Case Study Answers
The four types of osteogenesis imperfecta are type I (mild), type II (perinatal, lethal), type III (progressive, deforming), and type IV (deforming with normal scleras). All forms of osteogenesis imperfecta are characterized by increased susceptibility to fractures (“brittle bones”), but there is considerable phenotypic heterogeneity, even within individual subtypes. Approximately one fourth of the cases of type I or type IV osteogenesis imperfecta represent new mutations; in the remainder, the history and examination of other family members reveal findings consistent with autosomal dominant inheritance. Type III is also transmitted as an autosomal dominant trait, although type III can occasionally be transmitted in an autosomal recessive manner. Type II, the most severe form, generally occurs as a result of a sporadic dominant mutation.
Type II osteogenesis imperfecta presents at birth (or even in utero) with multiple fractures and bony deformities, resulting in death in infancy and, therefore, not likely to be seen in a child 4 years of age. Type III presents at birth or in early infancy with multiple fractures—often prenatal—and progressive bony deformities. The absence of prenatal fractures and early deformities in this patient’s history is most suggestive of type I or type IV osteogenesis imperfecta. These individuals generally present in early childhood with one or a few fractures of long bones in response to minimal or no trauma, as seen in this case. Type I and type IV osteogenesis imperfecta are differentiated by their clinical severity and scleral hue. Type I tends to be less severe, with 10–20 fractures during childhood plus short stature but few or no deformities. These patients tend to have blue scleras. Patients with type IV osteogenesis imperfecta tend to have more fractures, resulting in significant short stature and mild to moderate deformities. Their scleras are normal or gray.
In patients with type I osteogenesis imperfecta, the fracture incidence decreases after puberty and the main features in adult life are mild short stature, conductive hearing loss, and occasionally dentinogenesis imperfecta (defective dentin formation in tooth development).
Advances in the last two decades demonstrate two genetically different groups: the “classical” group, in which more than 90% of cases are caused by a mutation of the COL1A1 or COL1A2 genes, which encode the subunits of type I collagen, proα1(I) and proα2(I), respectively, and a newer group, caused by loss-of-function mutations in proteins required for proper folding, processing, and secretion of collagen. The fundamental defect in most individuals with type I osteogenesis imperfecta is reduced synthesis of type I collagen resulting from loss-of-function mutations in COL1A1. Several potential molecular defects are responsible for COL1A1 mutations in type I osteogenesis imperfecta, including alterations in a regulatory region leading to reduced transcription, splicing abnormalities leading to reduced steady-state levels of RNA, and deletion of the entire COL1A1 gene. However, in many cases, the underlying defect is a single base pair change that creates a premature stop codon (also known as a “nonsense mutation”) in an internal exon. In a process referred to as “nonsense-mediated decay,” partially synthesized mRNA precursors that carry the nonsense codon are recognized and degraded by the cell. Each of these mutations gives rise to greatly reduced (partial loss-of-function) or no (complete loss-of-function) mRNA. Because the nonmutant COL1A1 allele continues to produce mRNA at a normal rate (ie, there is no dosage compensation), heterozygosity for a complete loss-of-function mutation results in a 50% reduction in the total rate of proα1(I) mRNA synthesis, whereas heterozygosity for a partial loss-of-function mutation results in a less severe reduction. A reduced concentration of pro1(I) chains limits the production of type I procollagen, leading to both a reduced amount of structurally normal type I collagen and an excess of unassembled proα2(I) chains, which are degraded inside the cell. This ultimately results in fragile bones.
The primary metabolic defect in phenylketonuria (PKU) is the inability to hydroxylate phenylalanine, an essential step in the conversion of phenylalanine to tyrosine and the synthesis of protein. This condition is most commonly due to a defect in phenylalanine hydroxylase, the responsible enzyme, or less commonly, to a defect in the metabolism of tetrahydrobiopterin (BH4), an essential co-factor in the hydroxylation of phenylalanine. This leads to the accumulation of phenylalanine and its metabolites.
The accumulation of phenylalanine and its metabolites, especially phenylpyruvate, directly reduces energy production and protein synthesis, and affects neurotransmitter homeostasis in the developing brain, since many neurotransmitters are derived from amino acids. Elevated levels of phenylalanine also inhibit amino acid transport across the blood-brain barrier, causing an amino acid deficit in the cerebrospinal fluid. All these effects combine to cause mental retardation, developmental delay, and seizures. Affected individuals also suffer from eczema, the mechanism of which is not well understood, and have hypopigmentation due to inhibition of melanocytes from the excess phenylalanine. Most, if not all, of the above consequences of PKU can be prevented by strict dietary management to ensure that excessive serum phenylalanine concentrations do not occur.
PKU is inherited as an autosomal recessive trait. The reproductive fitness of affected untreated individuals is poor, meaning that they are unlikely to produce offspring. Theories have been proposed about why the trait has persisted at a relatively high rate in the population. It is known that the rate of spontaneous PKU mutation is low. Two potential explanations for the high rate of the defective gene are the founder effect and heterozygote advantage. The founder effect occurs when a population founded by a small number of ancestors has by chance a high frequency of a deleterious gene. Heterozygote advantage refers to the fact that certain genes may actually confer a benefit in the heterozygote state even though the homozygote state is disadvantageous. This is the case for the genetic defect in sickle cell disease, in which heterozygote carriers have a relative resistance to malaria.
Fragile X–associated mental retardation is a syndrome caused by a genetic mutation of the X chromosome. The mutation leads to failure of the region between bands Xq27 and Xq28 to condense at metaphase, thereby increasing the “fragility” of the region. The mutation appears as an amplification of a (CGG)n repeat within the untranslated region of a gene named FMR1. The FMR1 gene encodes an RNA-binding protein named FMR1. However, in affected individuals, amplification of the gene results in methylation of an area known as the CpG island, located at Xq27.3. This methylation prevents expression of the FMR1 protein.
