Tumors in the Conus ,Cauda Equina

Tumors in the Conus ,Cauda Equina



Author: Sagar Jung Rana, MD,Frcs, Senior Neuro Surgeon ,Departments of Neurosurgery,St.George Mahabert Hospital and Research Center ,Las Vegas,NV
Contributor Information and Disclosures
Updated: May 27, 2009



Introduction


The spinal cord transmits information between the spinal cord and brain to the nerves and muscles. The distal or terminal portion of the spinal cord is also referred to as the conus medullaris. In adults, the spinal cord terminates at approximately the level of L1. This space is created by the differential growth of the vertebral column compared with the spinal cord, which causes the spinal cord to ascend with growth. The nerve roots then descend through this fluid sac containing cerebrospinal fluid and are referred to as the cauda equina ("tail of a horse"). This is the collection of lumbar and sacral spinal nerve roots that course in a caudal direction to emerge from their respective foramina.
Tumors of the cauda equina and the conus medullaris manifest with progressive symptoms, including pain, motor weakness, sensory deficit, and bowel and bladder symptoms. These symptoms are collectively known as the cauda equina syndrome (see the eMedicine article Cauda Equina Syndrome). Tumors, disk herniations, fractures, and infection (ie epidural abscesses) are all possible causes of this syndrome. Determining the precise nature of the lesion (eg, intradural-extramedullary vs intramedullary) and the exact type of tumor (eg, ependymoma vs astrocytoma) based on clinical findings can be difficult.
The ability to noninvasively image the neural elements with magnetic resonance imaging (MRI) for evolving neurological deficits in addition to chronic conditions such as low back pain has facilitated the diagnosis of this disorder.
For excellent patient education resources, visit eMedicine's Back, Ribs, Neck, and Head Center; Cancer and Tumors Center; and Brain and Nervous System Center. Also, see eMedicine's patien
education articles Back Pain, Lumbar Laminectomy, and Cauda Equina Syndrome.

Tumor of the conus medullaris.




















Tumor of the conus medullaris

History of the Procedure

In 1887, Sir Victor Horsley performed the first successful
removal of spinal cord tumor in a British Army major, William Gowers. He had an extramedullary-intradural fibromyxoma compressing the spinal cord that was removed after general anesthesia and a laminectomy. The patient was able to subsequently regain his gait function.

In 1907, Eiselsberg-Renzi first successfully removed an intradural intramedullary tumor. However, in 1905, Cushing reported the first attempted surgical resection of an intramedullary spinal neoplasm. In 1925, Charles Elsberg published the first large series of patients that underwent a resection of spinal cord neoplasms. Unfortunately, these patients endured significant associated morbidity and mortality related to operative techniques during this period. Then in 1963, Greenwood reported a modern series on removal of intramedullary tumors with good success.1 The conclusion was reached that because of the relatively direct surgical approach to the lumbar spinal canal, tumors in that area are amenable to successful surgical resection.

Problem

Patients present due to a deterioration of neurologic function or pain. These tumors of the spinal cord can cause significant dysfunction due to compression of the spinal cord and nerve roots. Patient may present with weakness, sensory changes, bowel/bladder dysfunction, and pain due to the interference of these nerve pulses.

The general classification is according to the tissue compartment in which the tumors are located. This classification is based on their relationship to the meninges that enclose the central nervous system, as follows:
• Extradural tumors - Arise outside the spinal cord and the meninges and the epidural tissue
• Intradural-extramedullary tumors
o Arise inside the dural sac, from the leptomeninges or the nerve root
o Outside the substance of the spinal cord parenchyma
• Intramedullary tumors - Arise within the substance of the spinal cord


Frequency

Tumors of the spinal cord are rare and reported to represent approximately 10-15% of all central nervous system tumors. Overall, they represent an estimated incidence of 0.5-2.5 cases per 100,000 population. Extradural spinal cord tumors are by far the greatest majority of spinal tumors and include metastatic tumors. Intradural extramedullary tumors account for approximately 20% of all spinal tumors, with intradural-intramedullary tumors accounting for less than 5% of all spinal tumors.
In the adult population, ependymomas (intradural intramedullary) are the most common intra-axial tumors of the conus medullaris and filum terminale. They comprise more than one third of the tumors in the region. Ependymomas represent approximately 60% of all glial neoplasms of the entire spinal cord and are the most common glial neoplasm below the midthoracic region. Conus medullaris tumors are diagnosed in the third to fourth decade of life, with a slight male predominance. A variant of ependymomas, myxopapillary, tend to affect the distal conus medullaris and filum terminale exclusively, and cystic degeneration in reported in approximately 50% of the cases. Tumors of the conus medullaris are also observed in the pediatric population.

