Pseudocholinesterase Deficiency

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.

This condition is recognized most often when respiratory paralysis unexpectedly persists for a prolonged period of time following administration of standard doses of succinylcholine.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. See the image below.

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.

Pathophysiology

Pseudocholinesterase 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.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.

Epidemiology

Frequency

International

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

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

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

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

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

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
   

  Laboratory Studies

  Diagnosis of pseudocholinesterase deficiency is made by plasma assays of pseudocholinesterase enzyme activity.

  • A sample of the patient's plasma is incubated with the substrate butyrylthiocholine along with the indicator chemical 5,5'-dithiobis-(2-nitrobenzoic acid), which will produce a colored product that is assayed using spectrophotometry. The resulting amount of spectrophotometric absorption is proportionate to the pseudocholinesterase enzyme activity that is present in the patient's plasma sample.
  • Because succinylcholine metabolites can interfere with this assay, plasma samples should be collected after muscle paralysis has completely resolved.
  • The dibucaine and fluoride numbers can be determined by repeating this assay in the presence of standard aliquots of either dibucaine (0.03 mmol/L) or fluoride (4 mmol/L) in the reaction mixture to determine the percent inhibition of enzyme activity caused by these agents.

  A simplified screening test of pseudocholinesterase enzyme activity can be performed using the Acholest Test Paper. When a drop of the patient's plasma is applied to the substrate-impregnated test paper, a colorimetric reaction occurs. The time it takes the exposed Acholest Test Paper to turn from green to yellow is inversely proportional to the pseudocholinesterase enzyme activity in the plasma sample.

  Table 2. Reaction Times for Acholest Test Paper 

  Reaction Time	Pseudocholinesterase Enzyme Activity
  < 5 min	Above normal
  5-20 min	Normal
  20-30 min	Borderline low
  >30 min	Below normal

  Imaging Studies

  No imaging studies aid in the diagnosis of pseudocholinesterase deficiency.

  Other Tests

  The complete DNA sequence and amino acid structure of both the normal pseudocholinesterase protein and most of its abnormal variants have now been identified. However, molecular genetic techniques such as polymerase chain reaction (PCR) amplification with allele-specific oligonucleotide probes for identifying abnormal pseudocholinesterase genotypes presently are available only in a limited number of research laboratories and are not in routine clinical use.

  Histologic Findings

  No characteristic alteration in liver histology is associated with genetic mutations in pseudocholinesterase enzyme synthesis.

  
  

  Medical Care

  • Pseudocholinesterase deficiency is a clinically silent condition in individuals who are not exposed to exogenous sources of choline esters.
  • Patients with prolonged paralysis following administration of succinylcholine can be treated in the following ways:

    • Prophylactic transfusion of fresh frozen plasma can augment the patient's endogenous plasma pseudocholinesterase activity. This practice is not recommended because of the risk of iatrogenic viral infectious complications. However, perioperative transfusion of fresh frozen plasma administered to correct a coagulopathy may mask an underlying pseudocholinesterase deficiency.
    • Mechanical ventilatory support is the mainstay of treatment until respiratory muscle paralysis spontaneously resolves. Recovery eventually occurs as a result of passive diffusion of succinylcholine away from the neuromuscular junction.
    • Administration of cholinesterase inhibitors, such as neostigmine, is controversial for reversing succinylcholine-related apnea in patients who are pseudocholinesterase deficient. The effects may be transient, possibly followed by intensified neuromuscular blockade.

  Consultations

  • Consultation with a geneticist may help to identify the specific atypical genotype alleles contributing to pseudocholinesterase deficiency.
  • Because the DNA sequence of the pseudocholinesterase gene and its amino acid structure is known, atypical alleles now can be identified by PCR amplification studies using DNA extracted from leukocytes in a blood sample.
     

    Complications

    • The main complication resulting from pseudocholinesterase deficiency is the possibility of respiratory failure secondary to succinylcholine or mivacurium-induced neuromuscular paralysis.
    • Individuals with pseudocholinesterase deficiency also may be at increased risk of toxic reactions, including sudden cardiac death, associated with recreational use of cocaine.

    Prognosis

    • Prognosis for recovery following administration of succinylcholine is excellent when medical support includes close monitoring and respiratory support measures.
    • In nonmedical settings in which subjects with pseudocholinesterase deficiency are exposed to cocaine, sudden cardiac death can occur.

    Patient Education

    • Patients with known pseudocholinesterase deficiency may wear a medic-alert bracelet that will notify healthcare workers of increased risk from administration of succinylcholine.
    • These patients also may notify others in their family who may be at risk for carrying one or more abnormal pseudocholinesterase gene alleles.

     

   

 

Spinal Hematoma

In 1850, Tellegen appears to have been the first to describe the clinical symptoms of spinal cord hematoma or hematomyelia. The symptoms have not changed significantly with the passage of time and only change slightly with varying etiologies.