The FMR1 protein is normally expressed in brain and testes. This protein resembles a group of proteins named hnRNPs (heterogeneous nuclear RNA-binding proteins) that function in the processing or transport of nuclear mRNA precursors. It is believed that the FMR1 protein plays a general role in the cellular metabolism of nuclear RNA but only in the tissues in which it is primarily expressed (ie, the CNS and testes). This would explain in part the symptoms of mental retardation and enlarged testes. It is not known why the absence of FMR1 expression leads to joint laxity and hyperextensibility and facial abnormalities.
Fragile X–associated mental retardation is an X-linked disease. Given that a male child inherits his X chromosome from his mother, she is clearly the carrier of the mutation.
The boy’s mother and grandparents do not demonstrate the phenotype of fragile X–associated mental retardation because of the processes of premutation and parental imprinting. As mentioned, the mutation in fragile X is associated with amplification of a segment of DNA containing the sequence (CGG)n. This segment is highly variable in length. In individuals who are neither carriers nor affected, the number of repeats is generally less than 50. In transmitting males and unaffected carrier females, the number of repeats is usually between 70 and 100. Alleles with 55 or more repeats are unstable and often exhibit expansion after maternal transmission; these individuals are generally considered to carry the premutation. They are unaffected phenotypically, but the regions are unstable, and when transmitted from generation to generation, the regions tend to undergo amplification into a full mutation. Although premutation carriers do not develop a typical FMR syndrome, recent studies indicate that female premutation carriers exhibit a 20% incidence of premature ovarian failure, whereas male premutation carriers are at increased risk for a tremor-ataxia syndrome. In both cases, the mechanism is likely to be explained by somatic expansion of the premutation. Full mutations, observed in all affected individuals, always have more than 200 amplifications.
The most important determinant of whether a premutation allele is subject to amplification is the sex of the parent who transmits the premutation allele. A premutation allele transmitted by a female expands to a full mutation with a likelihood proportionate to the length of the premutation. In contrast, a premutation allele transmitted by a male rarely expands to a full mutation regardless of the length of the premutation. This process is called parental imprinting. Thus, it is likely that the boy’s mother and grandfather are carriers of a premutation allele and are, therefore, unaffected and that this gene amplified to a full mutation on transmission to the boy.
The chance that her unborn child will be affected depends on its gender. If it is a boy, the chance that it will be affected is approximately 80%, whereas if it is a girl the chance is only 32%.
Leber hereditary optic neuropathy (LHON) arises from a mutation in mitochondrial DNA (mtDNA). The mtDNA encodes protein components of the electron transport chain involved in the generation of adenosine triphosphate (ATP). Mutations in the mtDNA can result in the inability to generate ATP. This defect especially affects tissues with intensive ATP use such as the skeletal muscle and the central nervous system. It is not understood why the defect in LHON is largely confined to the optic nerve and the retina. Other mitochondrial disorders do affect skeletal muscle, most notably, mitochondrial encephalomyopathy with ragged red fibers (MERRF).
LHON is inherited through mtDNA mutations. All the mtDNA in our bodies comes exclusively from the egg. The sperm makes no contribution of mtDNA. Therefore, LHON is inherited only from the mother. In addition, a typical cell carries 10–100 separate mtDNA molecules, only a fraction of which carry the mutation. This is known as heteroplasmy. Within any one affected woman, the level of mutant DNA in different eggs may vary from 10% to 90%. Thus, some offspring may be severely affected, while others may not show any signs. Furthermore, within any given offspring, the level of mutant mtDNA will vary from tissue to tissue and from cell to cell.
LHON affects males 4 to 5 times more often than females. This difference is thought to be due to a factor on the X chromosome that modifies the severity of a mitochondrial mutation. Even though mtDNA encodes essential components of the electron transport chain, there are copies for most mitochondrial components also encoded on the nuclear genome.
Down syndrome occurs approximately once in every 700 live births. Common features include developmental delay, growth retardation, congenital heart disease (50%), immunodeficiency, and characteristic major and minor facial and dysmorphic features, including upslanting palpebral fissures (82%), excess skin on the back of the neck (81%), brachycephaly (75%), hyperextensible joints (75%), flat nasal bridge (68%), epicanthal folds (59%), small ears (50%), and transverse palmar creases (53%).
There are two major genetic abnormalities associated with Down syndrome. The most common abnormality occurs in children born to parents with normal karyotypes. It is caused by nondisjunction of chromosome 21 during meiotic segregation, resulting in one extra chromosome 21 or in trisomy 21 with 47 chromosomes on karyotyping. Alternatively, Down syndrome can be caused by DNA rearrangement resulting in fusion of chromosome 21 to another acrocentric chromosome via its centromere. This abnormal chromosome is called a robertsonian translocation chromosome. Unlike those with trisomy 21, these individuals have 46 chromosomes on karyotyping. This type of translocation can sometimes be inherited from a carrier parent.
Both of these genetic abnormalities result in a 50% increase in gene dosage for nearly all genes on chromosome 21. In other words, the amount of protein produced by all or nearly all genes on chromosome 21 is approximately 150% of normal in Down syndrome. The genes that have been shown to contribute to the Down syndrome phenotype include the gene that encodes the amyloid protein found in the senile plaques of Alzheimer disease and the one that encodes the cytoplasmic form of superoxide dismutase, which plays an important role in free radical metabolism.