In the cranium, ependymomas are relatively rare intracranial gliomas and comprise only 5-6% of these tumors, typically more common in children.
Astrocytomas, another primary glial neoplasm, occur less frequently in the region of the conus medullaris and the filum terminale (just less than one third of cases) compared with ependymomas. Astrocytomas also have a slight male predominance and tend to occur in the third to fifth decade of life. In contrast to ependymomas, astrocytomas are the most common intra-axial brain tumor.
Other tumors of the spinal cord comprise less than one third of intramedullary spinal cord tumors. This includes dermoid and epidermoid tumors, vascular tumors, hemangioblastomas, and, rarely, lymphomas or oligodendrogliomas. Other rare tumors have been reported periodically.
Intradural-extramedullary tumors are predominantly (more than two thirds) schwannomas, neurofibromas, or meningiomas. Their reported incidence is approximately equal. Lipomas have also been described. The exophytic components of intramedullary ependymoma and astrocytoma can occur and extend into the intradural-extramedullary compartment.


Etiology

Tumors of the nervous system and spinal cord are classified according to their cells of origin. The following is a modified classification by the World Health Organization:


Tumors of the neuroepithelial tissue

• Astrocytic tumors
o Pilocytic astrocytoma - Grade I
o Diffuse (fibrillary) astrocytoma (low grade) - Grade II
o Anaplastic astrocytoma - Grade III
o Glioblastoma- Grade IV
• Oligodendroglial tumors
o Oligodendroglioma
o Anaplastic oligodendroglioma
• Mixed gliomas
o Oligoastrocytoma
o Anaplastic oligoastrocytoma
• Ependymal tumors
o Ependymoma
 Cellular
 Papillary
 Clear cell
 Tanycytic
o Anaplastic ependymoma
o Myxopapillary ependymoma
• Neuronal and mixed neuronal-glial tumors
o Gangliocytoma
o Desmoplastic infantile astrocytoma / ganglioglioma
o Dysembryoplastic neuroepithelial tumour
o Ganglioglioma
o Paraganglioma of the filum terminale
• Tumors of primitive undifferentiated cells (Medulloblastoma)
• Tumors of meninges
o Meningioma
o Meningeal hemangiopericytoma
• Tumors of nerve sheath cells
o Schwannoma (ie, neurilemmoma)
o Neurofibroma
• Lymphoma
o Primary
o Secondary
• Metastatic tumors


Pathophysiology

The distal or terminal region of the spinal cord, the conus medullaris and cauda equina, is a complex region of spinal anatomy and transition from the central to peripheral nervous system. The motor nerve roots of the cauda equina exit and sensory nerves enter through the conus and are considered peripheral nerves. An isolated lesion at the conus therefore may causes symptoms of a lower motor neuron lesion with or without spinal cord symptoms. Therefore, the patient may present with various symptoms, from flaccid paralysis or paresis of the lower extremities to spasticity.

Early on, the symptoms may be unilateral and localized to a specific muscle group. The sensory deficit, at least initially, maybe localized to a unilateral dermatomal distribution. As lesions progress in size, symptoms may progress and become bilateral. The numbness and paresthesia progress to a saddle distribution and extend into the lower extremity.
Lesions of the conus medullaris may manifest as sensory dysfunction of the perineum in a saddle distribution and as bowel and bladder dysfunction. Patients may present with back pain that is primarily midline and less radicular in nature. Lesions that are truly isolated to the conus medullaris may demonstrate sparing of the lower extremities and affect only the bladder and perineum. If the lesion is large enough to include some lumbar cord segments, symptoms extend into the lower extremities. If the lumbar cord is affected, the lesions have the characteristics of upper motor neuron lesions with hyperreflexic motor weakness.
Genitourinary (GU) dysfunction is present in persons with either conus medullaris lesions or cauda equina lesions. No distinct signs or symptoms differentiate one type of lesion from the other. Because the conus medullaris includes most of the sacral cord that controls GU function, a lesion frequently results in GU deficits. By comparison, the cauda equina has roots of both lumbar and sacral origin, and GU sparing may occur. Both types of lesions are associated with urinary retention and incontinence and fecal incontinence or constipation. Both types of lesions maybe associated with sexual dysfunction, including erectile dysfunction and impotence.


Presentation

The manifestations of spinal cord tumors may include myriad neurologic symptoms. Findings from a careful history and physical examination can help guide the clinician to the diagnosis of a spinal cord tumor. The evolution of symptoms may be slow and progressive, or it may be abrupt with rapid progression. Neurologic symptoms affecting the distal nerve roots are known as the cauda equina syndrome symptoms (see Cauda Equina Syndrome) or conus medullaris syndrome (see the eMedicine article Cauda Equina and Conus Medullaris Syndromes. The following are the main elements of the neurologic presentation:
• Pain (the most common symptom)
o Pain increases with movement or the Valsalva maneuver (if radicular).
o Pain that increases during recumbency, particularly at night, may suggest a spinal cord tumor.
o The pain may be described as follows:
• Radicular, usually of dermatomal distribution
• Localized, near the midline of the spine
• Medullary and nonradicular in distribution, possibly bilateral, and possibly described as burning or dysesthetic pain
• Motor disturbance (next most common symptom)
o Weakness
o Ataxia
o Clumsiness
o Atrophy
o Twitching and fasciculation
o Gait disturbance
• Nonpainful sensory disturbances
o Paresthesia
o Dysesthesia
o Dissociative syndrome (ie, decreased pain and temperature sensation while touch is preserved)
o Radicular or medullary distribution
• Bowel and bladder dysfunction
o Sphincter problems
o Possible incontinence, retention, and incomplete bowel or bladder evacuation
o Possible erectile dysfunction and impotence
• Physical deformity (visible mass over the area), which may indicate a coronal deformity (scoliosis)