Spinal cord hematoma or hematomyelia is an infrequently encountered condition that is the result of several unusual disease processes. The causes of spontaneous, nontraumatic spinal cord hematoma include vascular malformations of the spinal cord (the most common), clotting disorders, inflammatory myelitis, spinal cord tumors, abscess, syringomyelia, and unknown etiologies. Traumatic events, such as spinal cord injury (closed or penetrating), and operative procedures involving the spinal cord also can cause a spinal cord hematoma. In addition, several instances of intramedullary spinal cord hematomas have been reported following lumbar or C1-C2 punctures.

Because of the rarity of hematomyelia, its numerous etiologies, and its varied clinical presentations, this article provides a general overview of spinal cord hematomas and briefly discusses each etiology separately. Because hematomyelia is a rare entity, treatment and outcomes, regardless of the cause, are based primarily upon anecdotal evidence and the treating surgeon's philosophy.

Since the original publication of this article, several other case reports have been published that discuss intramedullary spinal cord hematomas. These case reports, while detailing several unusual presentations of patients with intramedullary spinal cord hematomas, add little to the core concepts described in the original article. Patients suffering from intramedullary spinal cord hematomas present with severe spinal pain and significant neurological findings related to the level of spinal cord involvement; MRI with and without gadolinium is still the procedure of choice for early diagnosis; and successful outcomes depend on early diagnosis, aggressive, emergent surgical treatment and drainage of the hematoma. Even when these guidelines are followed, outcome following surgery is highly correlated with the initial neurological status of the patient.

Epidemiology

Frequency

The epidemiology of hematomyelia is based directly upon the underlying pathological process. No general statements can be made with regard to age, incidence, gender, or specificity of symptoms because these depend upon the underlying pathology.

Etiology

• Hematomyelia associated with vascular malformations
  

  • A spinal cord hematoma can be associated with an intramedullary vascular malformation. This malformation can be either a true arteriovenous malformation (AVM) or an angioma.
  • Neurological deficits are related to the location of the malformation and occur emergently, with no change over time. Diagnosis and treatment follow those of any spinal cord AVM—a subject too broad for this article.
• Hematomyelia associated with coagulopathies
  

  • Both congenital coagulopathies, such as hemophilia and factor XI deficiency, and drug-induced coagulopathies, primarily from Coumadin, have been associated with hematomyelia.
  • Schenk and Wisoff,in separate reports, detail cases in which patients suffered a spinal cord hematoma secondary to their intrinsic coagulopathies. One case, a cervical clot, was the result of hemophilia, and the other, also a cervical clot, was secondary to factor XI deficiency. Both patients underwent surgery with minimal improvement of their neurological deficits.
  • Other reports detail intramedullary clots following treatment with Coumadin. In these patients, treatment was not only surgical but also involved the correction of the coagulopathy by reversing the effects of Coumadin.
• Hematomyelia associated with myelitis/vasculitis
  

  • Allen, in 1991, reported a patient who suffered a spinal cord hematoma secondary to a vasculitis/ vasculopathy/myelitis of the cord attributable to radiation treatment.
  • Evacuation of the patient's thoracic clot provided some improvement in function.
• Hematomyelia associated with intramedullary tumors (See the image below.)
  
  This T1-weighted sagittal MRI is from a 19-year-old man with 4-month history of progressive motor loss and an inability to ambulate. He underwent spinal biopsy that confirmed an intramedullary glioblastoma.
• • • Surprisingly, hemorrhage into a spinal cord tumor is a rare event. Cauda equina tumors bleed fairly frequently but usually only produce subarachnoid blood.
    • Tumors most commonly associated with an intramedullary hematoma include ependymomas, hemangioblastomas, cavernous angiomas, schwannomas, and astrocytomas. Treatment consists of both tumor and clot removal. Outcome is determined primarily by the tumor pathology.
  • Hematomyelia associated with syringomyelia
    

    • Bleeding into a syrinx is a well-recognized phenomenon that Gowers first described in 1886.Since then, several cases of hematomyelia in a syrinx have been reported.
    • Clinical presentation is usually that of a sudden exacerbation of the symptoms of the syrinx itself, other symptomatology includes an acute worsening of symptoms that subsequently improves or a gradual deterioration of function. Most cases of intrasyringal hemorrhage are associated with either scoliosis or a Chiari I malformation. Some authors believe that the hemorrhage is caused by abnormal blood vessels lining the walls of the cyst cavity, and others believe that an acute dilatation of the syrinx tears existing vessels lining the cavity. Treatment is drainage of the clot and drainage of the syrinx. Most patients improve after surgery.
  • Hematomyelia of unknown etiology
    

    • Several cases of spinal cord hematoma appear to have no underlying cause or pathology.
    • Both Brandt and Leech reported such cases. Even at autopsy, no underlying cause could be identified. Their patients underwent surgical removal of the clot, but no significant improvement in function was noted.

  Presentation

  Regardless of the cause, the almost universal initial symptom of spinal cord hematoma is sudden onset of excruciating back or neck pain. The location of this pain relates directly to the location of the underlying pathology and hematoma.