It is not known why advanced maternal age is associated with an increased risk of Down syndrome. One theory suggests that biochemical abnormalities affect the ability of paired chromosomes to disjoin and that these abnormalities accumulate over time. Because germ cell development is completed in females before birth, these biochemical abnormalities are able to accumulate within the egg cells as the mother ages, thereby increasing the risk of nondisjunction. Another hypothesis is that structural, hormonal, and immunologic changes occur in the uterus as the woman ages, producing an environment less able to reject a developmentally abnormal embryo. Therefore, an older uterus would be more likely to support a trisomy 21 conceptus to term. Alternatively, it is possible that a combination of these and other genetic factors may contribute to the relationship between advanced maternal age and an increased incidence of Down syndrome.
Cross-linking of surface-bound IgE by antigen activates tissue mast cells and basophils, inducing the immediate release of preformed mediators and the synthesis of newly generated mediators. Mast cells and basophils also have the ability to synthesize and release proinflammatory cytokines, which are growth and regulatory factors that interact in complex networks. The interaction of mediators with various target organs and cells of the airway can induce a biphasic allergic response: an early phase mediated chiefly by release of histamine and other stored mediators (tryptase, chymase, heparin, chondroitin sulfate, and tumor necrosis factor [TNF]), whereas late-phase events are induced after generation of arachidonic acid metabolites (leukotrienes and prostaglandins), platelet-activating factor, and de novo cytokine synthesis.
Histologically, the early response is characterized by vascular permeability, vasodilatation, tissue edema, and a mild cellular infiltrate of mostly granulocytes. The late-phase response is characterized by erythema, induration, heat, burning, and itching and microscopically by a significant cellular influx of mainly eosinophils and mononuclear cells. Changes consistent with airway remodeling and tissue hyper-reactivity may also occur.
Patients with allergic rhinitis develop chronic or episodic paroxysmal sneezing; nasal, ocular, or palatal pruritus; and watery rhinorrhea triggered by exposure to a specific allergen. Patients may demonstrate signs of chronic pruritus of the upper airway, including a horizontal nasal crease from frequent nose rubbing (“allergic salute”) and palatal “clicking” from rubbing the itching palate with the tongue. Symptoms of nasal obstruction may become chronic as a result of persistent late-phase allergic mechanisms. Nasal mucous membranes may appear pale blue and boggy. Children frequently show signs of obligate mouth breathing, including long facies, narrow maxillae, flattened malar eminences, marked overbite, and high-arched palates (so-called adenoid facies).
Serous otitis media and sinusitis are major comorbidities in patients with allergic rhinitis. Both conditions occur secondarily to the obstructed nasal passages and sinus ostia in patients with chronic allergic or nonallergic rhinitis. Complications of chronic rhinitis should be considered in patients with protracted rhinitis unresponsive to therapy, refractory asthma, or persistent bronchitis. Serous otitis results from auditory tube obstruction by mucosal edema and hypersecretion. Children with serous otitis media can present with conductive hearing loss, delayed speech, and recurrent otitis media associated with chronic nasal obstruction.
Sinusitis may be acute, subacute, or chronic depending on the duration of symptoms. Obstruction of osteomeatal drainage in patients with chronic rhinitis predisposes to bacterial infection in the sinus cavities. Patients manifest symptoms of persistent nasal discharge, cough, sinus discomfort, and nasal obstruction. Examination may reveal chronic otitis media, infraorbital edema, inflamed nasal mucosa, and purulent nasal discharge. Radiographic diagnosis by x-ray film or computed tomographic (CT) scan reveals sinus opacification, membrane thickening, or the presence of an air-fluid level.
The most likely cause of this child’s recurrent infections is severe combined immunodeficiency disease (SCID). These patients have complete or near-complete failure of development of both cellular and humoral components of the immune system. Placental transfer of maternal immunoglobulin is insufficient to protect these children from infection, and for that reason they present at a very early age with severe infections.
SCID is a heterogeneous group of genetic and cellular disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors, but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection.
The most common genetic defect is an X-linked form of SCID (XSCID) in which the maturation defect is mainly in the T-lymphocyte lineage and is due to a point mutation in the γ chain of the IL-2 receptor. This defective γ chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Circulating B-cell numbers may be preserved, but defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients.
Several autosomally inherited defects have also been identified. A defect in the α chain of the IL-7 receptor can lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.
About 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, are identical to those of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease.
An alternate autosomally recessive form of SCID is a deficiency of ZAP-70, a tyrosine kinase important in normal T-lymphocyte function. Deficiency of this tyrosine kinase results in total absence of CD8 T lymphocytes and functionally defective CD4 T lymphocytes, but normal B-lymphocyte and NK activity. Mutations of CD3δ, CD3γ, and CD3ε subunits may lead to partially arrested development of TCR expression and severe T-cell deficiency.
Deficiencies of both p56kk and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction; p56kk is a T-cell receptor–associated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor–associated signaling molecule. Finally, patients have been identified with defective recombination activating gene (RAG-1 and RAG-2) products. RAG-1 and RAG-2 initiate recombination of antigen-binding proteins, immunoglobulins and T-cell receptors. The defect leads to both quantitative and qualitative (functional) deficiencies of T and B lymphocytes.
Without treatment, most patients with SCID die within the first 1–2 years.
This child has X-linked agammaglobinemia, formerly called Bruton agammaglobinemia. The history of multiple infections occurring after the age of 6 months, the family history of a maternal uncle with lethal infection, the severe current infection with Streptococcus pneumoniae, and the absence of circulating B lymphocytes are characteristic of this disorder.