Differential diagnosis

The differential diagnosis for lumbosacral cord dysfunction includes nonneoplastic causes of myelopathy. An expanded differential diagnosis is presented in the eMedicine article Cauda Equina Syndrome. The following are some of the major groupings:
• Congenital
o Tethered cord syndrome: This is an abnormally low conus medullaris that is associated with a short thickened filum terminale and is most common in children with myelomeningocele. It can also be present in adults. Adults are initially asymptomatic and may develop symptoms after trauma.
o Syringomyelia: This is a cystic cavitation of the spinal cord that may communicate with the central canal or the subarachnoid space. It can be congenital or posttraumatic.
• Acquired
o Herniated lumbar disk: This causes nerve root impingement, usually in the setting of congenital stenosis. Quite often, it manifests as sciatica or radiculopathy. A herniated disk maybe associated with the following:
• Pain radiating to the lower extremity
• Motor weakness in a specific distribution
• Sensory loss or paresthesia in a specific dermatomal pattern
• Diminished reflexes
o Spinal stenosis: This can be the result of a congenitally shallow canal, with the following:
• Arthropathy of the facet
• Hypertrophied ligamentum flavum
• A bulging annulus or herniated disc
o Neurogenic claudication (compared with vascular claudication): The pain is dermatomal and worsens with ambulation.
o Fractures: In the setting of major trauma, these fractures are likely nonpathologic. The bony fragments can compress the neural elements.
• Vascular
o Hemorrhage or hematoma: Epidural spinal hematoma may be posttraumatic, the result of anticoagulation with presumed minor trauma, or a dural vascular malformation.
o Arteriovenous malformations: These may cause a hemorrhage that affects the conus medullaris but is less likely to affect individual roots.
o Infarction: This may result from disruption of the radicular vessels as a result of atherosclerotic disease of the aorta or another disease. The cord is especially at risk if infarction affects the L2 vessel (ie, artery of Adamkiewicz, usually on the left).
• Infectious
o Epidural abscess: The presentation may include fever, back pain, and localized tenderness. Risk factors include intravenous drug abuse, diabetes, and renal failure. Staphylococcus aureus is the major causative organism. Typically, patients have an elevated sedimentation rate and WBC count.
o Vertebral osteomyelitis: This is an infection of the vertebral bodies. The lumbar area is affected most commonly. Tuberculous osteomyelitis or spondylitis is referred to as Pott disease.
o Diskitis: This is an infection of the nucleus pulposus. Causative organisms include Escherichia coli and Staphylococcus, Streptococcus, and Pseudomonas species. Diskitis may be spontaneous or may occur following a procedure, such as discectomy.
• Syrinx
o Posttraumatic
o Congenital
• Autoimmune and degenerative disorders
o Transverse myelitis
o Multiple sclerosis
o Viral infection or its sequela
o Amyotrophic lateral sclerosis
o Guillain-Barré syndrome


Indications
Surgical considerations

Surgical excision is the primary modality of treatment for spinal tumors. In general, the earlier the detection of the tumor and the more minor the neurological deficit, the better the prognosis for treatment and recovery. Advanced age and severe neurologic deficit are associated with a poor prognosis. The correlation of the American Spinal Injury Association (ASIA) score and prognosis are presented in the eMedicine article Cauda Equina Syndrome.
When preparing for surgery, pay special attention to the cardiopulmonary status and the correction of any coagulation, electrolyte, or metabolic disorders.
Informed consent should be obtained from patients or their guardians. A realistic portrayal of the results should be presented, and the expectations of the patient should be addressed. Neurologic deficits may not improve, and a risk of worsening exists, including pain, paralysis, paresthesia, bowel or bladder problems, and sexual dysfunction.


Indications for surgery

The management of spinal cord tumors is primarily surgical. Urgent or emergent surgery should be performed in patients with rapidly progressing neurologic deficits. Radiation therapy and intrathecal chemotherapy are reasonable adjuvants for the treatment of these tumors in patients with contraindications for surgical treatment.


Relevant Anatomy

Nerve fibers descend and ascend from the brain to and from the peripheral nerves. The distal spinal cord terminates as the conus medullaris, and it contains the sacral cord and the vestigial coccygeal cord. The nerve roots form the cauda equina, the collection of nerve roots distal to the conus that supply the lower part of the body. The conus may terminate along the canal by typically is at the L1-2 level.
Extending distally from the conus medullaris is a delicate filament, the filum terminale. The first 15 cm are contained within the dural sac, the filum terminale internum. The filum terminale consists of fibrous tissue that is continuous with the pia mater.

The central canal of the spinal cord continues down into the filum terminale for the first 5-6 cm, an area that also contains neural and ependymal cells. The extension beyond the apex of the dural sac is the filum terminale externum, which extends to attach to the first coccygeal vertebra. The filum terminale externum actually has a closely adherent dural layer around it.


