Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 30, 2008 — Optic nerve sheath meningiomas are seen most commonly in women between ages 30 and 50. Bilateral tumors are associated with neurofibromatosis 2. Primary optic nerve sheath meningiomas arise from the arachnoid cap cells of the arachnoid sheath; secondary tumors represent an extension of intracranial meningiomas into the orbit via the optic canal, superior orbital fissure, or bone.[1] Optic nerve sheath meningiomas impair the vascular supply and axonal transport of the optic nerve, thereby comprising its function.

These tumors present with slowly progressive visual loss and painless proptosis. Transient visual obscurations may be one of the initial symptoms. Ophthalmoscopic examination shows disc pallor and retinochoroidal shunts.

MRI and CT features are fusiform or eccentric thickening of the optic nerve sheath complex.[1,2] CT frequently shows calcification within the tumor (Fig. 10A). MRI provides better detail of the tumor extension than CT and contrast-enhanced, fat-suppressed, T1-weighted images are particularly useful. MRI typically shows a hypodense optic nerve surrounded by a fusiform or globular rim of enhancing tissue with very fine extensions into the orbital fat (Fig. 1B). The tram-track sign is typical but not specific for meningiomas.[3] It is the result of the relative hypointensity or hypodensity of the optic nerve, compared with the surrounding tumor, which enhances strongly and may be hyperdense on CT because of calcification.

Figure 1. (A) Axial contrast-enhanced CT in a patient who had a right optic nerve sheath meningioma exhibiting fusiform dilatation of the optic nerve sheath with a tram-track sign and focal calcification (arrow). (B) Axial contrast-enhanced, fat-saturated, T1-weighted image in a different patient who had a right optic nerve sheath meningioma. There is an enhancing tumor surrounding the right optic nerve, which extends into the globe (short arrow) and has fine extensions into the orbital fat (long arrow). (Click to magnify figure)

Once the meningioma has extended through the optic canal, it spreads along the intracranial meninges and can endanger the contralateral optic nerve, if it crosses the midline at the level of the planum sphenoidale, which is appreciated best on coronal MRI.

Assessment of tumor extension and progression with imaging is relevant to clinical management. Optic nerve sheath menigiomas are slowly progressive and do not metastasize, so that observation without invasive treatment is an option. In conservatively treated menigiomas, MRI studies at 6-month intervals in the first 2 years followed by yearly studies for 2 to 3 years are recommended. [4]

Recent evidence suggests that patients treated with radiotherapy alone have a better long-term visual outcome compared with patients who have optic nerve sheath meningioma who are managed conservatively and surgically.[5] A major concern with radiotherapy is its toxicity to the optic nerve, retina, and pituitary gland. Stereotactic fractionated radiotherapy can deliver a sufficient dose to the optic nerve while minimizing the exposure to adjacent structures. Stereotactic fractionated radiotherapy requires complex planning based on pretreatment CT and MRI and has emerged as the primary treatment option for optic nerve sheath meningiomas after several published series demonstrated disease control in more than 90% and visual improvement in more than 50% of patients.[4]

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References

1. Mafee MF, Goodwin J, Dorodi S. Optic nerve sheath meningiomas. Role of MR imaging. Radiol Clin North Am. 1999;37:37–58ix.
2. Ortiz O, Flores RA. Clinical and radiologic evaluation of optic pathway lesions. Semin Ultrasound CT MR. 1998;19:225–239.
3. Kanamalla US. The optic nerve tram-track sign. Radiology. 2003;227:718–719.
4. Miller NR. New concepts in the diagnosis and management of optic nerve sheath meningioma. J Neuroophthalmol. 2006;26:200–208.
5. Turbin RE, Thompson CR, Kennerdell JS, et al.. A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology. 2002;109:890–899[discussion 899–900].

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 30, 2008 — Dystonia is a disorder characterized by involuntary sustained muscle contractions resulting in repetitive movements or abnormal postures. Despite an incomplete understanding of the neurological mechanisms underlying dystonia, relief of dystonic posturing and associated pain and discomfort has markedly improved since the introduction of botulinum toxin (BTX) therapy in the late 1980’s.

Botulinum toxin (BTX) is one of the most potent biologic substances known. There are 7 distinct serotypes: A, B, C, D, E, F, and G, each of similar size and structure. However, the serotypes differ in their potency, duration of action and cellular target sites. Types A and B have been shown to be safe and effective in double-blind clinical trials for the treatment of dystonia. One formulation of BTX-A is marketed worldwide under the name Botox (Allergan Inc.) and another in Europe as Dysport (Speywood, UK). Botox was approved in December 1989 by the US Food and Drug Administration (FDA) for “the treatment of strabismus, blepharospasm, and focal spasms including hemifacial spasm.” A formulation of botulinum toxin type B (BTX-B), was approved in December 2000 by the FDA for treatment of cervical dystonia, and will be marketed under the name Myobloc in the US and Neurobloc in Europe (Elan Pharmaceuticals).

It is important to recognize that the various commercial formulations of botulinum toxin differ in the dosages used clinically owing to differences in potency and diffusion (see below).

BOTULINUM TOXIN TYPE A (BTX-A)

BTX proteins have been studied since the early 1900’s, initially to gain an understanding of botulism, a form of food poisoning. Later, they were studied because of the unique and specific muscle paralysis induced by minute amounts of the toxins. During the past 30 years of work on the use of the toxin for human treatment, selective procedures for the production, purification and dispensing of the toxin have been developed to make it suitable for injection. Today botulinum toxin type A (BTX-A) is employed and considered safe and effective for treatment of movement disorders and spasticity. One of the more common movement disorders treated with BTX-A is focal dystonia, the most frequently occurring types of which include cervical dystonia, blepharospasm, hand dystonia, oromandibular dystonia, occupational dystonia, and laryngeal dystonia.

Applications for botulinum toxin injections

• Focal dystonia

  • Blepharospasm

  • Focal hand dystonia

  • Cervical dystonia (torticollis)

  • Foot dystonia

  • Oromandibular-facial-lingual dystonia

• Hemifacial spasm

• Myoclonus

• Dystonic tics

• Tremors

• Bruxism

• Spasticity

Treatment of focal dystonia using BTX is designed to improve patient’s posture and function and to relieve associated pain. As BTX-A has been studied most intensely and used most widely this section will outline its structure, origin and mechanism of action.

The toxin inhibits release of acetylcholine, a neurotransmitter responsible for activation of muscle contraction. Administration of the toxin results in weakness in the injected muscle. Some nerve terminals are not affected by the toxin, allowing the injected dystonic muscle to contract, but with less force. This weakness allows for improved posture and function of the dystonic muscle(s). The degree of weakness depends on the dose, and the duration of weakness is further dependent on the serotype employed.