  The neurological deficit caused by the hematoma also directly correlates with the region of hemorrhage. Neurological deficits vary somewhat with the underlying etiology. The deficit associated with a vascular malformation occurs suddenly, along with the pain, and does not usually increase substantially over time. The deficits associated with hematomas from other etiologies may lag the initial onset of pain by several hours. The deficit also may evolve over a period of 2-24 hours, or it may even take days.
  
  

  Surgical Therapy

  • Surgical treatment varies with individual physicians and the underlying pathology. Some surgeons believe that urgent clot evacuation is necessary, while others contest that early exploration damages otherwise viable spinal neurons.

    • Surgeons who believe in clot evacuation operate immediately upon diagnosing a clot. Their rationale assumes an urgent need to remove mass effect and pressure from the spinal cord.
    • Less aggressive surgeons believe that the neurologic deficit should plateau before removing the clot to keep from damaging viable tissue.
  • Regardless of the timing, both groups of surgeons believe that the underlying pathology must be addressed. Any accompanying disorders, such as clotting problems, should be corrected as soon as possible. Intraspinal tumors should be surgically removed using the tenets of individual tumor management, while AVMs are managed by embolization, surgical removal, or a combination of those modalities.
  • Because of the paucity of cases, empirical data do not exist to clarify which treatment course provides a better outcome.

  Outcome and Prognosis

  Too few data are available to derive solid outcome and prognosis figures for this disease. As noted above, however, the ultimate outcome of a patient correlates strongly with their initial neurological status; in other words, a patient with minimal findings upon presentation will likely experience a much better outcome than a patient who presents with a significant neurological deficit.

  Future and Controversies

  Spinal cord hematoma or hematomyelia is a fairly rare entity that is usually caused by some underlying pathology or disease process. These causative diseases include AVMs, coagulopathies, tumors, syringomyelia, and vasculitis. No associated problems occur in a subset of these patients.

  Clinical presentation is usually a sudden onset of spinal pain accompanied by neurological deficits correlative with the site of the clot. Treatment is aimed at correcting the underlying pathology or clotting disorder and at removing the clot. Timing of treatment and its results are still controversial.
   

Fuctional tremor/Spasms/Walking Problems and Functional Movement Disorders

What are Functional Movement Disorders

A functional movement disorder means that there is abnormal movement or positioning of part of the body due to the nervous system not working properly (but not due to an underlying neurological disease).

Patients with a functional movement disorder may experience a range of distressing and disabling symptoms:

Tremor – When an arm or leg shakes uncontrollably. In functional tremor this is often quite variable. It may even disappear when you are distracted but at other times be very disabling

Jerks / Twitches – Some people experience jerky types of movements. This may be particularly in response to loud noises, certain kinds of lighting or bursts of pain

Spasm / Contractures – Some people find that their hands or feet develop abnormal postures which are hard to overcome. This may be a temporary intermittent problem (a spasm) or may be more chronic (this is usually called fixed / functional dystonia or contracture). Patients with functional dystonia often have a ‘clenched hand’ or a twisted foot (See opposite)

Gait problems – A variety of gait (walking) problems can occur as part of a functional illness. Most common is the ‘dragging’ gait seen in patients with functional weakness of one leg. Other types of gait include a generally unsteady gait, often associated with a history of previous falls and a heightened fear of future falls.

Unlike other movement disorders (e.g., Parkinson's disease), a functional movement disorder is not caused by damage or disease of the nervous system. It is however due to a reversible problem in the way that the nervous system is working.

This means that a functional movement disorder can get better and even go away completely.

How is the diagnosis made?
The diagnosis of a functional movement disorder is usually made by a neurologist. It can be a particularly difficult diagnosis to make because it requires expert knowledge of the full range of movement disorders due to neurological disease, many of which are unusual or even bizarre.

It is therefore difficult to summarise all of the clinical features of functional movement disorders. They often occur in relation to injury and the onset can be sudden. The following are some examples

1.    Tremor (shaking) – typically a functional tremor is characterised by:
a.    Variable amplitude (how big the movements are)
b.    Variable frequency (how fast the shake is)
c.    Times when the tremor is absent
d.    Tremor that disappears transiently during tasks involving a lot of mental effort (like complex arithmetic)
e.    Difficulty making rhythmical movements with your good hand (or leg)
f.    Tremor that gets a lot worse when someone tries to hold your arm or leg still

2.    Jerks – this is called myoclonus. Functional myoclonus is characterised by
a.    Jerks in anticipation or response to loud sounds or noise (although there are other causes of this)
b.    Presence of a special brainwave called “Bereitschaftpotential” which is not usually present in patients with myoclonus cause by neurological disease

3.    Benign Twitches – these are sometimes called ‘benign fasciculations’. Most people have small twitches from time to time, especially around the eye and in the fingers. Such twitching is so common that to experience it occasionally is normal.  However, some people find that they experience more and more of this muscle twitching until it is present in multiple areas of their body, for most of the time. This can lead to understandable anxiety about what is causing the symptoms, which in turn makes the twitching even worse.  Generalised benign twitching like this is known to occur more frequently in medical students and doctors who, on developing these symptoms, worry that they might have motor neurone disease (known in the USA as ALS). In fact the twitching seen in this condition, which affects the whole muscle fibre, is different to the smaller wriggling movements, called fasciculations, seen in motor neurone disease.  The condition is therefore somewhat misnamed as benign fasciculation. There are other causes of generalised muscle twitching but benign fasciculation remains the most common clinically.