Contraindications

Contraindications for surgery relate to the overall health, condition of the patient as well as overall life-expectancy of the patient. Patients with significant comorbidity are poor candidates for any surgery, including spinal surgery. A relative contraindication for surgery is tumors that are in a difficult anatomical location, especially on the ventral aspect of the cord. However, experienced surgeons using microsurgical techniques can obtain the appropriate exposure. Fortunately, the roots of the cauda equina may be retracted gently to provide for exposure of most tumors in this area.

Skull Fracture

Skull Fracture
Author:Dr.Sagar Jung Rana, MD,FRCS Senior Neurosergeon, Department of Neurosurgery, St.George Mahabert Hospital And Research Center

Updated: Feb 1, 2009
•
Introduction
The brain is surrounded by cerebrospinal fluid (CSF), enclosed in meningeal covering, and protected inside the skull. Furthermore, the fascia and muscles of the scalp provide additional cushioning to the brain. Test results have shown that 10 times more force is required to fracture a cadaveric skull with overlaying scalp than the one without.1 Although these layers play a protective role, meningeal attachments to the interior of the skull may limit the movement of the brain, transmitting shearing forces on the brain.
CSF plays a major role in coup and countercoup injuries to the brain. A blow to a stationary but moveable head causes acceleration, and the brain floating in CSF lags behind, sustaining an injury directly underneath the point of impact (coup injury). When a moving head hits the floor, sudden deceleration results in an injury to the brain on the opposite side (countercoup injury).
Anatomy of fracture
The causative forces and fracture pattern, type, extent, and position are important in assessing the sustained injury. The skull is thickened at the glabella, external occipital protuberance, mastoid processes, and external angular process and is joined by 3 arches on either side. The skull vault is composed of cancellous bone (diploë) sandwiched between 2 tablets, the lamina externa (1.5 mm), and the lamina interna (0.5 mm). The diploë does not form where the skull is covered with muscles, leaving the vault thin and prone to fracture.
The skull is prone to fracture at certain anatomic sites that include the thin squamous temporal and parietal bones over the temples and the sphenoid sinus, the foramen magnum, the petrous temporal ridge, and the inner parts of the sphenoid wings at the skull base. The middle cranial fossa is the weakest, with thin bones and multiple foramina. Other places prone to fracture include the cribriform plate and the roof of orbits in the anterior cranial fossa and the areas between the mastoid and dural sinuses in the posterior cranial fossa.
History of the Procedure
Skull fracture is described in Edwin Smith's papyrus, the oldest known surgical paper.2 The papyrus describes a conservative and expectant approach to skull trauma, with better results compared with a more aggressive and less favorable approach described in Hippocratic medicine.3
Charles Bell first described occipital condylar fracture in 1817 based on an autopsy finding.4 The same fracture was described for the first time as an x-ray finding in 1962 and by computed tomography (CT) in 1983.5,6
Problem
Fractures of the skull can be classified as linear or depressed. Linear fractures are either vault fractures or skull base fractures. Vault fractures and depressed fractures can be either closed or open (clean or dirty/contaminated), as is depicted in
Linear skull fracture
Linear fracture results from low-energy blunt trauma over a wide surface area of the skull. It runs through the entire thickness of the bone and, by itself, is of little significance except when it runs through a vascular channel, venous sinus groove, or a suture. In these situations, it may cause epidural hematoma, venous sinus thrombosis and occlusion, and sutural diastasis, respectively. Differences between sutures and fractures are summarized in Table 1.
Table 1. Differences Between Skull Fractures and Sutures
Fractures Sutures
• Greater than 3 mm in width
• Widest at the center and narrow at the ends
• Runs through both the outer and the inner lamina of bone, hence appears darker
• Usually over temporoparietal area
• Usually runs in a straight line
• Angular turns • Less than 2 mm in width
• Same width throughout
• Lighter on x-rays compared with fracture lines
• At specific anatomic sites
• Does not run in a straight line
• Curvaceous
Fractures Sutures
• Greater than 3 mm in width
• Widest at the center and narrow at the ends
• Runs through both the outer and the inner lamina of bone, hence appears darker
• Usually over temporoparietal area
• Usually runs in a straight line
• Angular turns • Less than 2 mm in width
• Same width throughout
• Lighter on x-rays compared with fracture lines
• At specific anatomic sites
• Does not run in a straight line
• Curvaceous