• Structure of BTX

Botulinum toxin is synthesized as a single chain peptide with a molecular mass of 150kDa. This form has relatively little potency as a neuromuscular blocking agent and activation requires a two-step modification in the tertiary structure of the protein. This process converts the single chain neurotoxin to a di-chain neurotoxin comprising a 100,000 dalton heavy chain (HC) linked by a disulfide bond to a 50,000 dalton light chain (LC). BTX acts at the neuromuscular junction where it exerts its effect by inhibiting the release of acetylcholine (ACH) from the presynaptic nerve terminal. ACH is contained in vesicles and several proteins (VAMP, SNAP-25 and syntaxin) are required to mediate fusion of these vesicles with the axon terminal membrane. BTX binds to the presynaptic terminal via the HC. The toxin is then internalized and the H and L chains are separated. The L-chain from BTX-A cleaves SNAP-25, the L-chains from B and F cleave VAMP and that from C cleaves syntaxin. This results in a disruption of ACHrelease and subsequent neuromuscular transmission resulting in weakness of the injected muscle.

• Preparation

The toxin is produced by gram-negative anaerobic bacteria Clostridium botulinum. It is harvested from a culture medium after fermentation of a toxin-producing strain of Clostridium botulinum, which lyses and liberates the toxin into the culture. The toxin is then extracted, precipitated, purified, and finally crystallized with ammonium sulfate. BTX-A should be diluted with preservative-free saline and the preparation should be used within 4 hours of reconstitution. Conditions for stability of the toxin in solution include ph 4.2-6.8 and temperature less than 20 degrees Celsius. Crystallized toxin is easily inactivated in solution by shaking. Biological activity of BTX-A distributed by Allergan Inc. (BOTOX) is different from the BTX-A produced in the UK by Speywood Pharmaceuticals in England (Dysport) or Japan. The potency of BTX is expressed as mouse units with 1 mouse unit equivalent to the median lethal dose (LD 50) for mice. BOTOX is dispensed in small vials containing 100 units (U), while avial of Dysport contains 500U. The relative potency of BOTOX units to Dysport units is approximately 1:4. BOTOX units are used throughout this chapter. Most physicians dilute the vial of BOTOX with 1 to 4 ml of saline, for a concentration of 2.5-10U/0.1 ml.

For injection purposes EMG guidance is generally advised with the exception of injections of muscles around the eye and some facial muscles. The dose of BOTOX injected intramuscularly depends on the muscle size. Small muscles, such as the vocal cords receive 0.75 U, whereas larger neck muscles may require 100 to 150 U and lower limb muscles may require 200-300 U to exert a desirable effect. After injection, BTX starts to weaken the muscle within 24 to 72 hours and maximal effect occurs after about 14 days and benefit can last for 3-6 months.

• Administration of BTX

BTX should only be administered by trained specialists utilizing correct equipment, which includes EMG monitoring to help diagnose the underlying disorder and to identify appropriate muscles for injection. Prior to treatment with BTX, patients should have a neurological evaluation and examination performed. Secondary causes of dystonia such as drug-induced dystonia or Wilson disease should be ruled out. Physicians administering BTX must have a good understanding of both the anatomy of affected muscles and the resultant movement disorder. Patient education and counseling are essential components of a comprehensive therapeutic approach to all patients with dystonia. BTX can be used as sole therapy or as an adjunct to oral medications. Physical therapy may play a role as a supplement to BTX.

Medications used to treat focal dystonia

• Botulinum toxin injections

• Benzodiazepines

  • Clonazepam

  • Lorazepam

  • Diazepam

• Baclofen

• Anticholinergics

  • Trihexyphenidyl

  • Benztropine

• Dopamine depleting agents

  • Tetrabenazine

  • Clozapine

• Optimum goals of BTX treatment

Achieve a balance between sufficient weakness to reduce spasm and without interfering with function. The best combination of reduction in dystonia and pain with optimization of function should be sought.

• Adverse Effects

During injection patients may report a stinging sensation especially with treatment around the eyelids and face. Bruising at the site of injection may occur. In general, side effects are usually localized to the site of injection and are related to excess weakness of injected muscles that is transient and well tolerated. Systemic side effects, though rare, consist of a flulike syndrome that is transient and may last up to a few weeks. Serious side effects are dysphagia and respiratory compromise, which may occur with injections into the neck, mouth region and vocal cords. Intravascular injection is to be avoided as this may cause generalized weakness. Pneumothorax is a rare, potentially serious complication, from pleural penetration when performing injections into the lower neck or back.

A number of cases of systemic botulism-like reaction to BTX-A injections have recently been reported. Generalized weakness including bulbar weakness developed in both cases and resolved over several weeks. One of these patients had been treated for torticollis for many years and the other had only one series of injections for spasticity.

The lethal dose of BOTOX in humans is not known, although it has been estimated to be about 3000 units. However, the usual maximum total recommended dose at an injection session is about 600-800U.

• Development of antibodies to BTX

Botulinum neurotoxins may be immunogenic. Antibodies may develop, bind to the BTX and inactivate it. The incidence of antibody-mediated resistance for BOTOX, as determined by the mouse lethality assay, is reported between 3% and 10%. The only apparent symptom of the development of antibodies is lack of response to further injections. The use of other serotypes (F or B) may benefit those who have developed antibody resistance. In a patient who no longer responds to BTX-A (“secondary non-responder”) and in whom immunogenicity is suspected the recommended approach is to inject 20 U Botox into hypothenar or forehead muscles. If the patient is still responsive, transient weakness will develop in the muscle 1-2 weeks after injection. An alternative or adjunct is to take blood for antibody assay but this is usually not covered by insurance. Risk factors for the development of antibodies include higher doses, shorter intervals between injections, booster doses, and young age. Recommendations to help preventdevelopment of antibodies include (1) use of smallest possible dose to achieve relief (2) interval between injections of at least 1 month (preferable interval is 3 months), and (3) avoid “booster injection.”

A patient who does not respond to the first injection of BTX-A is referred to as a “primary non-responder,” but reasons for non-response can include inappropriate site of injection and too low a dose. A person should not be considered an initial non-responder until they have been injected by an expert using increasing doses or lack of response demonstrated using one of the clinical tests discussed above.

• Contra-indications

There are no known absolute contra-indications to the use of BTX-A. Relative contra-indications include myasthenia gravis or motor neuron disease. Patients who are pregnant or lactating may not be appropriate candidates for BTX therapy.