4.    Spasms  – Functional spasms often occur in the hand and wrists. The hand may go in to something called ‘carpopedal spasm’. (see picture). This does occur with other medical conditions too such as having a low blood calcium and your doctor should consider these before deciding they are ‘functional’. Carpopedal spasm is especially likely to occur during hyperventilation (click here to find out more)


5.    Fixed posture (functional dystonia). This describes a position, usually of the hand or feet which remains fixed for all or most of the time. Fixed postures like this are usually associated with some functional weakness of the limb and commonly associated with pain. There is an overlap here with a condition called Complex Regional Pain type 1 . The two most common types are:

a.    in the hand (where the appearances can be similar to carpopedal spasm or sometimes with a hand that is “clenched”)

b.    in the foot where the ankle typically turns inwards.

6.    Functional Gait Disorder. There are various types of functional gait disorder. describes difficulty walking (an abnormal gait) which is not due to an underlying neurological disease. Different types have been described including:
a.    Excessive slowness – a very slow walk with the feet having a tendency to stick to the ground.
b.     ‘Walking on ice’ pattern – a cautious gait with the feet far apart and the legs quiet stiff.
c.    Crouching. A gait where the person looks as if they are crouching. Often this is associated with a fear of falling
d.    Sudden knee buckling. Typically this is associated with a finding of functional weakness in the legs. Sometimes this problem is called ‘drop attacks’, although it is important to recognise that there may be other causes of this such as knee problems.    .
e.    Unsteady. A generally unsteady gait with sudden sidesteps.


Am I imagining it then?
The answer is ‘no’ but See my another article on ‘Am I imagining it’ to find out more



How do functional movement disorders happen?

Functional movement disorders arise for different reasons in different people. Some of the apparent precipitating factors are similar to those described for functional weakness especially:

After an injury / with pain—A high proportion of patients with functional dystonia (and to a lesser extent tremor) have a physical injury or a painful limb at the time of onset. There is a There is an overlap here with a condition called Complex Regional Pain type 1 . The movement disorders seen in this condition (especially the dystonias) are indistinguishable from those described as functional movement disorders. Functional jerks and tremors also occur in patients with chronic pain syndromes such as back pain and neck pain.

Penetrating Head Trauma

Background

Traumatic brain injury (TBI) is the fourth leading cause of death in the United States and is the leading cause of death in persons aged 1-44 years. Approximately 2 million traumatic brain injuries occur each year, and an approximate $25 billion per year is spent in social and medical management of people with such injuries.
Analysis of the trauma literature has shown that 50% of all trauma deaths are secondary to traumatic brain injury (TBI), and gunshot wounds to the head caused 35% of these. The current increase in firearm-related violence and subsequent increase in penetrating head injury remains of concern to neurosurgeons in particular and to the community as a whole.
The CT scan below is of a patient after a gunshot wound to the brain.

A young man arrived in the emergency department after experiencing a gunshot wound to the brain. The entrance was on the left occipital region. A CT scan shows the skull fracture and a large underlying cerebral contusion. The patient was taken to the operating room for debridement of the wound and skull fracture, with repair of the dura mater. He was discharged in good neurological condition, with a significant visual field defect. 

The definition of a penetrating head trauma is a wound in which a projectile breaches the cranium but does not exit it. Despite the prevalence of these injuries, the morbidity and mortality of penetrating head injury remains high. Improvements in the understanding of the mechanisms of injury and aggressive medical and surgical management of patients with these injuries may lead to improved outcomes.
This chapter focuses on the pathophysiology of both primary and secondary mechanisms of injury, describes the treatment of patients from presentation to discharge, and concludes with a discussion of possible complications and patient outcome. For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Brain Infection.

History of the Procedure

The earliest reported series of head injuries and their management appears in the Edwin Smith papyrus around 1700 BC, reporting 4 depressed skull fractures treated by the Egyptians by leaving the wound unbandaged, providing free drainage of the intracranial cavity, and anointing the scalp wound with grease. Hippocrates (460-357 BC) performed trephination for contusions, fissure fractures, and skull indentations. Galen's experience in 130-210 AD treating wounded gladiators led to recognition of a correlation between the side of injury and the side of motor loss.
During the Dark Ages, little progress was made in the surgical management of head wounds and medicine continued to hold a pessimistic view of head wounds with torn dura mater. In the 17th century, Richard Wiseman provided a better understanding of surgical management of penetrating brain injuries; he recommended the evacuation of subdural hematomas and the extraction of bone fragments. In his experience, deep wounds had a much worse prognosis than superficial ones.
Major advances in the management of penetrating craniocerebral injuries in the mid-19th century were related to the work of Louis Pasteur (1867), Robert Koch in bacteriology (1876), and Joseph Lister in asepsis (1867). Such advances dramatically reduced the incidence of local and systemic infections, as well as mortality.