Basilar skull fracture
In essence, a basilar fracture is a linear fracture at the base of the skull. It is usually associated with a dural tear and is found at specific points on the skull base.
Temporal fracture
Temporal bone fracture is encountered in 75% of all skull base fractures. The 3 subtypes of temporal fractures are longitudinal, transverse, and mixed.7
Longitudinal fracture occurs in the temporoparietal region and involves the squamous portion of the temporal bone, the superior wall of the external auditory canal, and the tegmen tympani. These fractures may run either anterior or posterior to the cochlea and labyrinthine capsule, ending in the middle cranial fossa near the foramen spinosum or in the mastoid air cells, respectively. Longitudinal fracture is the most common of the 3 subtypes (70-90%)
Transverse fractures begin at the foramen magnum and extend through the cochlea and labyrinth, ending in the middle cranial fossa (5-30%).
Mixed fractures have elements of both longitudinal and transverse fractures.
Yet another classification system of temporal bone fractures has been proposed. This system divides temporal bone fractures into petrous and nonpetrous fractures; the latter includes fractures that involve mastoid air cells. These fractures do not present with cranial nerve deficits.8
Occipital condylar fracture
Occipital condylar fracture results from a high-energy blunt trauma with axial compression, lateral bending, or rotational injury to the alar ligament. These fractures are subdivided into 3 types based on the morphology and mechanism of injury.9 An alternative classification divides these fractures into displaced and stable, ie, with and without ligamentous injury.10
Type I fracture is secondary to axial compression resulting in comminution of the occipital condyle. This is a stable injury.
Type II fracture results from a direct blow, and, despite being a more extensive basioccipital fracture, type II fracture is classified as stable because of the preserved alar ligament and tectorial membrane.
Type III fracture is an avulsion injury as a result of forced rotation and lateral bending. This is potentially an unstable fracture.
Clivus fractures
Fractures of the clivus are described as a result of high-energy impact sustained in motor vehicle accidents. Longitudinal, transverse, and oblique types have been described in the literature. A longitudinal fracture carries the worst prognosis, especially when it involves the vertebrobasilar system. Cranial nerves VI and VII deficits are usually coined with this fracture type.11
Depressed skull fracture
Depressed skull fractures result from a high-energy direct blow to a small surface area of the skull with a blunt object such as a baseball bat. Comminution of fragments starts from the point of maximum impact and spreads centrifugally. Most of the depressed fractures are over the frontoparietal region because the bone is thin and the specific location is prone to an assailant's attack. A free piece of bone should be depressed greater than the adjacent inner table of the skull to be of clinical significance and requiring elevation
A depressed fracture may be open or closed. Open fractures, by definition, have either a skin laceration over the fracture or the fracture runs through the paranasal sinuses and the middle ear structures, resulting in communication between the external environment and the cranial cavity. Open fractures may be clean or contaminated/dirty.
Frequency
Simple linear fracture is by far the most common type of fracture, especially in children younger than 5 years. Temporal bone fractures represent 15-48% of all skull fractures. Basilar skull fractures represent 19-21% of all skull fractures. Depressed fractures are frontoparietal (75%), temporal (10%), occipital (5%), and other (10%). Most of the depressed fractures are open fractures (75-90%).
Etiology
In newborns, "ping-pong" depressed fractures are secondary to the baby's head impinging against the mother's sacral promontory during uterine contractions.12 The use of forceps also may cause injury to the skull, but this is rare.
Skull fractures in infants originate from neglect, fall, or abuse. Most of the fractures seen in children are a result of falls and bicycle accidents. In adults, fractures typically occur from motor vehicle accidents or violence.
Presentation
Linear skull fracture
Most patients with linear skull fractures are asymptomatic and present without loss of consciousness. Swelling occurs at the site of impact, and the skin may or may not be breached.
Basilar skull fracture
Patients with fractures of the petrous temporal bone present with CSF otorrhea and bruising over the mastoids, ie, Battle sign. Presentation with anterior cranial fossa fractures is with CSF rhinorrhea and bruising around the eyes, ie, "raccoon eyes." Loss of consciousness and Glasgow Coma Score may vary depending on an associated intracranial pathologic condition.
Longitudinal temporal bone fractures result in ossicular chain disruption and conductive deafness of greater than 30 dB that lasts longer than 6-7 weeks. Temporary deafness that resolves in less than 3 weeks is due to hemotympanum and mucosal edema in the middle ear fossa. Facial palsy, nystagmus, and facial numbness are secondary to involvement of the VII, VI, and V cranial nerves, respectively. Transverse temporal bone fractures involve the VIII cranial nerve and the labyrinth, resulting in nystagmus, ataxia, and permanent neural hearing loss.
Occipital condylar fracture is a very rare and serious injury.13 Most of the patients with occipital condylar fracture, especially with type III, are in a coma and have other associated cervical spinal injuries. These patients also may present with other lower cranial nerve injuries and hemiplegia or quadriplegia
Vernet syndrome or jugular foramen syndrome is involvement of the IX, X, and XI cranial nerves with the fracture. Patients present with difficulty in phonation and aspiration and ipsilateral motor paralysis of the vocal cord, soft palate (curtain sign), superior pharyngeal constrictor, sternocleidomastoid, and trapezius.
Collet-Sicard syndrome is occipital condylar fracture with IX, X, XI, and XII cranial nerve involvement.
Depressed skull fracture
Approximately 25% of patients with depressed skull fracture do not report loss of consciousness, and another 25% loose consciousness for less than an hour. The presentation may vary depending on other associated intracranial injuries such as epidural hematoma, dural tears, and seizures.

Pseudocholine Deficiency

Pseudocholinesterase Deficiency

Author: Dr.Sagar Jung Rana, MD,FRCS,SeniorNeurosurgeon, Departments of Internal Medicine and Pathology, St.George Mahabert Hospital & Research Center

Updated: May 25, 2009

Introduction

Background

Pseudocholinesterase deficiency is an inherited enzyme abnormality that results in abnormally slow metabolic degradation of exogenous choline ester drugs such as succinylcholine. A variety of pathologic conditions, physiologic alterations, and medications also can lower plasma pseudocholinesterase activity.¹

This condition is recognized most often when respiratory paralysis unexpectedly persists for a prolonged period of time following administration of standard doses of succinylcholine.² The mainstay of treatment in these cases is ventilatory support until diffusion of succinylcholine from the myoneural junction permits return of neuromuscular function of skeletal muscle. The diagnosis is confirmed by a laboratory assay demonstrating decreased plasma cholinesterase enzyme activity.