Relative contra-indications for clinical application of botulinum toxin

• Pregnancy and lactation

• Neuromuscular disease (eg, myasthenia gravis, Eaton Lambert syndrome)

• Motor neuron disease

• Concurrent use of aminoglycosides

CLINICAL APPLICATIONS OF BOTULINUM TOXIN

• Blepharospasm

Blepharospasm (BS) is characterized by involuntary, intermittent, forced eyelid closure. BTX is considered the treatment of choice for blepharospasm and has been used for this disorder since 1983. It has also been used effectively in the treatment of blepharospasm induced by drugs such as L-dopa or neuroleptics, dystonic eyelid and facial tics in patients with Tourette syndrome and in patients with “apraxia of eyelid opening.”

• Injection technique

Treatment may be started with 10U of BOTOX per eyelid, injecting a total of 20U per patient. The most common effective dose is 25U per eye. It is recommended to dilute the BOTOX with 4ml of normal saline. As the orbicularis oculi muscle lies superficially, intradermal injection with a 27- to 30-gauge needle is recommended. Typically 3-5 points around each eye are injected. The principle is to avoid the mid-portion of the upper eye-lid to avoid inadvertent diffusion into the levator palpebrae superiores, which would lead to undesirable ptosis. Injection into the medial lower lid is also usually avoided.

• Therapeutic efficacy

Onset of improvement is seen in 4-7 days and benefit can last for up to 4 months 

• Risk and side effects

Ten percent of patients develop ptosis, which improves spontaneously in less than 2 weeks. Other complications include blurring of vision, tearing, and local hemorrhage.

• Focal hand dystonia

This condition typically presents with loss of speed and fluency of movement during a specific task. Neurological evaluation is required to rule out radiculopathy or peripheral nerve entrapment for which specific treatment might be available. Nerve conduction studies may be required to exclude ulnar neuropathy or median entrapment neuropathy at the wrist. Examination of the forearm muscles should be performed during the specific task so as to determine which muscles are involved in the dystonia. Observations should be made at rest and during the provoking activity. The patient should be instructed to avoid compensating for the dystonia. The selection of muscles for injection depends on clinical examination, patient report of local pain or tightness, and/or EMG evidence of excessive activity.

• Injection technique

BTX is injected into the muscle belly; localizing muscles for injection in the forearm may be difficult as many of the muscles are deep and overlapping. EMG is recommended to help identify the ‘target’ dystonic muscle. Once proper needle location is confirmed, BTX can be injected. Common initial doses of BOTOX for writer’s cramp are 5 U for small muscles and 10-20 U for the muscles in the forearm. Large doses into a single muscle are best given in multiple sites to aid diffusion of the toxin to a greater number of end plates. The dose of BTX is titrated over several injection sessions to the dose that maximizes relief from dystonia while minimizing muscle weakness. Subsequent injections should be given at 2-4 month intervals. At each subsequent session, the patient should be examined for weakness that might indicate postponing treatment or reducing the dose. As the pattern of muscle contraction can change, the dystonia should be re-evaluated at each session. 

• Therapeutic efficacy

Treatment may lead to an improvement in abnormal posture, pain, and/or restoration of normal function. Benefit has been reported in up to 80-90% patients and is usually apparent 5-7 days after injection. Symptomatic relief peaks about 2 weeks after treatment and may last for 3-4 months.

• Cervical dystonia (Click for more details)

Cervical dystonia (CD) is the most common form of focal dystonia and is characterized by sustained postures or contractions of the neck muscles. Deviation of the head can occur in multiple directions; turning of head (torticollis) is the most common subtype of cervical dystonia. Laterocollis (titling) bends the head laterally, moving the ear towards the ipsilateral shoulder; anterocollis (forward flexion) deviates the chin downward towards the chest; while retrocollis (extension) produces upward extension of the chin. Cervical dystonia can involve any combination of these deviations. 

• Examination of patient

CD is usually idiopathic but in some cases it follows trauma. A study including 300 patients at Baylor College of Medicine revealed that up to 11% patients had significant neck injury less than 1 year prior to the onset of CD. Exposure to neuroleptic drugs accounted for 6% of the CD patients in the Baylor series. Neurological examination is essential to rule out radicular processes or ophthalmologic disorders, which can present with abnormal posture of the head.

The anatomy of the neck is complex; a basic familiarity with anatomic landmarks, muscle origins and insertions, and vital structures in that region is necessary to effectively use BTX injections to treat these patients. The abnormal postures of CD usually result from abnormal activity of multiple muscles. Postures are complex with combinations of turning, tilting, head flexion or extension, and shoulder elevation.

Proper selection of the involved muscles is the most important determinant of response to BTX treatment. Thus, careful examination of the patient in different positions is indicated; instruct the patient to position the head in a comfortable upright posture. Passively adjust the head and observe for additional extension, flexion, and rotation that may be compensated for by the patient and note any contractures. Palpate for contracting muscles and hypertrophy and any point tenderness. The patient should then be asked to walk and the head position is observed and recorded. The head position that is most abnormal is used to select the muscles for injection. Electromyography (EMG) is recommended to localize involved muscles and it can facilitate the accuracy of injection.

• Injection techniques

Most commonly injected muscles include sternocleidomastoid, trapezius, splenius capitis, levator scapulae, and scalene complex. Muscles involved in the abnormal posturing are isolated using standard anatomical landmarks. EMG guidance is recommended for injection purposes. Once the EMG electrode is inserted, the patient is instructed to activate the muscle evoking a full recruitment pattern. Needle is held in position and the patient resumes a relaxed position. The syringe is aspirated to ensure that the tip is not within a blood vessel and the appropriate amount of BTX is then directly injected through the electrode into the muscle. BOTOX treatment doses range from 10-600 U, with 200-300 U most commonly used; usually 2-6 muscles are injected at multiple sites along the belly of the muscle to allow for adequate diffusion of the toxin. 

• Therapeutic efficacy

Ninety percent of patients report some improvement in the postural deviation. In published reports 76-93% of patients experienced pain relief following treatment with BTX. In some studies, subjective pain relief is frequently more impressive than objective improvement in head posture. Latency between injections and onset of clinical benefit is around 7 days. Duration of effect is 3-4 months. 

• Risks and side effects

The most common side effects include neck weakness (20-30%), dysphagia (10-20%), and local pain. The occurrence of dysphagia appears to be related to the dose and the muscles injected. Side effects are transient and usually resolve spontaneously within 2-3 weeks.

• Oromandibular dystonia

Oromandibular dystonia (OMD) is characterized by abnormal involuntary movements or spasms of lower face, jaw, and tongue muscles. Patients present with spasms of these muscles and jaw deviation.

• Injection technique

Treatment of this condition with BTX requires a detailed knowledge of the local anatomy. Evaluation by both a neurologist and otolaryngologist is recommended. OMD can involve different combinations of muscles including the masseter, lateral and medial pterygoids, and temporalis. The recommended dose of BTX is 20 U in each muscle. 

• Therapeutic efficacy

Seventy to eighty percent of patients with OMD benefit from local injections of BTX into the inappropriately contracting muscles. Improvement is observed within the first week after BTX and the benefit can last for 3-4 months.