Problem

In the past 20 years, a dramatic increase in the incidence of penetrating injuries to the brain has occurred. Gunshot wounds to the head have become the leading or second leading cause of head injury in many cities in the United States. These injuries are devastating to the patient, family, and society.
Siccardi et al (1991) prospectively studied a series of 314 patients with craniocerebral missile wounds and found that 73% of the victims died at the scene, 12% died within 3 hours of injury, and 7% died later, yielding a total mortality of 92% in his series.In another study, gunshot wounds were responsible for at least 14% of the head injury-related deaths from 1979-1986.
Age-adjusted death rates for injury by firearms have increased nearly every year since 1985. A study using multiple logistic regressions found that injury from firearms greatly increases the probability of death and that the victim of a gunshot wound to the head is approximately 35 times more likely to die than is a patient with a comparable nonpenetrating brain injury.

Epidemiology

Frequency

A National Institutes of Health survey estimates that in the United States, 1.9 million persons annually experience a skull fracture or intracranial injury, and, of these cases, one-half have a suboptimal outcome. In 1992, firearms accounted for the largest proportion of deaths from traumatic brain injury in the United States, and gunshot wounds were the most common cause of mortality in African Americans.

Etiology

Penetrating head injuries can be the result of numerous intentional or unintentional events, including missile wounds, stab wounds, and motor vehicle or occupational accidents (nails, screwdrivers).
Stab wounds to the cranium are typically caused by a weapon with a small impact area and wielded at low velocity. The most common wound is a knife injury, although bizarre craniocerebral-perforating injuries have been reported that were caused by nails, metal poles, ice picks, keys, pencils, chopsticks, and power drills.

Pathophysiology

The pathological consequences of penetrating head wounds depend on the circumstances of the injury, including the properties of the weapon or missile, the energy of the impact, and the location and characteristics of the intracranial trajectory. Following the primary injury or impact, secondary injuries may develop. Secondary injury mechanisms are defined as pathological processes that occur after the time of the injury and adversely affect the ability of the brain to recover from the primary insult. A biochemical cascade begins when a mechanical force disrupts the normal cell integrity, producing the release of numerous enzymes, phospholipids, excitatory neurotransmitters (glutamate), Ca, and free oxygen radicals that propagate further cell damage.

Missile wounds

Missiles range from low-velocity bullets used in handguns, as shown in the image below, or shotguns to high-velocity metal-jacket bullets fired from military weapons.Low-velocity civilian missile wounds occur from air rifle projectiles, nail guns used in construction devices, stun guns used for animal slaughter, and shrapnel produced during explosions. Bullets can cause damage to brain parenchyma through 3 mechanisms: (1) laceration and crushing, (2) cavitation, and (3) shock waves. The injury may range from a depressed fracture of the skull resulting in a focal hemorrhage to devastating diffuse damage to the brain.

A 65-year-old man experienced a gunshot wound to the right frontoparietal region. A CT scan shows that the bullet crossed the midline, lacerated the superior longitudinal sinus, and produced a large midline subdural hematoma. The patient presented with a Glasgow Coma Scale (GCS) score of 4 and died. 

As stated previously, a wound in which the projectile breaches the cranium but does not exit is described technically as penetrating, and an injury in which the projectile passes entirely though the head, leaving both entrance and exit wounds, is described as perforating. This distinction has some prognostic implications. In a series of missile-related head injuries during the Iran-Iraq war, a poor postsurgical outcome occurred in 50% of patients treated for perforating wounds, as compared with only 20% of those with penetrating wounds.
In missile wounds, the amount of damage to the brain depends on numerous factors including (1) the kinetic energy imparted, (2) the trajectory of the missile and bone fragments through the brain, (3) intracranial pressure (ICP) changes at the moment of impact, and (4) secondary mechanisms of injury. The kinetic energy is calculated employing the formula 1/2mv², where m is the bullet mass and v is the impact velocity.
At the time of impact, injury is related to (1) the direct crush injury produced by the missile, (2) the cavitation produced by the centrifugal effects of the missile on the parenchyma, and (3) the shock waves that cause a stretch injury. As a projectile passes through the head, tissue is destroyed and is either ejected out of the entrance or exit wounds or compressed into the walls of the missile tract. This creates both a permanent cavity that is 3-4 times larger than the missile diameter and a pulsating temporary cavity that expands outward. The temporary cavity can be as much as 30 times larger than the missile diameter and causes injury to structures a considerable distance from the actual missile tract.