Noninvasive ventilation. A bilevel positive airway pressure (BIPAP) prototype is shown here. Expiratory positive airway pressure is the expiratory pressure setting that determines the amount of positive end-expiratory pressure that is applied. The inspiratory positive airway pressure setting is the pressure support. The device can be used in spontaneous mode or timed mode (with a mandatory backup respiratory frequency).

Noninvasive ventilation. A bilevel positive airway pressure (BIPAP) prototype is shown here. Expiratory positive airway pressure is the expiratory pressure setting that determines the amount of positive end-expiratory pressure that is applied. The inspiratory positive airway pressure setting is the pressure support. The device can be used in spontaneous mode or timed mode (with a mandatory backup respiratory frequency).

Genetic analysis may demonstrate a number of allelic mutations in the pseudocholinesterase gene, including point mutations resulting in abnormal enzyme structure and function and frameshift or stop codon mutations resulting in absent enzyme synthesis. Partial deficiencies in inherited pseudocholinesterase enzyme activity may be clinically insignificant unless accompanied by a concomitant acquired cause of pseudocholinesterase deficiency. Clinically significant effects generally are not observed until the plasma cholinesterase activity is reduced to less than 75% of normal.

PathophysiologyPseudocholinesterase is a glycoprotein enzyme, produced by the liver, circulating in the plasma. It specifically hydrolyzes exogenous choline esters; however, it has no known physiologic function.

Pseudocholinesterase deficiency results in delayed metabolism of only a few compounds of clinical significance, including the following: succinylcholine, mivacurium, procaine, and cocaine.³ Of these, its most clinically important substrate is the depolarizing neuromuscular blocking agent, succinylcholine, which the pseudocholinesterase enzyme hydrolyzes to succinylmonocholine and then to succinic acid.

In individuals with normal plasma levels of normally functioning pseudocholinesterase enzyme, hydrolysis and inactivation of approximately 90-95% of an intravenous dose of succinylcholine occurs before it reaches the neuromuscular junction. The remaining 5-10% of the succinylcholine dose acts as an acetylcholine receptor agonist at the neuromuscular junction, causing prolonged depolarization of the postsynaptic junction of the motor-end plate. This depolarization initially triggers fasciculation of skeletal muscle. As a result of prolonged depolarization, endogenous acetylcholine released from the presynaptic membrane of the motor neuron does not produce any additional change in membrane potential after binding to its receptor on the myocyte. Flaccid paralysis of skeletal muscles develops within 1 minute.

In normal subjects, skeletal muscle function returns to normal approximately 5 minutes after a single bolus injection of succinylcholine as it passively diffuses away from the neuromuscular junction. Pseudocholinesterase deficiency can result in higher levels of intact succinylcholine molecules reaching receptors in the neuromuscular junction, causing the duration of paralytic effect to continue for as long as 8 hours.

This condition is recognized clinically when paralysis of the respiratory and other skeletal muscles fails to spontaneously resolve after succinylcholine is administered as an adjunctive paralytic agent during anesthesia procedures.

Frequency

International

Pseudocholinesterase deficiency is most common in people of European descent; it is rare in Asians.

Clinical

History

A personal or family history of an adverse drug reaction to one of the choline ester compounds, such as succinylcholine, mivacurium, or cocaine, may be the only clue suggesting pseudocholinesterase deficiency.

Physical

No characteristic physical examination findings correlate with the presence of pseudocholinesterase deficiency.

Causes

• Most clinically significant causes of pseudocholinesterase deficiency are due to one or more inherited abnormal alleles that code for the synthesis of the enzyme.
• These abnormal alleles may result in a failure to produce normal amounts of the enzyme or in production of abnormal forms of pseudocholinesterase with altered structure and lacking full enzymatic function, as described below.
• Patients with only partial deficiencies of inherited pseudocholinesterase enzyme activity often do not manifest clinically significant prolongation of paralysis following administration of succinylcholine unless a concomitant acquired cause of pseudocholinesterase deficiency is present. The acquired causes of pseudocholinesterase deficiency include a variety of physiologic conditions, pathologic states, and medications listed below.
• Inherited causes of pseudocholinesterase deficiency include the following:
• The gene that codes for the pseudocholinesterase enzyme is located at the E1 locus on the long arm of chromosome 3, and 96% of the population is homozygous for the normal pseudocholinesterase genotype, which is designated as EuEu.
• The remaining 4% of the population carries one or more of the following atypical gene alleles for the pseudocholinesterase gene in either a heterozygous or homozygous fashion. Table 1. Atypical Gene Alleles for the Pseudocholinesterase Genotype

Ea	Atypical dibucaine-resistant variant	Point mutation
Ef	Fluoride-resistant variant	Point mutation
Es	Silent variant	Frameshift mutation
Ea	Atypical dibucaine-resistant variant	Point mutation
Ef	Fluoride-resistant variant	Point mutation
Es	Silent variant	Frameshift mutation

*These alleles may occur either in the homozygous form or in any heterozygous combination with each other, with the normal Eu allele, or with a number of additional rare variant abnormal alleles.