The main defect is a mutation in the BTK (Bruton tyrosine kinase) gene, which is located on the X chromosome. This gene’s product is a B-cell–specific signaling protein necessary for normal B-cell maturation. The mutation affects the catalytic domain of the protein, halting B-cell maturation. This, in turn, leads to absence or greatly reduced levels of the immunoglobulins IgA, IgG, and IgM. Their absence or reduction is a particular problem with fighting infections from encapsulated bacteria because these bacteria require antibody binding for efficient opsonization. Therefore, patients are particularly susceptible to infections with bacteria such as Haemophilus influenzae and S pneumoniae. Because they cannot mount an antibody response, they also develop very little immunity to these infections and are thus susceptible to repeated infections with the same organism.
The affected child is relatively protected by circulating maternal antibodies until 4–6 months of age. The child’s immune system is otherwise unaffected, but as the levels of maternal antibodies decrease, the child becomes increasingly susceptible to infection, particularly from encapsulated bacteria.
Individuals with common variable immunodeficiency (CVI) commonly develop recurrent sinopulmonary infections such as sinusitis, otitis media, bronchitis, and pneumonia. Common pathogens are encapsulated bacteria such as S pneumoniae, H influenzae, and Moraxella catarrhalis. Bronchiectasis may develop as a result of these recurrent infections. They may also develop GI malabsorption from bacterial overgrowth or chronic Giardia infection in the small bowel.
CVI is a heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production, with normal or reduced numbers of circulating B cells. This is most commonly caused by a defect in the terminal differentiation of B lymphocytes in response to T-lymphocyte–dependent and T-lymphocyte–independent stimuli. However, defects in B-lymphocyte development have been shown to occur at any stage of the maturation pathway.
In many patients, the defect is intrinsic to the B-lymphocyte population. Approximately 15% of patients with CVI demonstrate defective B-cell surface expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), a member of the TNF receptor family. Lacking a functional TACI, the affected B cells will not respond to B-cell–activating factors, resulting in deficient immunoglobulin production. Another defect, which may lead to CVI, involves deficient expression of the B-cell surface marker, CD19. When complexed with CD21 and CD81, CD19 facilitates cellular activation through B-cell receptors. B-cell development is not affected but humoral function is deficient. A variety of T-cell abnormalities may also lead to immune defects with subsequent impairment of B-cell differentiation. A mutation of inducible T-cell costimulator gene (ICOS), expressed by activated T cells and responsible for B-cell activation and antibody production, may be the molecular defect in some cases of CVI. T-lymphocyte dysfunction can be manifested as increased suppressor T-lymphocyte activity, decreased cytokine production, defective synthesis of B-lymphocyte growth factors, defective cytokine gene expression in T cells, decreased T-cell mitogenesis, and deficient lymphokine-activated killer cell function.
Individuals with CVI are at increased risk of autoimmune disorders and malignancies. The autoimmune disorders most commonly seen in association with CVI include immune thrombocytopenic purpura, hemolytic anemia, and symmetric seronegative arthritis. The malignancies associated with CVI include lymphomas, gastric carcinoma, and skin cancers.
Treatment is mainly symptomatic along with replacement of immune globulin with monthly infusions of IVIG.
Pneumocystis pneumonia is commonly seen in AIDS. An HIV-1 antibody test should be obtained whenever the diagnosis of Pneumocystis jirovecii is suspected.
AIDS is the consequence of infection with HIV-1, a retrovirus that infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells. With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T-lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. The resultant immunosuppression predisposes patients to the constellation of opportunistic infections that characterizes AIDS.
The loss of CD4 cells seen in HIV infection is the result of multiple mechanisms, including (1) autoimmune destruction, (2) direct viral infection and destruction, (3) fusion and formation into multinucleated giant cells, (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) apoptosis (programmed cell death).
The clinical manifestations of HIV infection and AIDS are the direct consequence of progressive and severe immunosuppression and can be correlated with the degree of CD4 T-lymphocyte destruction. HIV infection may present as an acute, self-limited febrile syndrome. This is often followed by a long, clinically silent period, sometimes associated with generalized lymphadenopathy. The time course of disease progression may vary; the majority of individuals remain asymptomatic for 5–10 years. Approximately 70% of HIV-infected individuals will develop AIDS after a decade of infection. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are “long-term nonprogressors.” Genetic factors, host cytotoxic immune responses, and viral load and virulence all appear to have an impact on susceptibility to infection and the rate of disease progression. Multidrug antiretroviral therapy has dramatically changed this natural history and markedly prolonged survival.
As the CD4 count declines, the incidence of infection increases. At CD4 counts between 200/μL and 500/μL, patients are at an increased risk for bacterial infections, including pneumonia and sinusitis. As CD4 counts continue to drop—generally below 250/μL—they are at high risk for opportunistic infections such as pneumocystic pneumonia, candidiasis, toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and Mycobacterium avium complex infection. HIV-infected individuals are also at increased risk for certain malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Other manifestations of AIDS include AIDS dementia complex, peripheral neuropathy, monoarticular and polyarticular arthritides, unexplained fevers, and weight loss. Since patients are living longer due to potent antiretroviral therapies (ART), cardiovascular complications are more prominent. ART has been associated with dyslipidemia and metabolic abnormalities including insulin resistance. HIV infection may be atherogenic as well, through effects on lipids and proinflammatory mechanisms.
This patient’s presentation is characteristic of untreated infective endocarditis, an infection of the cardiac valves. The most common predisposing factor is the presence of structurally abnormal cardiac valves related to rheumatic heart disease, congenital heart disease, prosthetic valve, or prior endocarditis. Injection drug use is also an important risk factor for this disease. The patient’s history of significant illness as a child after a sore throat suggests the possibility of rheumatic heart disease.
