, or respiratory disturbances often correlate with alphalike EEG patterns. These may be ictal discharges without clinical seizures that are not limited to iatrogenically paralyzed infants.These occult or electrographic seizures without clinically detectable signs may result from iatrogenic loading, causing serious neurological injury that disables the effector structures or silent cortical areas, which might be more generalized in newborns than in older patients.

Conversely, clinical seizures in the absence of EEG discharges suggest nonepileptic events that should be closely monitored to avoid misdiagnosis. Minimal seizure behavior, uncoupled to ictal EEG patterns, can be seen in healthy neonates and especially in encephalopathic neonates whose brains are seriously compromised by hypoxic-ischemic insults. Severe neurological injury seen in these cases causes severe background EEG abnormalities.

Several ictal discharge patterns have been identified and reported, including the following patterns:

Focal spikes or sharp wave discharges of progressively increasing amplitude over the course of the seizure - These discharges correspond to contralateral jerking and occur predominantly in the rolandic and temporal regions.
Multifocal spike and sharp wave discharges, which are often erratic with independent frequencies in multiple foci, are associated with variable seizure types. The underlying cause may range from benign conditions to CNS infection to various hypoxic-ischemic injuries. The prognosis is dependent on the background EEG abnormalities and the specific underlying etiology.
Prehypsarrhythmic or hypsarrhythmic patterns can be seen early in compromised newborns, representing the most severe examples of the previous pattern, and are usually associated with anarchic and refractory seizures. A separate group may be the brief ictal discharge pattern and questionable EEG ictal discharges. Decremental discharges, which sometimes accompany neonatal tonic seizures, must be distinguished from the normal arousal response that follows postural change or stimulation.

The expression of ictal activity in relation to sleep stages (REM/NREM) may have age-dependent mechanisms in the developing brain. Schmutzler et al 2005 tried to assess the relationship between ictal activity and sleep stages in the newborn EEG, finding the highest association with unrecognizable sleep states where sleep organization is already disrupted. Ictal activity predominates otherwise in REM sleep (p=0.01) with longer duration of discharges, contradicting findings in adults with epilepsy. However, the mechanisms responsible for increased seizures during NREM in adults (synchronous EEG oscillations promoting electrographic seizure propagation and asynchronous discharge patterns reducing seizures during REM sleep) cannot be extrapolated to the immature developing brain.

There is in fact an age-related differential regional distribution of GABA with excitatory and not inhibitory roles (Mosche, 2000) in subcortical areas like the substantia nigra that could facilitate the release of focal discharges during REM in newborns. Furthermore, an immaturity of REM-related inhibitory systems at a peripheral level have been shown in infants, which might affect the cortex influencing the frequency of ictal discharges during REM sleep in newborns.

Tekgul et al (2005) compared the yielding power of a reduced montage (9 electrodes) with the full 10/20 electrode montage to detect and characterize neonatal seizures and background EEG features. The sensitivity and specificity of the reduced montage for electrographic seizure detection was 96.8% and 100%, respectively, and only in 1 patient's record (over 31 pts) the single seizure was missed altogether. For assessing background abnormalities, the sensitivity and specificity of the reduced montage was 87% and 80%, respectively. The authors conclude that a reduced montage proves to be a sensitive tool for identification of neonatal seizures and grading of background EEG features in newborns.

Specific syndromes of neonatal seizures include the following:

Early myoclonic encephalopathy (EME) was first proposed by Aicardi in 1978 to describe neonates who had myoclonic jerks and a burst-suppression EEG pattern. The main criteria include severe neurological abnormalities in otherwise healthy neonates with early fragmentary erratic myoclonia and a burst-suppression pattern. A microdysgenesic malformation or metabolic disorder may be discovered later.
Early infantile epileptic encephalopathy (EIEE) was proposed by Otahara in 1976 and includes infants who, within 3 months after birth, develop refractory tonic spasm, developmental delay, and a burst-suppression EEG pattern. Most of these infants later develop a full-blown hypsarrhythmia in the context of West syndrome. Unlike EME, burst-suppression accompanies wakefulness as well as sleep. It is rarely familial but may be linked to cerebral malformations.
Benign idiopathic neonatal convulsions (BINC), also known as fifth day convulsions, can be seen in both symptomatic and cryptogenic infants and are associated with a favorable outcome. BINC are associated with a specific EEG parameter (even with the variability of clinical manifestations) of alternating sharp-theta bursts that are observed in the interictal period. Occasionally, seizures may be described as GTCS consisting in tonic extension of the arms and legs, cyanosis, and clonic jerks (Guerra, 2002). The EEG correlate to these events, however, despite being described as generalized, points to a unilateral frontocentral onset on either side as a sign of focal seizure with secondary generalization.
In 1966, Rett first described benign familial neonatal convulsions (BFNC), which are transmitted through autosomal dominant inheritance. The gene is localized on the long arm of chromosome 20 with regular penetration but variable expression. The incidence (0.9-2.1%) as well as the prevalence of epilepsy at later stages of life is low. EEG patterns are nonspecific. Seizure phenotype is highly variable as well as EEG ictal expressions, occasionally demonstrating generalized suppression and seizure onset followed by symmetric rhythmic slow wave and diffuse spikes in infants exhibiting tonic-clonic seizures (Ronen, 1993). GTCS in infants younger than 2 years are extremely rare (Korff and Nordly, 2005) probably due to the immaturity of the developing brain lacking substantial synchronization mechanisms in the absence of sufficient myelination and mature interhemispheric connections.
Benign myoclonic epilepsy in infants (BMEI) is a rare epileptic syndrome characterized only by generalized myoclonic seizures occurring in normal children during the first 2 years of life. A recent review (Auvin, 2005) found a high incidence of a positive family history of febrile seizures or epilepsy suggesting the importance of the genetic factor in the pathogenesis of BMEI. Reflex myoclonic seizures are frequently observed. VPA therapy is effective. BMEI may be followed by JME and, despite a favorable neuropsychological outcome, mental retardation can be observed.
Neonatal pyridoxine dependency is a rare autosomal recessive disorder, defined by the empirical resolution of all symptoms with pyridoxine administration. It is attributed to GAD deficiency in GABA synthesis, but no gene defect has been yet identified. The EEG pattern consists of repetitive runs of 1-4 Hz high-amplitude waves and spikes that are similar to the typical spike and wave discharges that are usually seen only in older children.
- In addition to neonatal seizures and reported infantile spasms from Japan, the phenotypic presentation for pyridoxine-responsive seizures includes epileptic encephalopathy of infancy and childhood and should be confirmed by pyridoxine challenge during a therapeutic EEG test. Normalization of follow-up EEGs after seizures response to pyridoxine therapy is the rule (Hwang, 2005). A recent report (Teune, 2005) suggests that IV pyridoxine affects EEG background activity with reduction in amplitude and total power in infants younger than age 1 year with therapy-resistant seizures as a nonspecific effect.
- Follow-up studies on the incidence of epilepsy following clinical neonatal seizures yield different results. According to Ronen et al (2005), results from a population-based study with more than 10 years follow-up, show the risk being highest for premature babies. The remote symptomatic epilepsies are usually accompanied by motor and cognitive comorbidities, mortality being seen only among patients whose epilepsy was associated with mental retardation and cerebral palsy. An adverse outcome (ie, death, severe developmental delay, CP) at age 2 years was strongly associated to seizures in preterm babies of very early GA and low birth weight (Pisani, 2005).