• Risks and side effects

Side effects are uncommon and include dysphagia and pain at the injection site.

• Laryngeal dystonia

Laryngeal dystonia, also called spasmodic dysphonia, is characterized by abnormal involuntary spasms of vocal muscles resulting in an abnormal voice pattern. 

• Injection technique

Before a patient can be considered as a potential candidate for BTX injections, the diagnosis of laryngeal dysphonia must be confirmed by neurological, otolaryngological, and voice assessment. Clinical findings should be documented by video and voice recording with fiberoptic laryngoscopy. The thyroarytenoid muscles are located with EMG guidance and percutaneous injections of BTX are administered through the cricothyroid membrane. BTX dose ranges from 1.5-3 U. Currently, a bilateral injection approach is the most frequently used technique.

• Therapeutic efficacy

Seventy-five percent patients note improvement in voice symptoms. Relief after BTX injection begins within 24-72 hours and lasts for an average of 4 months. 

• Risks and side effects

Swallowing difficulties in 60% patients, which can last for 3-7 days. Transient hypophonia and stridor have also been reported.

• Hemifacial Spasm (HFS)

Hemifacial spasm (HFS) is one of the more common craniofacial movement disorders. It is characterized by unilateral muscle contractions of the face. Hemifacial spasm may involve any combination of orbicularis oculi, frontalis, risorius, zygomaticus major, and platysmas muscles. This is not a form of focal dystonia but rather is most probably caused by irritation of the seventh cranial nerve by an artery compressing the nerve as it exits the brain stem. Injections of BTX are tailored to the facial muscles in spasm and the muscles affected differ from patient to patient. Side effects depend on location of injection; lower face injections may result in facial weakness and asymmetry, face and mouth droop, drooling and loss of facial expression. Forehead injections can result in brow ptosis or loss of eyebrow elevation. Most patients receive substantial benefit within 48 to 72 hours after an injection and benefit peaks by 2 to 3 weeks and can last for 3 to 4 months.

BOTULINUM TOXIN TYPE B (BTX-B) FOR DYSTONIA

Myobloc (Elan Pharmaceuticals) was approved by the FDA in December 2000 for treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. BTX-B has also received marketing authorization from the European Union’s Committee for Proprietary Medicinal Products and will be marketed as Neurobloc (Elan Pharmaceuticals). Reported clinical studies have shown Myobloc/Neurobloc to be a safe and effective treatment for cervical dystonia in patients who have responded to BTX A and in those who developed resistance to BTX A. As with all the botulinum toxins, BTX-B acts at the neuromuscular junction inhibiting the release of acetylcholine (ACh) at the presynaptic membrane. This primary mechanism of action of BTX-B differs from BTX-A, as BTX-B inactivates a different protein involved in the release of ACh at the presynaptic nerve terminal.

FUTURE AND CONTROVERSIES

Unresolved issues concerning BTX include the following:

• Lack of standardization of biological activity of the different preparations

• Poor understanding of the toxin, including its mechanism of action, potency, and long-term effects

• Inadequate assays of Botulinum toxin antigens

• Variations in method of injection

Future directions include improving the efficacy of BTX or finding a superior NMJ blocking agent with a prolonged duration of action. Given the potential for development of an immune response against the toxin, it will be necessary to have (1) alternative serotypes that can replace the ones to which patients are immune, (2) formulations that are engineered to be less immunogenic, and (3) alternative drugs with little or no probability of evoking antibody formation.

Greater clinical utility would occur with formulations that can be stored longer once partially used, provide more prolonged benefit, and less frequently induce antibody formation causing non-responsiveness.

References

1. Brin MF, Lew MF, Adler CH: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A- resistant cervical dystonia. Neurology 1999 Oct 22; 53(7): 1431-8.
2. Elston JS: Botulinum toxin for blepharospasm. Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin, New York: Marcel Dekker 1994; 299-306.
3. Hallett M: Physiology of dystonia. Fahn S, Marsden CD, Delong M, eds. Advances in Neurology, New York: Lippincott-Raven 1997; 11-19.
4. Illowsky K, Hallett M: Botulinum toxin treatment of focal hand dystonia. Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin, New York: Marcel Dekker 1994; 299-306.
5. Jankovic J, Schwartz K, Donovan DT: Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990 Aug; 53(8): 633-9.
6. Jankovic J: Botulinum toxin in movement disorders. Curr Opin Neurol 1994 Aug; 7(4): 358-66.
7. Report of the Therapeutics and Technology Assessment Subcommittee of the America: Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990 Sep; 40(9): 1332-6.
8. Metwally, MYM: Cervical dystonia. An online post at www.yassermetwally.net [Full text]
9. MetwallyMYM: Botox: Effective Treatment for Dystonia and Muscle Spasm. An online post at www.yassermetwally.net [Full text]
10. Metwally MY: Pharmacology of Botulinum toxins. An online post at www.yassermetwally.net [Full text]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 29, 2008 — In nursing home residents with Alzheimer’s disease and psychosis, aripiprazole is not associated with any specific benefit vs placebo for the treatment of psychosis. However, psychological and behavioral symptoms do improve, according to the results of a parallel-group, randomized, double-blind, placebo-controlled, flexible-dose trial reported in the July issue of the American Journal of Geriatric Psychiatry.

“Several published randomized controlled trials have shown the efficacy of atypical antipsychotics in treating behavioral symptoms associated with AD [Alzheimer's disease], and an expert consensus guideline has recommended the use of atypical antipsychotics for the treatment of such symptoms,” write Joel E. Streim, MD, from the University of Pennsylvania in Philadelphia, and colleagues. “However, the efficacy of these agents specifically for the control of psychosis of AD is less well established, with evidence arising mostly from secondary or subgroup analyses. The aim of this double-blind, randomized study was to evaluate the effects of the atypical antipsychotic aripiprazole (at flexible doses of 2 – 15 mg/day) on psychotic symptoms associated with AD in institutionalized patients.”

Nursing home residents with Alzheimer’s disease and psychotic symptoms were randomized to receive aripiprazole (n = 131) or placebo (n = 125) for 10 weeks, with a starting dose of aripiprazole of 2 mg/day, which could be titrated to 5, 10, and 15 mg/day according to efficacy and tolerability.

There were no significant differences in mean change (2 x SD) from baseline between aripiprazole and placebo in the coprimary efficacy endpoints of the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Psychosis score (aripiprazole, –4.53 [9.23]; placebo, –4.62 [9.56]) and Clinical Global Impression (CGI)–Severity score (aripiprazole, –0.57 [1.63]; placebo, –0.43 [1.65]).

However, aripiprazole vs placebo was associated with improvements in several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI-improvement, Cohen-Mansfield Agitation Inventory, and Cornell Depression Scale scores).