The most common infectious agents causing native valve endocarditis are gram-positive bacteria, including viridans group streptococci, S aureus, and enterococci. Given the history of recent dental work, the most likely pathogen in this patient would be viridans group streptococci, which are normal mouth flora that can become transiently bloodborne after dental work.
The hemodynamic factors that predispose patients to the development of endocarditis include (1) a high-velocity jet stream causing turbulent flow, (2) flow from a high- to a low-pressure chamber, and (3) a comparatively narrow orifice separating two chambers that creates a pressure gradient. The lesions of endocarditis tend to form on the surface of the valve in the lower pressure cardiac chamber. The predisposed, damaged endothelium of an abnormal valve—or jet stream–damaged endothelium—promotes the deposition of fibrin and platelets, forming sterile vegetations. When bacteremia occurs, such as after dental work, microorganisms can be deposited on these sterile vegetations. Once infected, the lesions continue to grow through further deposition of platelets and fibrin. These vegetations act as a sanctuary from host defense mechanisms such as phagocytosis and complement-mediated lysis. It is for this reason that prolonged administration of bactericidal antibiotics and possible operative intervention are required for cure.
The painful papules found on the pads of this man’s fingers and toes are Osler nodes. They are thought to be caused by deposition of immune complexes in the skin. The painless hemorrhagic macules (Janeway lesions) and splinter hemorrhages are thought to result from microembolization of the cardiac vegetations.
In addition to the symptoms described in this man (fever, chills, night sweats, malaise, Roth spots, Janeway lesions, splinter hemorrhages, and Osler nodes), patients with infective endocarditis can develop multisystem complaints, including headaches, back pain, focal neurologic symptoms, shortness of breath, pulmonary edema, chest pain, cough, decreased urine output, hematuria, flank pain, abdominal pain, and others. These symptoms and signs reflect (1) hemodynamic changes from valvular damage, (2) end-organ damage by septic emboli (right-sided endocarditis causes emboli to the lungs; left-sided endocarditis causes emboli to the brain, spleen, kidney, GI tract, and extremities), (3) immune complex deposition causing acute glomerulonephritis, and (4) persistent bacteremia and distal seeding of infection, resulting in abscess formation.
Death is usually caused by hemodynamic collapse after rupture of the aortic or mitral valves or by septic emboli to the CNS, resulting in brain abscesses or mycotic aneurysms with resultant intracranial hemorrhage. Risk factors for a fatal outcome include left-sided cardiac involvement, bacterial causes other than viridans group streptococci, medical comorbidities, complications from endocarditis (heart failure, valve ring abscess, or embolic disease), and, for those with large vegetations and significant valvular destruction, delayed valvular surgery.
The most likely diagnosis in this patient is meningitis. The acuity and severity of presentation are most consistent with a pyogenic bacterial cause, although viral, mycobacterial, and fungal causes should be considered as well. In adults, the most likely bacterial pathogens are Neisseria meningitidis and S pneumoniae. In newborns younger than 3 months, the most common pathogens are those to which the infant is exposed in the maternal genitourinary canal, including E coli and other gram-negative bacilli, group B and other streptococci, and Listeria monocytogenes. Between the ages of 3 months and 15 years, N meningitidis and S pneumoniae are the most common pathogens. H influenzae, previously the most common cause of meningitis in this age group, is now primarily a concern in the unimmunized child.
Most cases of bacterial meningitis begin with colonization of the host’s nasopharynx. This is followed by local invasion of the mucosal epithelium and subsequent bacteremia. Cerebral endothelial cell injury follows and results in increased blood-brain barrier permeability, facilitating meningeal invasion. The resultant inflammatory response in the subarachnoid space causes cerebral edema, vasculitis, and infarction, ultimately leading to decreased cerebrospinal fluid flow, hydrocephalus, worsening cerebral edema, increased intracranial pressure, and decreased cerebral blood flow.
Bacterial pathogens responsible for meningitis possess several characteristics that facilitate the steps just listed. Nasal colonization is facilitated by pili on the bacterial surface of N meningitidis that assist in mucosal attachment. N meningitidis, H influenzae, and S pneumoniae also produce IgA proteases that cleave IgA, the antibody commonly responsible for inhibiting adherence of pathogens to the mucosal surface. By cleaving the antibody, the bacteria are able to evade this important host defense mechanism. In addition, N meningitidis, H influenzae, and S pneumoniae are often encapsulated, which can assist in nasopharyngeal colonization as well as systemic invasion. The capsule inhibits neutrophil phagocytosis and resists classic complement-mediated bactericidal activity, enhancing bacterial survival and replication.
It remains unclear how bacterial pathogens gain access to the CNS. It is thought that cells of the choroid plexus may contain receptors for them, facilitating movement into the subarachnoid space. Once the bacterial pathogen is in the subarachnoid space, host defense mechanisms are inadequate to control the infection. Subcapsular surface components of the bacteria, such as the cell wall and lipopolysaccharide, induce a marked inflammatory response mediated by IL-1, IL-6, matrix metalloproteinases, and TNF. Despite the induction of a marked inflammatory response and leukocytosis, there is a relative lack of opsonization and bactericidal activity such that the bacteria are poorly cleared from the cerebrospinal fluid. The host inflammatory response, with cytokine and proteolytic enzyme release, leads to loss of membrane integrity, with resultant cellular swelling and cerebral edema, contributing to many of the pathophysiologic consequences of this disease.
Cerebral edema may be vasogenic, cytotoxic, or interstitial in origin. Vasogenic cerebral edema is principally caused by the increase in the blood-brain barrier permeability that occurs when the bacteria invade the cerebrospinal fluid. Cytotoxic cerebral edema results from swelling of the cellular elements of the brain. This occurs because of toxic factors released by the bacteria and neutrophils. Interstitial edema is due to obstruction of cerebrospinal fluid flow.