• In individuals with an inherited form of pseudocholinesterase deficiency, only a single atypical allele is carried in a heterozygous fashion, resulting in a partial deficiency in enzyme activity, which manifests as a slightly prolonged duration of paralysis, longer than 5 minutes but shorter than 1 hour, following administration of succinylcholine. Less than 0.1% of the general population carries 2 pseudocholinesterase gene allele mutations that will produce clinically significant effects from succinylcholine lasting longer than 1 hour.
• One rare variant allele of the pseudocholinesterase gene, designated the C5 variant, actually has higher than normal enzyme activity, resulting in relative resistance to the paralytic effects of succinylcholine.
• The dibucaine-resistant genetic variant form of pseudocholinesterase is identified by the percent inhibition of hydrolysis of benzyl choline caused by the addition of dibucaine to the pseudocholinesterase enzymatic assay. The dibucaine number is the percent inhibition of hydrolysis of benzyl choline by dibucaine added to the plasma sample. The normal dibucaine number for the homozygous typical genotype (EuEu) is 80%. Individuals homozygous for the atypical dibucaine resistant genotype (EaEa) have a dibucaine number of 20%, which correlates with a marked prolongation of the paralytic effect of standard doses of succinylcholine to well over 1-hour duration. Heterozygotes (EuEa) have intermediate dibucaine numbers and modest prolongation of muscle paralysis with succinylcholine. The EuEa heterozygous genotype is found in 2.5% of the general population, making it more common than all other abnormal pseudocholinesterase genotypes combined.
• The fluoride-resistant pseudocholinesterase enzyme variant is identified by its percent inhibition of benzyl choline hydrolysis when fluoride is added to the assay. The fluoride number (percentage inhibition of enzyme activity in the presence of fluoride) is 60% for the EuEu genotype and is 36% for the EfEf genotype. This homozygous fluoride-resistant genotype exhibits mild to moderate prolongation of succinylcholine-induced paralysis. The heterozygous fluoride-resistant genotype usually is clinically insignificant unless accompanied by a second abnormal allele or by a coexisting acquired cause of pseudocholinesterase deficiency.
• The most severe form of inherited pseudocholinesterase deficiency occurs in only 1 in 100,000 individuals who are homozygous for the silent Es genotype, with no detectible pseudocholinesterase enzyme activity. These individuals may exhibit prolonged muscle paralysis for as long as 8 hours following a single dose of succinylcholine. Gene mutations that produce silent alleles are caused by frameshift or stop codon mutations, resulting in no functional pseudocholinesterase enzyme synthesis.
• Acquired causes of pseudocholinesterase deficiency include the following:
• People, such as neonates, elderly individuals, and pregnant women, with certain physiologic conditions may have lower plasma pseudocholinesterase activity.
• Pathologic conditions that may lower plasma pseudocholinesterase activity include the following:
• Chronic infections (tuberculosis)
• Extensive burn injuries
• Liver disease
• Malignancy
• Malnutrition
• Organophosphate pesticide poisoning
• Uremia
• Iatrogenic causes of lower plasma pseudocholinesterase activity include plasmapheresis and medications such as the following:
• Anticholinesterase inhibitors
• Bambuterol
• Chlorpromazine
• Contraceptives
• Cyclophosphamide
• Echothiophate eye drops
• Esmolol
• Glucocorticoids
• Hexafluorenium
• Metoclopramide
• Monoamine oxidase inhibitors
• Pancuronium
• Phenelzine
• Tetrahydroaminacrine

Critical Thinking

A SUPER-STREAMLINED CONCEPTION
OF CRITICAL THINKING
by Sagar Jung Rana , 05/25/09

Assuming that critical thinking is reasonable reflective thinking focused on deciding what to believe or do, a critical thinker:
1. Is open-minded and mindful of alternatives
2. Tries to be well-informed
3. Judges well the credibility of sources
4. Identifies conclusions, reasons, and assumptions
5. Judges well the quality of an argument, including the acceptability of its reasons, assumptions, and evidence
6. Can well develop and defend a reasonable position
7. Asks appropriate clarifying questions
8. Formulates plausible hypotheses; plans experiments well
9. Defines terms in a way appropriate for the context
10. Draws conclusions when warranted, but with caution
11. Integrates all items in this list when deciding what to believe or do
Critical Thinkers are disposed to:
1. Care that their beliefs be true, and that their decisions be justified; that is, care to "get it right" to the extent possible. This includes the dispositions to

a. Seek alternative hypotheses, explanations, conclusions, plans, sources, etc., and be open to them
b. Endorse a position to the extent that, but only to the extent that, it is justified by the information that is available
c. Be well informed
d. Consider seriously other points of view than their own

2. Care to present a position honestly and clearly, theirs as well as others'. This includes the dispositions to

a. Be clear about the intended meaning of what is said, written, or otherwise communicated, seeking as much precision as the situation requires
b. Determine, and maintain focus on, the conclusion or question
c. Seek and offer reasons
d. Take into account the total situation
e. Be reflectively aware of their own basic beliefs