Stab wounds

This group of wounds, example depicted below, represents a smaller fraction of penetrating head injuries. The causes may be from knives, nails, spikes, forks, scissors, and other assorted objects. Penetrations most commonly occur in the thin bones of the skull, especially in the orbital surfaces and the squamous portion of the temporal bone. The mechanisms of neuronal and vascular injury caused by cranial stab wounds may differ from those caused by other types of head trauma. Unlike missile injuries, no concentric zone of coagulative necrosis caused by dissipated energy is present. Unlike motor vehicle accidents, no diffuse shearing injury to the brain occurs

A CT scan of a young female who presented to the emergency department with a stab wound to the head produced by a large knife shows the extent of intracranial damage, which affects midline structures.

Unless an associated hematoma or infarct is present, cerebral damage caused by stabbing is largely restricted to the wound tract. A narrow elongated defect, or so-called slot fracture, sometimes is produced by a stab wound and is diagnostic when identified. However, in some cases in which skull penetration is proven, no radiological abnormality can be identified. In a series of stab wounds, de Villiers (1975) reported a mortality of 17%, mostly related to vascular injury and massive intracerebral hematomas.
Stab wounds to the temporal fossa are more likely to result in major neurological deficits because of the thinness of the temporal squama and the shorter distance to the deep brain stem and vascular structures. Patients in whom the penetrating object is left in place have a significantly lower mortality than those in whom the objects are inserted and then removed (26% versus 11% respectively).

Skull perforations and fractures

The local variations in thickness and strength of the skull and the angle of the impact determine the severity of the fracture and injury to the brain, as shown below. Impacts striking the skull at nearly perpendicular angles may cause bone fragments to travel along the same trajectory as the penetrating object, to shatter the skull in an irregular pattern, or to produce linear fractures that radiate away from the entry defect. Grazing or tangential impacts produce complex single defects with both internal and external beveling of the skull, with varied degrees of brain damage.

Lateral skull x-ray film of a patient who presented with a severe intracranial injury produced by a golf club.

The patient presented to the emergency department with a golf club in his head. The club was removed in the operating room. 

Presentation

The clinical condition of the patient depends mainly on the mechanism (velocity, kinetic energy), anatomical location of the lesions, and associated injuries.

Traumatic intracranial hematomas

These can occur alone or in combination and constitute a common and treatable source of morbidity and mortality resulting from brain shift, brain swelling, cerebral ischemia, and elevated ICP. Patients present with the signs and symptoms of an expanding intracranial mass, and the clinical course varies according to the location and rate of accumulation of the hematoma. The classic clinical picture of epidural hematomas is described as involving a lucid interval following the injury; the patient is stunned by the blow, recovers consciousness, and lapses into unconsciousness as the clot expands.

Epidural hematomas

Most traumatic epidural hematomas become rapidly symptomatic with progression to coma. Acute subdural hematoma occurs in association with high rates of acceleration and deceleration of the head that takes place at the time of trauma. This remains one of the most lethal of all head injuries because the impact causing acute subdural hematoma commonly results in associated severe parenchymal brain injuries.

Intracerebral hematomas

These result from direct rupture of small vessels within the parenchyma at the moment of impact. Patients typically present with a focal neurological deficit related to the location of the hematoma or with signs of mass effect and increased ICP. The occurrence of delayed traumatic intracerebral hematomas is well documented in the literature.

Delayed intracerebral hematomas

The time interval for the development of delayed intracerebral hematomas ranges from hours to days. Although these lesions may develop in areas of previously demonstrated contusion, they frequently occur in the presence of completely normal results on the initial computed tomography (CT) scan. Patients with this diagnosis typically meet the following criteria: (1) a definite history of trauma, (2) an asymptomatic interval, and (3) an apoplectic event with sudden clinical deterioration.

Contusions

These consist of areas of perivascular hemorrhage about small blood vessels and necrotic brain. Typically, they assume a wedgelike shape, extending through the cortex to the white matter. When the pia-arachnoid layer is torn, the injury is termed a cerebral laceration. Clinically, cerebral contusions serve as niduses for delayed hemorrhage and brain swelling, which can cause clinical deterioration and secondary brain injury.

Traumatic subarachnoid hemorrhage

This type of hemorrhage usually is a result of various forces that produce stress sufficient to damage superficial vascular structures running in the subarachnoid space. Traumatic subarachnoid hemorrhage may predispose to cerebral vasospasm and diminished cerebral blood flow, thereby increasing morbidity and mortality as a result of secondary ischemic damage.

Diffuse axonal injury or shearing injury

This has become recognized as one of the most important forms of primary injury to the brain. In the most extreme form, patients present with immediate prolonged unconsciousness from the moment of injury and subsequently remain vegetative or severely impaired.