In both groups, treatment-emergent adverse events were similar, except that somnolence occurred in 14% in the aripiprazole group and 4% in the placebo group. Somnolence with aripiprazole was mild or moderate and was not linked to unintentional injury. Adverse events related to extrapyramidal symptoms were infrequent in both groups (5% with aripiprazole and 4% with placebo).

“In nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs [adverse events],” the study authors write.

Limitations of the study were that not all patients treated with aripiprazole received a dose of 10 mg/day, which was shown in other studies to be most beneficial.

“Data from the current study, considered together with those from other aripiprazole studies in patients with AD, indicate that aripiprazole 10 mg/day may be an efficacious dose for treating psychological and behavioral symptoms in this population,” the study authors conclude. “Although somnolence was more commonly reported in aripiprazole-versus placebo-treated subjects, somnolence was not associated with accidental injury. Overall, benefits were achieved with a low risk of AEs, including EPS [extrapyramidal symptoms] and other events that are known to cause or contribute to the risk of falls and fractures in the elderly.”

Bristol-Myers Squibb Co and Otsuka Pharmaceutical Co, Ltd, supported and funded this study. Two of the study authors have disclosed various financial relationships with Bristol-Myers Squibb. Two other study authors are employed with Bristol-Myers Squibb. Another study author is employed with Otsuka.

• Clinical Context

Although the hallmark of Alzheimer’s disease is declining cognitive function, there is also a high prevalence of psychotic symptoms, such as delusions and hallucinations. Psychological and behavioral symptoms, including agitation, aggression, depression, and anxiety, are also common. Of patients with Alzheimer’s disease and agitated behavior requiring treatment, three quarters have delusions or hallucinations.

Atypical antipsychotics have been shown to be effective in the treatment of the behavioral symptoms of Alzheimer’s disease, but their efficacy in the control of psychosis associated with Alzheimer’s disease has not been conclusively demonstrated. Since the present study was designed and completed, analyses of safety data from several studies have raised concerns about an increased risk for cerebrovascular adverse events with the use of atypical antipsychotics in elderly patients with dementia, leading to warnings and guidance from regulatory authorities concerning the use of these drugs to treat behavioral and psychological symptoms in elderly patients with dementia, particularly those with a history of cerebrovascular disease.

• Study Highlights
  1. The objective of this parallel-group, double-blind, randomized study was to assess the effects of aripiprazole (at flexible doses of 2 – 15 mg/day) on psychotic symptoms in nursing home residents with Alzheimer’s disease.
  2. This study was designed in 2000, and patients completed participation in the study protocol in 2003.
  3. Patients with Alzheimer’s disease and psychotic symptoms were randomized to receive aripiprazole (n = 131) or placebo (n = 125) for 10 weeks.
  4. Starting dose for aripiprazole was 2 mg/day. On the basis of efficacy and tolerability, this could be titrated to higher doses (5, 10, and 15 mg/day).
  5. At endpoint, mean dose of aripiprazole was approximately 9 mg/day (range, 0.7 – 15.0 mg/day).
  6. There were no significant differences in mean change (2 x SD) from baseline between aripiprazole and placebo in the coprimary efficacy endpoints of the NPI-NH Psychosis score (aripiprazole, –4.53 [9.23]; placebo, –4.62 [9.56]; P = .883) and the CGI-Severity score (aripiprazole, –0.57 [1.63]; placebo, –0.43 [1.65]).
  7. However, aripiprazole was associated with clinical benefits beyond the primary outcome measures.
  8. Improvements were noted for aripiprazole vs placebo for several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI-improvement, Cohen–Mansfield Agitation Inventory, and Cornell Depression Scale scores).
  9. Both groups had similar treatment-emergent adverse events, except for somnolence, which was present in 14% of patients receiving aripiprazole and 4% of patients receiving placebo.
  10. Somnolence associated with aripiprazole was mild or moderate in intensity and not associated with unintentional injury.
  11. Incidence of extrapyramidal symptoms was low both with aripiprazole (5%) and with placebo (4%).
  12. Extrapyramidal symptom rating scale scores showed slight mean baseline-endpoint improvements with aripiprazole.
  13. Aripiprazole was associated with minimal mean weight loss; few subjects in either group had clinically relevant weight loss.
  14. Only 1 cerebrovascular adverse event was reported, and that was in the placebo group. There was no difference in the number of deaths with aripiprazole vs placebo.
  15. The investigators concluded that in nursing home residents with Alzheimer’s disease and psychosis, aripiprazole did not provide specific benefits for the treatment of psychotic symptoms.
  16. They also concluded that agitation, anxiety, depression, and some other psychological and behavioral symptoms were relieved with aripiprazole, with a low risk for adverse events.
  17. However, in light of the warnings of the risk for cerebrovascular adverse events and mortality with atypical antipsychotic therapy, they recommend careful review of each patient’s medical history before any antipsychotic is started.
  18. Limitations of the study include flexible-dosing schedule preventing all aripiprazole-treated patients from receiving a dose of 10 mg/day, which was shown in other studies to be most beneficial.
• Pearls for Practice
  1. In this study of nursing home residents with Alzheimer’s disease and psychosis, aripiprazole did not provide specific benefits for the treatment of psychotic symptoms. There were no significant differences in mean change from baseline between aripiprazole and placebo in the NPI-NH Psychosis score or in the CGI-Severity score.
  2. Agitation, anxiety, depression, and some other psychological and behavioral symptoms were relieved with aripiprazole, with a low risk for
  3. adverse events. However, in light of the warnings of the risk for cerebrovascular adverse events and mortality with atypical antipsychotic therapy, each patient’s medical history should be carefully reviewed before treatment with any antipsychotic is started.

References

1. Am J Geriatr Psychiatry. 2008;16:537-550.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 29, 2008 — Although moderate drinking can offer health benefits, new research in mice suggests that abstinence following moderate drinking can lead to depression and blunt the growth of new neurons (neurogenesis) in the hippocampus.

The study, with lead author Jennie R. Stevenson, a neurobiology graduate student, and colleagues from the University of North Carolina at Chapel Hill, is published online June 18 in Neuropsychopharmacology.

“Our research in an animal model establishes a causal link between abstinence from alcohol drinking and depression,” said study senior author Clyde W. Hodge, PhD, professor of psychiatry and pharmacology at the University of North Carolina School of Medicine. “In mice that voluntarily drank alcohol for 28 days, depressionlike behavior was evident 14 days after termination of alcohol drinking. This suggests that people who stop drinking may experience negative mood states days or weeks after the alcohol has cleared their systems.

“This research provides the first evidence that long-term abstinence from moderate alcohol drinking — rather than drinking per se — leads to a negative mood state, depression,” he added.