3. Care about the dignity and worth of every person (a correlative disposition). This includes the dispositions to

a. Discover and listen to others' view and reasons
b. Avoid intimidating or confusing others with their critical thinking prowess, taking into account others' feelings and level of understanding
c. Be concerned about others' welfare

Critical Thinking Abilities:
Ideal critical thinkers have the ability to
(The first three items involve elementary clarification.)
1. Focus on a question

a. Identify or formulate a question
b. Identify or formulate criteria for judging possible answers
c. Keep the situation in mind

2. Analyze arguments

a. Identify conclusions
b. Identify stated reasons
c. Identify unstated reasons
d. Identify and handle irrelevance
e. See the structure of an argument
f. Summarize

3. Ask and answer questions of clarification and/or challenge, such as,

a. Why?
b. What is your main point?
c. What do you mean by…?
d. What would be an example?
e. What would not be an example (though close to being one)?
f. How does that apply to this case (describe a case, which might well appear to be a counter example)?
g. What difference does it make?
h. What are the facts?
i. Is this what you are saying: ____________?
j. Would you say some more about that?

(The next two involve the basis for the decision.)
4. Judge the credibility of a source. Major criteria (but not necessary conditions):

a. Expertise
b. Lack of conflict of interest
c. Agreement among sources
d. Reputation
e. Use of established procedures
f. Known risk to reputation
g. Ability to give reasons
h. Careful habits

5. Observe, and judge observation reports. Major criteria (but not necessary conditions, except for the first):

a. Minimal inferring involved
b. Short time interval between observation and report
c. Report by the observer, rather than someone else (that is, the report is not hearsay)
d. Provision of records.
e. Corroboration
f. Possibility of corroboration
g. Good access
h. Competent employment of technology, if technology is useful
i. Satisfaction by observer (and reporter, if a different person) of the credibility criteria in Ability # 4 above.

(The next three involve inference.)
6. Deduce, and judge deduction

a. Class logic
b. Conditional logic
c. Interpretation of logical terminology in statements, including
(1) Negation and double negation
(2) Necessary and sufficient condition language
(3) Such words as "only", "if and only if", "or", "some", "unless", "not both".

7. Induce, and judge induction

a. To generalizations. Broad considerations:
(1) Typicality of data, including sampling where appropriate
(2) Breadth of coverage
(3) Acceptability of evidence
b. To explanatory conclusions (including hypotheses)
(1) Major types of explanatory conclusions and hypotheses:
(a) Causal claims
(b) Claims about the beliefs and attitudes of people
(c) Interpretation of authors’ intended meanings
(d) Historical claims that certain things happened (including criminal accusations)
(e) Reported definitions
(f) Claims that some proposition is an unstated reason that the person actually used
(2) Characteristic investigative activities
(a) Designing experiments, including planning to control variables
(b) Seeking evidence and counterevidence
(c) Seeking other possible explanations
(3) Criteria, the first five being essential, the sixth being desirable
(a) The proposed conclusion would explain the evidence
(b) The proposed conclusion is consistent with all known facts
(c) Competitive alternative explanations are inconsistent with facts
(d) The evidence on which the hypothesis depends is acceptable.
(e) A legitimate effort should have been made to uncover counter-evidence
(f) The proposed conclusion seems plausible

8. Make and judge value judgments: Important factors:

a. Background facts
b. Consequences of accepting or rejecting the judgment
c. Prima facie application of acceptable principles
d. Alternatives
e. Balancing, weighing, deciding

(The next two abilities involve advanced clarification.)
9. Define terms and judge definitions. Three dimensions are form, strategy, and content.

a. Form. Some useful forms are:
(1) Synonym
(2) Classification
(3) Range
(4) Equivalent expression
(5) Operational
(6) Example and nonexample
b. Definitional strategy
(1) Acts
(a) Report a meaning
(b) Stipulate a meaning
(c) Express a position on an issue (including "programmatic" and "persuasive" definitions)
(2) Identifying and handling equivocation
c. Content of the definition

10. Attribute unstated assumptions (an ability that belongs under both clarification and, in a way, inference)

(The next two abilities involve supposition and integration.)

11. Consider and reason from premises, reasons, assumptions, positions, and other propositions with which they disagree or about which they are in doubt -- without letting the disagreement or doubt interfere with their thinking ("suppositional thinking")
12. Integrate the other abilities and dispositions in making and defending a decision

(The first twelve abilities are constitutive abilities. The next three are auxiliary critical thinking abilities: Having them, though very helpful in various ways, is not constitutive of being a critical thinker.)

13. Proceed in an orderly manner appropriate to the situation. For example:

a. Follow problem solving steps
b. Monitor one's own thinking (that is, engage in metacognition)
c. Employ a reasonable critical thinking checklist

14. Be sensitive to the feelings, level of knowledge, and degree of sophistication of others
15. Employ appropriate rhetorical strategies in discussion and presentation (orally and in writing), including employing and reacting to "fallacy" labels in an appropriate manner.

Examples of fallacy labels are "circularity," "bandwagon," "post hoc," "equivocation," "non sequitur," and "straw person."