Indications

A critical factor in early treatment decisions and in long-term outcome after penetrating head injuries is the patient's initial level of consciousness. Although many methods of defining level of consciousness exist, the most widely used measure is the Glasgow Coma Scale (GCS) introduced by Teasdale and Jennett in 1974.
Table. Glasgow Coma Scale

Points	Eye Opening	Best Verbal	Best Motor
6	…	…	Follows commands
5	…	Appropriate	Localizes pain
4	Spontaneous	Inappropriate	Withdraws to pain
3	In response to voice	Moaning	Flexion (decorticate)
2	In response to pain	Incomprehensible	Extension (decerebrate)
1	None	None	None

The level of consciousness can be lowered independent of head injury for numerous reasons, including shock, hypoxia, hypothermia, alcohol intoxication, postictal state, and administration of sedatives or narcotics. Therefore, a more reliable assessment of severity and, thus a more meaningful predictor of outcome, is provided by the postresuscitation GCS score (hereafter referred to as GCS), which generally refers to the best level obtained within the first 6-8 hours of injury following nonsurgical resuscitation. This allows patients to be categorized into 3 levels, as follows:

• Minor or mild injury includes those patients with an initial level of 13-15.
• Moderate injury includes patients with a score of 9-12.
• Severe injury refers to a postresuscitation level of 3-8 or a subsequent deterioration to 8 or less.

Patients with severe head injury typically fulfill the criteria for coma, have the highest incidence of intracranial mass lesions, and require intensive medical and, often, surgical intervention.

Relevant Anatomy

Penetrating objects to the cranium must traverse through the scalp, through the skull bones, and through the dura mater before reaching the brain.
The scalp consist of 5 different anatomical layers that include the skin (S); the subcutaneous tissue (C); the galea aponeurotica (A), which is continuous with the musculoaponeurotic system of the frontalis, occipitalis, and superficial temporal fascia; underlying loose areolar tissue (L); and the skull periosteum (P).
The subcutaneous layer possesses a rich vascular supply that contains an abundant communication of vessels that can result in a significant blood loss when the scalp is lacerated. The relatively poor fixation of the galea to the underlying periosteum of the skull provides little resistance to shear injuries that can result in large scalp flaps or so-called scalping injuries. This layer also provides little resistance to hematomas or abscess formation, and extensive fluid collections related to the scalp tend to accumulate in the subgaleal plane.
The bones of the calvaria have 3 distinct layers in the adult—the hard internal and external tables and the cancellous middle layer, or diploë. Although the average thickness is approximately 5 mm, the thickest area is usually the occipital bone and the thinnest is the temporal bone. The calvaria is covered by periosteum on both the outer and inner surfaces. On the inner surface, it fuses with the dura to become the outer layer of the dura.
Aesthetically, the frontal bone is the most important because only a small portion of the frontal bone is covered by hair. In addition, it forms the roof and portions of the medial and lateral walls of the orbit. Displaced frontal fractures therefore may cause significant deformities, exophthalmus, or enophthalmos. The frontal bone also contains the frontal sinuses, which are paired cavities located between the inner and outer lamellae of the frontal bone. The lesser thickness of the anterior wall of the frontal sinus makes this area more susceptible to fracture than the adjacent tempora-orbital areas.
The dura mater or pachymeninx is the thickest and most superficial meninx. It consists of 2 layers—a superficial layer that fuses with the periosteum and a deeper layer. In the same region between both layers, large venous compartments or sinuses are present. A laceration through these structures can produce significant blood loss or be responsible for producing epidural or subdural hematomas.

 

 

Choroid Plexus Papilloma

Background

Choroid plexus papillomas (CPPs) are benign neoplasms of the choroid plexus, a structure made from tufts of villi within the ventricular system that produces cerebrospinal fluid (CSF). CPPs are commonly observed in the lateral ventricles of children, but they can be encountered in adults. While the vast majority of these neoplasms are benign, a small percentage can be malignant.
An image depicting a choroid plexus papilloma can be seen below.

Imaging appearance of a fourth ventricular choroid plexus papilloma (CPP).

History of the Procedure

Guerard described the first CPP (in a 3-year-old girl) in 1832, and Perthes described the first successful surgical removal in 1919.

Problem

The choroid plexus is a neuroepithelial-lined papillary projection of the ventricular ependyma. The papillae consist of cores of fibrovascular tissue lined by low-cuboidal neuroepithelial cells. While benign cystic lesions of the choroid plexus are not uncommon, neoplasms are rare. Although most choroid plexus neoplasms are benign, they can become symptomatic by obstructing CSF flow, eventually leading to generalized increased intracranial pressure or mass effect.

Epidemiology

Frequency

CPPs are rare, comprising less than 1% of brain tumors in patients of all ages. However, CPPs most often occur in children and constitute up to 3% of childhood intracranial neoplasms with a predilection for younger ages. CPPs comprise 4-6% of the intracranial neoplasms in children younger than 2 years and 12-13% of intracranial neoplasms in children younger than 1 year.
CPPs have been associated with von Hippel-Lindau syndrome and Li-Fraumeni syndrome.
The frequency of CPPs in children is similar in China (1.5%) and France (2.3%)
The male-to-female incidence ratio of CPP is 2.8:1.
No distribution by race has been described.