Alcoholism and depression are 2 of the most costly and widespread neuropsychiatric disorders worldwide, the group writes. Converging evidence suggests that both alcoholism and depression are linked to reductions in hippocampal neurogenesis and that antidepressants may increase neurogenesis.

The group hypothesized that decreased hippocampal neurogenesis may be a neurobiological mechanism that contributes to the co-occurrence of alcoholism and depression, and they investigated this using a novel preclinical behavioral model in mice.

• Floating, Depressed Mice

In a first set of experiments, alcohol-drinking mice were allowed to voluntarily consume alcohol or water for 28 days. Then, using the Porsolt forced-swim test, which measures depressionlike behavior, half were tested after alcohol was removed for 1 day and half were tested after alcohol was removed for 14 days.

In the forced-swim test, the mice are placed in a large beaker of water and forced to swim for 6 minutes, which they normally do readily. The amount of time the mice spend floating (being immobile) and not swimming is used as an index of depressionlike behavior.

A comparison group of control mice had access to water for 28 days and were tested 1 day later.

The alcohol-drinking mice voluntarily consumed an average of 17.8 ± 1.0 g/kg/day of alcohol, which is considered to be a moderate amount. After 14 days, but not after 1 day of abstinence, they showed a significant increase in depressionlike behavior. This emergence of depression was associated with a profound reduction in the number of neural stem cells and in the number of new neurons in the hippocampus — a brain region critical for normal learning and memory.

According to Dr. Hodge, the negative mood state in mice may represent depression in humans and appears to be linked to a diminished capacity of the brain to form new neurons.

“Thus, people who drink moderate alcohol socially or for potential health benefits may experience negative mood or diminished cognitive abilities due to a loss of the brain’s ability to form new neurons,” he said.

• Antidepressant-Treated Mice Swim On

In a second set of experiments, alcohol-drinking mice voluntarily consumed alcohol or water for 28 days and then, during a 14-day abstinence period, received daily injections of either placebo or desipramine, a tricyclic antidepressant that has been shown to be highly effective in the forced-swim test in mice.

A control group of mice received water for 28 days and then were injected with either placebo or desipramine, in parallel with the alcohol-abstinent mice.

Mouse behavior was evaluated using the forced-swim test 1 day after the last injection.

The investigators found that chronic treatment with desipramine during abstinence prevented the development of depression and restored the capability of the brain to produce new cells.

“Treatment with antidepressant drugs may help people who suffer from both alcoholism and depression by restoring the brain’s ability to form new neurons,” said Dr. Hodge.

This study provides an animal model of alcohol-related depression that can be used to begin to fully understand the neurobiological mechanisms underlying co-occurring alcoholism and depression and thereby develop successful treatment options, he added.

References

1. Neuropsychopharmacology. Published online June 18, 2008. Abstract

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 29, 2008 — New research showing that vitamin D deficiency is common in patients with chronic migraine suggests that this patient group, like other vitamin D–deficient populations, is at increased risk for cardiovascular disease, malignancy, and other serious illnesses that have been linked to low levels of this “good-health” vitamin.

Investigators presented the results of an observational study here at the 50th Annual Meeting of the American Headache Society, which showed that 41.8% of patients with chronic migraine were deficient in 25-hydroxyvitamin D. The study also showed that the longer individuals had chronic migraine, the more likely they were to be vitamin D deficient.

“As far as I am aware, no one has looked at vitamin D deficiency in migraineurs before. Recognizing that vitamin D deficiency is epidemic in the general population, we know that patients with migraine have other health concerns, among them an increased risk for cardiovascular disease, cerebrovascular disease, and fibromyalgia, conditions that have also been linked to vitamin D deficiency.

“So in this population, where we know there’s a good chance other health issues are present, treating vitamin D deficiency is something that we can easily assess and treat to try to minimize some of these other health issues,” said study investigator Steve Wheeler, MD, from the Ryan Wheeler Headache Treatment Center, in Miami, Florida.

• ‘The First Person I Tested Was Myself’

Dr. Wheeler decided to investigate vitamin D deficiency in his own clinic population of chronic migraineurs after reading a paper published in 2007 (Arch Intern Med. 2007;167:1159-1165). The study showed a strong link between the prevalence of cardiovascular risk factors and serum levels of 25-hydroxyvitamin D.

“Until that point, I had no idea vitamin D deficiency was a cardiovascular risk factor, although I was aware there was a link between migraine and cardiovascular disease.”

A migraineur himself, Dr. Wheeler has a strong family history of cardiovascular disease, cerebrovascular disease, cancer, and diabetes. Dr. Wheeler said he read several other studies on the negative effect of vitamin D deficiency on health, including a seminal review by world expert Michael Holick, MD, PhD, from Boston University Medical Center, in Massachusetts (N Engl J Med. 2007;357:266-281).

He pointed out that the research shows that vitamin D deficiency is associated with a variety of diseases in multiple-organ systems, including hypertension, diabetes, cancer, multiple sclerosis, rheumatoid arthritis, fibromyalgia, depression, stroke, and myocardial infarction.

After looking at the literature and considering vitamin D deficiency in the context of his own family history, Dr. Wheeler said the issue “became personal.”

“The first person I tested was myself, and I found I was severely vitamin D deficient (with a 25-hydroxyvitamin D level of 8.2 ng/mL). Levels greater than 30 ng/mL are considered sufficient, but only for bone health. Optimal levels for other conditions, such as cardiovascular disease, are still unknown, although it is believed they should be much higher,” he said.

• Underrecognized

Dr. Wheeler then decided to look at levels in his patients. He reviewed the records from consecutive chronic migraine patients who had vitamin D levels assessed at a single outpatient laboratory over a 6-month period.

The study consisted of 55 migraineurs. Of these subjects, 54 had chronic and 1 had frequent migraine attacks. The mean age of the subjects was 49.8 years. Vitamin D level consisted of total 25-hydroxyvitaimin D, 25-hydroxyvitamin D3, and 25-hydroxyvitamin D2.

Optimal or sufficient total vitamin D was defined as levels greater than 30 ng/mL. Levels between 20 and 30 ng/mL were defined as insufficient, and levels less than 20 ng/mL were defined as deficient.

The study showed that 41.8% of patients had levels of 30 ng/mL or less. Of these, 27.3% had insufficient levels and 14.5% had deficient levels.

According to the study, there was a trend toward hypertension (26.1% vs 18.8%) and type 2 diabetes (13% vs 3.1%) in vitamin D–deficient patients. The researchers also found a trend toward earlier onset of headache (14.3 vs 18 years) and migraine (16.7 vs 22.2 years) in vitamin D–deficient patients.

There was also a trend toward osteopenia (71.4% vs 44.4%) with vitamin D sufficiency and a trend toward osteoporosis (22.2% vs 0%) with vitamin D deficiency.