Any patient suspected of having bacterial meningitis should have emergent lumbar puncture with Gram stain and culture of the cerebrospinal fluid. If there is concern about a focal neurologic problem—such as may occur with abscess—CT or MRI of the brain may be performed before lumbar puncture.
Antibiotics should be started immediately, without waiting for imaging study or lumbar puncture if delay is anticipated in these procedures. Corticosteroids should also be given if pneumococcal meningitis is suspected. The importance of the immune response in triggering cerebral edema has led researchers to study the role of adjuvant anti-inflammatory medications for bacterial meningitis. The use of corticosteroids has been shown to decrease the risk of sensorineural hearing loss among children with H influenzae meningitis and mortality among adults with pneumococcal meningitis. The benefit of adjuvant corticosteroids for other types of meningitis is unproven.
The patient described in this case has a moderately severe infection and an underlying diagnosis of COPD, requiring hospitalization but not ICU admission. The most likely pathogens are S pneumoniae, H influenzae, and M catarrhalis. Other potential pathogens include Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, and respiratory viruses. Tuberculosis and fungi should also be considered, although these are less likely in this patient with such an acute presentation. Anaerobes are also unlikely without a history of substance abuse or recent depressed mental status. If this patient required ICU admission, the atypical pathogens, M pneumoniae and C pneumoniae, are much less likely, and S aureus and Pseudomonas aeruginosa should be added to the differential diagnosis, particularly if the patient had been recently hospitalized.
Pulmonary pathogens reach the lungs by one of four routes: (1) inhalation of infectious droplets into the lower airways, (2) aspiration of oropharyngeal contents, (3) spread along the mucosal membrane surface, and (4) hematogenous spread.
Normal pulmonary antimicrobial defense mechanisms include the following: (1) aerodynamic filtration by subjection of incoming air to turbulence in the nasal passages and then abrupt changes in the direction of the airstream as it moves through the pharynx and tracheobronchial tree; (2) the cough reflex to remove aspirated material, excess secretions, and foreign bodies; (3) the mucociliary transport system, moving the mucous layer upward to the larynx; (4) phagocytic cells, including alveolar macrophages and PMNs, as well as humoral and cellular immune responses, which help to eliminate the pathogens; and (5) pulmonary secretions containing surfactant, lysozyme, and iron-binding proteins, which further aid in bacterial killing.
Common host risk factors include the following: (1) an immunocompromised state, resulting in immune dysfunction and increased risk of infection; (2) chronic lung disease, resulting in decreased mucociliary clearance; (3) alcoholism or other reduction of the level of consciousness, which increases the risk of aspiration; (4) injection drug abuse, which increases the risk of hematogenous spread of pathogens; (5) environmental or animal exposure, resulting in inhalation of specific pathogens; (6) residence in an institution, with its associated risk of microaspirations, and exposure via instrumentation (catheters and intubation); and (7) recent influenza infection, leading to disruption of respiratory epithelium, ciliary dysfunction, and inhibition of PMNs. This patient has a history of chronic lung disease, increasing his risk of pneumonia, and he is immunocompromised by the use of corticosteroids for his COPD.
There are three primary modes of transmission of pathogens causing infectious diarrhea. Pathogens such as Vibrio cholerae are water-borne and transmitted via a contaminated water supply. Several pathogens, including S aureus and Bacillus cereus, are transmitted by contaminated food. Finally, some pathogens, such as Shigella and Rotavirus, are transmitted by person-to-person spread and are, therefore, commonly seen in institutional settings such as child care centers.
The description of this patient’s diarrhea as profuse and watery suggests a small bowel site of infection. The small bowel is the site of significant electrolyte and fluid transportation. Disruption of this process leads to the production of profuse watery diarrhea, as seen in this patient.
The most likely cause of diarrhea in this patient, who has recently returned from Mexico, is enterotoxigenic E coli (ETEC), which is the most common cause of traveler’s diarrhea. Diarrhea results from the production of two enterotoxins that “poison” the cells of the small intestine, causing watery diarrhea. ETEC produces both a heat-labile and a heat-stable enterotoxin. The heat-labile enterotoxin activates adenylyl cyclase and formation of cAMP, which stimulates water and electrolyte secretion by intestinal endothelial cells. The heat-stable toxin produced by ETEC results in guanylyl cyclase activation, also causing watery diarrhea.
Factors that contribute to hospital-related sepsis are invasive monitoring devices, indwelling catheters, extensive surgical procedures, and the increased numbers of immunocompromised patients.
Sepsis generally starts with a localized infection. Bacteria may then invade the bloodstream directly (leading to bacteremia and positive blood cultures) or may proliferate locally and release toxins into the bloodstream. Gram-negative bacteria contain an endotoxin, the lipid A component of the lipopolysaccharide-phospholipid-protein complex present in the outer cell membrane. Endotoxin activates the coagulation cascade, the complement system, and the kinin system as well as the release of several host mediators such as cytokines, platelet-activating factor, endorphins, endothelium-derived relaxing factor, arachidonic acid metabolites, myocardial depressant factors, nitric oxide, and others. As sepsis persists, host immunosuppression plays a critical role. Specific stimuli such as organism, inoculum, and site of infection stimulate CD4 T cells to secrete cytokines with either inflammatory (type 1 helper T cell) or anti-inflammatory (type 2 helper T cell) properties (Figure 4–11). Among patients who die of sepsis, there is significant loss of cells essential for the adaptive immune response (B lymphocytes, CD4 T cells, dendritic cells). Apoptosis is thought to play a key role in the decrease in these cell lines and downregulates the surviving immune cells.
