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.