According to Dr. Wheeler, the high frequency of vitamin D deficiency, with its concomitant risk for cardiovascular disease, malignancy, and other illnesses, suggests that it is an unrecognized yet treatable cause of cardiovascular disease and morbidity in migraine.

“Clinicians generally don’t recognize the importance of vitamin D deficiency, and so they don’t screen for it — not just in migraineurs, but in all of their patients. But it is a condition that is easily treated and may confer major, wide-ranging health benefits,” he said.

References

1. American Headache Society 50th Annual Scientific Meeting: Abstract S33. Presented June 28, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 29, 2008 — New recommendations on antithrombotic and thrombolytic therapy from the American College of Chest Physicians (ACCP) have been published as a supplement to the June issue of Chest [1]. said Guidelines panel chair Dr Jack Hirsh (Henderson Research Centre, Hamilton, ON) that the 900-page document contains the most comprehensive advice to date on the prevention, treatment, and long-term management of thrombotic disorders.

“We’ve markedly increased the number of non-North American participants, so the recommendations are more international. The process of evaluation has improved dramatically — it’s much more rigorous, with panelists for each chapter developing questions sent out to an evidenced-based center, which then performed a literature search. Tables of all the clinical trials that have been done for every single clinical condition are included. The review process has changed too, with each chapter and the manuscript as a whole reviewed by two independent people,” he explained.

Hirsh said it is impossible to cover all the subjects discussed in the new guidelines, which consist of 22 chapters, but a good starting point is the almost 40-page-long executive summary. He tried to pick out some of the most significant changes from previous guidelines that are of relevance to cardiologists.

• First-ever chapter on perioperative management

For the first time, the guidelines dedicate a full chapter (chapter 10) to the perioperative management of patients on long-term antithrombotic therapy who require surgery or other invasive procedures, Hirsh said.

Unfortunately, he explained, the previous recommendations for the most appropriate approach to the pre- and perioperative management of such patients was “based on one randomized trial.” People might be taking warfarin, aspirin, or clopidogrel, and doctors need guidance on whether or not to stop such therapies before surgery.

The recommendations offer a couple of options for warfarin: lowering the dose for simple procedures, such as cataract surgery; or stopping therapy altogether around 5 days before surgery and instead using low-molecular-weight heparins (LMWHs), or heparin, for coverage, Hirsh said. In certain circumstances, warfarin can be continued until 48 hours before surgery, when patients should be given a low dose of vitamin K. For aspirin, the recommendation is normally to continue therapy, he said. For clopidogrel, it is usually stopped 5 to 7 days before surgery.

Rather than going into too much detail, Hirsh said he wanted to stress that the guidelines provide physicians with a rationale based on the likelihood of a thromboembolic event in any individual person weighed against the risk of bleeding when antithrombotic therapy is stopped before surgery.

• HIT: Heparin can still be used for bypass surgery

Another chapter of relevance to cardiologists is the one on the treatment and prevention of heparin-induced thrombocytopenia (HIT), Hirsh noted. “If someone has had an issue with HIT and requires bypass surgery, what do you use as anticoagulation during bypass?”

He explained that any anticoagulant, apart from heparin, can be problematic for conventional on-pump bypass surgery because the risk of bleeding is greater, experience is limited, and the procedure is much riskier.

Hirsh said that in someone who has had HIT but who now has a negative HIT antibody level, “it’s safe to use heparin for bypass surgery because it is only used short-term and is cleared very quickly. Physicians are uncomfortable with this because of medico-legal implications, but it is perfectly rational.”

Another important issue for physicians to understand is that the enzyme-linked immunosorbent assay (ELIZA) test normally used to diagnose HIT “is commonly falsely positive after surgery,” Hirsh explained. It is important for doctors to remember that falling platelet counts continue to occur four to five days after heparin, he noted “and if you did this ELIZA test on all patients after bypass surgery, 20% to 30% would be positive. It creates almost as much harm as good.”

An alternative is to use another test — a serotonin-release test — “which is much more specific but not always available,” he said.

• Prevention of venous thromboembolism; not much new in AF

Hirsh said that research has revealed that certain high-risk medical patients and nonorthopedic surgical patients are not getting venous thromboembolism (VTE) prophylaxis, “when there is good evidence that it works. Often it’s not been given because people just don’t think about it.”

Thus, the guidelines recommend that hospitals adopt an opt-out policy when it comes to VTE prevention, in which all relevant patients are routinely given it unless doctors remove it because they think it is not warranted.

The recommendations also add more about the surgical management of VTE, he noted, and advice on the duration of anticoagulant therapy following VTE.

For atrial fibrillation (AF), there is “not a lot that is new,” Hirsh said. The guidelines make treatment recommendations on the basis of low-, moderate-, and-high risk AF. Hirsh said that one of the problems with AF is that, despite “an enormous amount of evidence” indicating the benefits of warfarin, it is “grossly underutilized” for those at moderate or high risk, particularly by family practitioners.

On a related note, he said that there are “more and more randomized clinical trials that have been published that demonstrate the benefits of computer-assisted INR [international normalized ratio] monitoring for warfarin therapy, showing it is superior to physician monitoring, with various nomograms for dose adjustment being more effective than decisions made ‘off-the-cuff’.”

• Other chapters of relevance

Other chapters in the guidelines of relevance to cardiologists include antithrombotic therapy for non-ST-segment elevation acute coronary syndrome, acute ST-segment elevation myocardial infarction, primary and secondary prevention of coronary artery disease, and valvular and structural heart disease.

There are also chapters on antithrombotic therapy for peripheral artery occlusive disease, on antithrombotic and thrombolytic therapy for ischemic stroke, and on pregnancy. The information on the use of antithrombotics in children and neonates has been expanded.

“Care for children with major cardiac problems has improved dramatically,” Hirsh said. “But thrombosis remains a major cause of secondary complications for these children, so effective antithrombotic therapy is critical.”

• Clinical Context

Antithrombotic and thrombolytic treatments are in widespread use for prophylaxis and therapeutic intervention for arterial, venous, and cardiac thrombosis. Despite the long-term experience in use of these therapies, certain clinical situations in thrombosis treatment present unique challenges, such as during pregnancy, in childhood, or in the perioperative period.

Therefore, the ACCP issued new evidence-based guidelines for thrombosis prevention and treatment, supporting previous recommendations regarding routine use of preventive therapies and highlighting management in children, pregnant women, and other specific patient subgroups.

• Study Highlights

  1. An international panel of 90 experts developed this 8th Edition of the ACCP Antithrombotic and Thrombolytic Therapy Guidelines.

  2. The revised guidelines include more than 700 comprehensive recommendations concerning prophylaxis, therapy, and long-term management of thrombotic disorders in pregnant women and children and in perioperative and postoperative patients.