A hyperdynamic circulatory state, described as distributive shock to emphasize the maldistribution of blood flow to various tissues, is the common hemodynamic finding in sepsis. The release of vasoactive substances (including nitric oxide) results in loss of normal mechanisms of vascular autoregulation, producing imbalances in blood flow with regional shunting and relative hypoperfusion of some organs. Myocardial depression also occurs, with reduction in both the left and the right ventricular ejection fractions and increases in end-diastolic and end-systolic volumes. This myocardial depression has been attributed to direct toxic effects of nitric oxide, TNF, and IL-1. Refractory hypotension can ensue, resulting in end-organ hypoperfusion and injury.
Organ failure results from a combination of decreased perfusion and microvascular injury induced by local and systemic inflammatory responses to infection. Maldistribution of blood flow is accentuated by impaired erythrocyte deformability, with microvascular obstruction. Aggregation of neutrophils and platelets may also reduce blood flow. Demargination of neutrophils from vascular endothelium results in further release of inflammatory mediators and subsequent migration of neutrophils into tissues. Components of the complement system are activated, attracting more neutrophils and releasing locally active substances such as prostaglandins and leukotrienes. The net result of all of these changes is microvascular collapse and, ultimately, organ failure.
The outcome in sepsis depends on the number of organs that fail, with a mortality rate of 70% in patients who develop failure of three or more organ systems.
Carcinoid tumors arise from neuroendocrine tissue, specifically the enterochromaffin cells. These cells migrate during embryogenesis to the submucosal layer of the intestines and the pulmonary bronchi. Therefore, carcinoid tumors are most commonly found in the intestines and lungs.
Since carcinoid tumors are derived from neuroendocrine tissue, they can secrete many peptides that have systemic effects. This secretion is due to the inappropriate activation of latent synthetic ability that all neuroendocrine cells possess. Many of the peptides are vasoactive and can cause vasodilation, resulting in flushing. They can also cause wheezing, diarrhea, excessive salivation, or fibrosis of the heart valves or other tissues.
Serotonin production is characteristic of gut carcinoid tumors. Serotonin is metabolized to 5-HIAA. Therefore, finding high levels of 5-HIAA in a 24-hour urine collection in a patient with flushing or other symptoms is highly suggestive of the diagnosis. Bronchial carcinoids rarely produce 5-HIAA and, therefore, rarely present with carcinoid syndrome; instead, they often produce ectopic ACTH, resulting in the Cushing syndrome.
Adenomas are thought to be related to colorectal carcinoma by means of stepwise genetic alterations (or hits), with adenomas representing a precancerous lesion that may ultimately progress to cancer. It is believed that stepwise genetic alterations, including both oncogene activation and tumor suppressor gene inactivation, result in phenotypic changes that progress to neoplasia.
Two principal lines of evidence support the model of stepwise genetic alterations in colon cancer: (1) Familial colon cancer syndromes are known to result from germline mutations, implicating a genomic cause. Familial adenomatous polyposis is the result of a mutation in the APC gene, whereas hereditary nonpolyposis colorectal carcinoma is associated with mutations in the DNA repair genes hMSH2 and hMLH1. (2) Several factors linked to an increased risk of colon cancer are known to be carcinogenic. Substances derived from bacterial colonic flora, foods, or endogenous metabolites are known to be mutagenic. Levels of these substances can be decreased by taking a low-fat, high-fiber diet. Epidemiologic studies suggest that such a change in diet might reduce the risk of colon cancer.
The earliest molecular defect in the pathogenesis of colon cancer is the acquisition of somatic mutations in the APC gene in the normal colonic mucosa. This defect causes abnormal regulation of β-catenin, which leads to abnormal cell proliferation and the initial steps in tumor formation. Subsequent defects in the TGF-β signaling pathway inactivate this important growth inhibitory pathway and lead to further tumor mucosal proliferation and the development of small adenomas. Mutational activation of the K-ras gene leads to constitutive activation of an important proliferative signaling pathway and is common at these stages. It further increases the proliferative potential of the adenomatous tumor cells. Deletion or loss of expression of the DCC gene is common in the progression to invasive colon cancers. The DCC protein is a transmembrane protein of the immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth or apoptosis. Mutational inactivation of p53 is also a commonly observed step in the development of invasive colon cancer, seen in late adenomas and early invasive cancers, and leads to loss of an important cell cycle checkpoint and inability to activate the p53-dependent apoptotic pathways. In parallel to these sequential abnormalities in the regulation of cell proliferation, colon cancers also acquire defects in mechanisms that protect genomic stability. These generally involve mutations in mismatch repair genes or genes that prevent chromosomal instability, including MSH2, MLH1, PMS1, and PMS2. Germline mutations in these genes cause the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Nonhereditary colon cancers develop genomic instability through defects in the chromosomal instability (CIN) genes. Defects in these genes lead to the gain or loss of large segments or entire chromosomes during replication, leading to aneuploidy.
Early in the progression of dysplasia, disrupted architecture results in the formation of fragile new blood vessels and destruction of existing blood vessels. These changes often occur before invasion of the basement membrane and, therefore, before progression to true cancer formation. These friable vessels can cause microscopic bleeding. This can be tested for by fecal occult blood testing, an important tool in the early detection of precancerous and cancerous colonic lesions.
Linkage analysis has identified genetic markers that are known to confer a high risk of developing breast cancer. Two such genes in particular have been found, BRCA1 and BRCA2. Both are involved in repair of DNA. Inherited mutations of BRCA1 or BRCA2 are associated with a lifetime risk of developing breast cancer of up to 80%. Mutations in these genes are also associated with a high incidence of ovarian cancer and can lead to increased incidences of prostate cancer, melanoma, and breast cancer in males.