Etiology

CPPs arise from the single layer of cuboidal epithelial cells lining the papillae of the choroid plexus. The choroid plexus is associated with the ventricular lining of the body, trigone, and inferior horn of the lateral ventricles; the foramen of Monro; the roof of the third ventricle; and the posterior portion of the roof of the fourth ventricle. The typical locations of normal choroid plexus correspond to the most common locations for a CPP to occur.
A recent study points to the role of a transmembrane receptor protein (Notch3) in the pathogenesis of human choroid plexus tumors. The Notch pathway helps regulate development of the mammalian nervous system, and activation of the Notch pathway has been increasingly recognized in human cancers. Notch3 is expressed in ventricular zone progenitor cells in the fetal brain and, when activated, can function as an oncogene.
CPPs are associated with the Li-Fraumeni cancer syndrome (an autosomal dominant syndrome characterized by a germline mutation in the TP53 gene) and the Aicardi syndrome (a rare X-linked dominant condition observed in females, characterized by visual impairment, developmental delay, and seizures).
Both somatic and germline abnormalities that involve multiple genetic loci have been associated with the development of choroid plexus tumors. Recent genomic hybridization data shows that choroid plexus papillomas and choroid plexus carcinomas have characteristic chromosomal additions and deletions, which suggests that the genetic basis for these tumors is distinct
The polyoma viruses SV40, JC, and BK have also been implicated in the development of choroid plexus tumors. Choroid plexus tumors have been induced experimentally in transgenic mice using the polyomavirus common gene product, T antigen. The mechanism is thought to involve the binding of T antigen with both pRb and p53 tumor suppressor proteins, as these complexes have been identified in humans with choroid plexus tumors.Research is ongoing to further elucidate the relationship between polyoma viruses and human CNS tumors.
Recent research has also demonstrated differential expression of several genes in choroid papilloma tumor cells using DNA microarray techniques on cells from 7 choroid plexus papillomas. Among the abnormalities identified was up-regulation of the TWIST-1 transcription factor, which was shown to promote proliferation and in vitro invasion. TWIST-1 is involved in the p53 tumor suppressor pathway as an inhibitor.

Pathophysiology

Symptoms from choroid plexus tumors generally result from secretion of CSF by tumor cells, leading to an increased amount of fluid and, eventually, to hydrocephalus. Not infrequently, the tumor itself can cause mass effect, with symptoms depending on tumor location. In either case, eventual progression and increased intracranial pressure can occur. Cases of hydrocephalus occasionally do not resolve with surgery, possibly because of derangement of reabsorption mechanisms or blockage at other sites in the ventricular system.

Presentation

Patients usually present with the following signs of increased intracranial pressure: headache, nausea and vomiting, drowsiness, ocular or gaze palsies (cranial nerves [CN] III and VI), papilledema, visual disturbances, and, eventually, blindness.
Infants, especially those with a tumor located in the third ventricle, can present with hydrocephalus or macrocephalus, as well as with associated increased intracranial pressure.
Unusual presentations include trochlear palsies (CN IV), psychosis, or occasionally, seizures.

Indications

As CPPs grow, they eventually obstruct the flow of CSF. Once the intracranial space can no longer compensate for the increase in pressure, a tension-obstruction type of hydrocephalus develops. Persistently increased intracranial pressure is not compatible with life. The pressure is alleviated by resection of the tumor or a ventricular shunting procedure.

Relevant Anatomy

Because the choroid plexus is located within the ventricles, the CPP can expand into a space-occupying lesion that may not cause symptoms until either the flow of CSF is blocked or the papilloma becomes large enough to press against the ventricular walls and, subsequently, the brain parenchyma.
These tumors most often occur in the lateral ventricles in children and in the fourth ventricle or cerebellopontine angle (CPA) of adults. Bilateral CPA choroid plexus papillomas have also been reported in the setting of neurofibromatosis Type 2 Rarely, CPPs can also be found in the third ventricle. Other unusual or rare sites include the sella and primary intraparenchymal sites.Occasionally, CPPs show extensive calcification or even ossification or may lack their usual radiographic contrast enhancement.
In some instances, choroid plexus can be found in the cerebellopontine angle, where it has escaped the ventricle via the lateral foramen of Luschka. From this unusual placement of the choroid, or from exophytic growth of the papilloma through the foramen of Luschka, CPPs sometimes manifest in the cerebellopontine angle.The appearance of CPPs in unusual sites most frequently occurs in the setting of von Hippel-Lindau syndrome.Grossly, these tumors are tan and lobulated. They fill the ventricles and compress the walls; when they are benign, they do not generally invade brain parenchyma.

Contraindications

Contraindications to surgical correction of CPP are based on the patient's comorbidities and his or her ability to tolerate surgery. However, watchful waiting is inappropriate in most cases. As choroid plexus tumors grow, the resulting hydrocephalus and other complications usually result in greater morbidity than occurs if tumors are removed when they are first discovered and smaller.