  3. The revised recommendations also support previous guidelines concerning the routine use of aspirin and other therapies to prevent thrombosis.

  4. Because warfarin and other vitamin K antagonists (VKA) increase the risk for birth defects and miscarriage, pregnant women should ideally stop taking VKAs before 6 weeks of fetal gestation.

  5. Some pregnant women with certain types of mechanical heart valves should continue VKAs, because alternative anticoagulants may be less effective in preventing stroke and valve thrombosis.

  6. For other pregnant women, LMWH or unfractionated heparin (UFH) should be substituted for VKAs.

  7. 2 options for implementing this recommendation are to continue VKA while conducting frequent pregnancy tests, then substituting LMWH or UFH when pregnancy is confirmed; or substituting VKAs with LMWH or UFH before conception.

  8. The latter option prevents fetal exposure to VKA but presents additional challenges. LMWH and UFH are more expensive than VKAs; they must be administered via once- or twice-daily injection; and long-term use of LMWH or UFH has been linked to osteoporosis.

  9. Recommendations on pediatric management and prevention of thrombosis have been significantly expanded since the previous guideline.

  10. Childhood stroke is one of the 10 leading causes of death in children. Embolism or thrombosis usually causes arterial ischemic stroke (AIS).

  11. Diagnosis of AIS is difficult in children because predisposing health conditions are markedly different from those in adult stroke and because nearly 15% of children with AIS have no clear risk factors.

  12. Until the underlying causes are determined, children with AIS should initially receive antithrombotic treatment, followed by maintenance therapy to prevent long-term recurrence.

  13. The revised recommendations regarding prevention and treatment of thrombosis after interventions for congenital heart disease highlight appropriate treatment options for children with ventricular assist devices and prosthetic heart valves.

  14. The revised guidelines emphasize the perioperative management of patients receiving long-term antithrombotic treatment who must undergo surgery or other invasive procedures.

  15. To minimize surgical bleeding, most patients must temporarily discontinue antithrombotic treatment immediately before and during surgery.

  16. Because discontinuing antithrombosis can increase the risk for a thromboembolic event; however, this risk must be weighed against the risk for bleeding when deciding whether or not to interrupt antithrombotic therapy just before surgery.

  17. Routine thromboprophylaxis use is recommended for patients undergoing major general, gynecologic, or orthopaedic surgery as well as bariatric and coronary artery bypass surgery.

  18. Most patients who are hospitalized should receive thromboprophylaxis, but routine thromboprophylaxis use is not recommended for patient groups with a very low risk for VTE.

  19. Patients undergoing laparoscopic surgery, knee arthroscopy, or those who take long airplane flights are considered to be at low risk. In these cases, decisions about thromboprophylaxis should be based on individual patient risk.

  20. Aspirin alone is not recommended to prevent VTE in any patient population because there are more effective methods.

• Pearls for Practice

  1. Pregnant women should ideally stop taking VKAs before 6 weeks of fetal gestation, but some pregnant women with certain types of mechanical heart valves should continue VKAs because alternative anticoagulants may be less effective to prevent stroke and valve thrombosis. For other pregnant women, LMWH or UFH should be substituted for VKAs. Until the underlying causes are determined, children with AIS should initially receive antithrombotic treatment, followed by maintenance therapy to prevent long-term recurrence.

  2. To minimize surgical bleeding, most patients must temporarily discontinue antithrombotic treatment immediately before and during surgery. Because discontinuing antithrombotic treatment can increase the risk for a thromboembolic event, however, this risk must be weighed against the risk for bleeding when deciding whether to interrupt antithrombotic therapy just before surgery. Routine use of thromboprophylaxis is recommended for patients undergoing major general, gynecologic, or orthopaedic surgery as well as bariatric and coronary artery bypass surgery.

References

1. Hirsh J, Guyatt G, Albers GW, et al. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6 suppl):110S-968S. Available at: http://www.chestnet.org/education/hsp/guidelinesAT8.php.

 The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

July 28, 2008 — New research suggests migraineurs who have suffered childhood abuse are much more likely than their counterparts who have not been abused to have comorbid pain conditions, including arthritis, irritable bowel syndrome (IBS), and fibromyalgia.

Furthermore, there is a significant dose response, with individuals who have suffered severe abuse experiencing an increased number of pain conditions.

Presented here at the 50th Annual Meeting of the American Headache Society by investigators from the University of Toledo Medical Center, in Ohio, the multicenter study examined the relationship of childhood maltreatment and migraine among individuals seeking treatment at designated headache centers in Canada and the United States.

“Individuals who have migraine plus pain syndromes, besides being more likely to have chronic migraine and psychiatric comorbidities, including depression and anxiety, are also significantly more likely to have a childhood history of maltreatment, including physical and sexual abuse as well as physical and emotional neglect,” said principal investigator Gretchen Tietjen, MD.

• Chronic Pain, Childhood Adversity Linked

According to Dr. Tietjen, comorbid chronic pain conditions are frequent in migraineurs, and chronic illness has been related to childhood adversity.

To examine the relationship between childhood maltreatment and chronic pain conditions in individuals with migraine, investigators recruited 1331 diagnosed with migraine based on the International Classification of Headache Disorders, 2nd ed (ICHD-2) criteria.

Of the subjects, 56% had migraine without aura and 39% had migraine with aura. Of the total study group, 88% were women and the average age of participants was 42 years.

All subjects completed a self-administered electronic survey to gather information on demographics, headache frequency, disability, and allodynia. Participants also provided information on maltreatment history using the Childhood Trauma Questionnaire (CTQ).

Severity of each of the 5 maltreatment types was quantified as none/minimal, low-moderate, moderate-severe, and severe-extreme. Comorbid pain conditions included IBS, chronic fatigue syndrome (CFS), fibromyalgia, interstitial cystitis, and arthritis.

There were 79% of study subjects who reported at least 1 comorbid pain condition, and 10% reported 4 or more.

• Emotional Abuse Most Common

Of the 5 different maltreatment types, 37% of the study population experienced emotional abuse, 25% sexual abuse, 21% physical abuse, 38% emotional neglect, and 22% physical neglect.

Adjusted analysis confirmed the relationship between the increasing number of pain conditions and severity of comorbid pain conditions and severity of each of the maltreatment types.

The researchers also found that those with 4 or more pain conditions were more likely to report a severe-extreme degree of maltreatment compared with those who reported moderate, low, or no history of abuse or neglect.

Individuals with 4 or more pain conditions were much more likely to have suffered some type of abuse, said Dr. Tietjen.

Table 1. Association of 4 or more pain conditions and history of childhood maltreatment

References

1. 50th Annual Meeting American Headache Society: Abstract OR 8. Presented June 27, 2008.