There are two major subtypes of breast cancer. Ductal carcinomas arise from the collecting ducts in the breast glandular tissue. Lobular carcinomas arise from the terminal lobules of the glands.
While it is still contained by the basement membrane, the tumor is called carcinoma in situ. Invasive carcinoma occurs when tumor cells breach the basement membrane. Both ductal and lobular carcinomas may be either in situ or invasive. By definition, an in situ tumor does not carry a risk of spreading to the lymph nodes or of creating distant metastases. Finding an in situ tumor raises the affected individual’s risk of developing a subsequent breast cancer, in either breast, and of either subtype. Therefore, carcinoma in situ is a marker of heightened susceptibility to developing invasive breast cancer.
There are specific therapies that target receptors present in breast cancer. The amount of estrogen exposure is correlated with breast cancer risk. Antiestrogen therapy has long been used with success in patients with estrogen receptor–positive breast cancer, although half of patients diagnosed with breast cancer are estrogen receptor–negative. More recently, antibodies that target the HER2 receptor, a tyrosine kinase growth factor receptor, are used in tumors with an overexpression of the HER2 receptor.
Testicular cancer arises from germinal elements within the testes. Germ cells give rise to spermatozoa and thus can theoretically retain the ability to differentiate into any cell type. The pluripotent nature of these cells is witnessed in the production of mature teratomas. These benign tumors often contain mature elements of all three germ cell layers, including hair and teeth.
During early embryogenesis, germline epithelium migrates along the midline of the embryo. This migration is followed by formation of the urogenital ridge and ultimately the aggregation of germline cells to form the testes and ovaries. The pattern of migration of the germline epithelium predicts the location of extragonadal testicular neoplasms. These neoplasms are found in the midline axis of the lower cranium, mediastinum, and retroperitoneum.
One can monitor the serum concentrations of proteins expressed during embryonic or trophoblastic development to monitor tumor progression and response to therapy. These proteins include alpha-fetoprotein and human chorionic gonadotropin.
Sarcomas arise from mesenchymal tissue. These include myocytes, adipocytes, osteoblasts, chondrocytes, fibroblasts, endothelial cells, and synovial cells.
Many sarcomas are more common in younger people. This is thought to be because the cells of origin such as chondrocytes or osteoblasts are dividing more rapidly in childhood and adolescence than in adulthood.
Because osteosarcomas arise from osteoblasts, they retain their ability to produce a bone matrix of calcium and phosphorus within the tumor.
The theory that chronic immune stimulation or modulation may play an early role in the formation of lymphoma is supported by several observations. Iatrogenic immunosuppression, as seen in this patient and in other transplant patients, can increase the risk of B-cell lymphoma, possibly associated with Epstein-Barr virus infection. An increased risk of lymphoma is also seen in other immunosuppressed patients, such as those with AIDS and autoimmune diseases.
This patient has been diagnosed with a follicular cleaved cell lymphoma, a well-differentiated or low-grade lymphoma. Low-grade lymphomas retain the morphology and patterns of gene expression of mature lymphocytes, including cell surface markers such as immunoglobulin in the case of B lymphocytes. Their clinical course is generally more favorable, being characterized by a slow growth rate. Paradoxically, however, these lymphomas tend to present at a more advanced stage, as in this case.
Follicular lymphomas arise from lymphoblasts of the B-cell lineage. Common chromosomal abnormalities include translocations of chromosome 14, including t(14;18), t(11;14), and t(14;19). The t(14;18) translocation results in a fusion gene known as IgH;bcl-2, which juxtaposes the immunoglobulin heavy chain enhancer on chromosome 14 in front of the bcl-2 gene on chromosome 18. This results in enhanced expression of an inner mitochondrial protein encoded by bcl-2, which has been found to inhibit the natural process of cell death, or apoptosis. Apoptosis is required to remove certain lymphoid clones whose function is not needed. Inhibition of this process probably contributes to proliferation of lymphoma cells.
This patient’s symptoms of fever and weight loss are known as B symptoms. They are thought to be mediated by a variety of cytokines produced by lymphoma cells or may occur as a reaction of normal immune cells to the lymphoma. Two commonly implicated cytokines are IL-1 and TNF.
Like all neoplasms, leukemias are classified by their cell of origin. The first branch point is whether the malignant cell is of myeloid or lymphoid lineage, resulting in either a myeloid or lymphocytic leukemia. All types can be acute, presenting with more than 20% blasts on bone marrow biopsy, or chronic, presenting in a more indolent fashion with a usually slowly progressive course of many years. Lymphocytic leukemias are further divided into T-cell or B-cell leukemias depending on the type of lymphoid cell of origin. This type can be distinguished by the cluster of differentiation (CD) antigens found on the surface of the tumor cells. Myeloid leukemias are also divided into subtypes depending on the type of myeloid cell from which the leukemia arises. AML types M1–M3 arise from myeloblasts. Types M4 and M5 arise from monocytes. Type M6 arises from erythrocyte precursors, called normoblasts. Type M7 arises from platelet precursors, called megakaryoblasts.
Acute leukemias typically present with pancytopenia, or a decrease in the counts of all of the normal blood cells, including the normal white cells (the leukemic cells accounting for almost all of the high total WBCs), red blood cells, and platelets. This is caused by the crowding out of normal precursors in the bone marrow by the abnormally dividing blast cells, and by the inhibition of normal hematopoiesis due to secretion of cytokines and inhibitory substances. The patient’s presenting symptoms are directly related to the blood abnormalities. The fatigue and pallor are due to the anemia (lack of red blood cells) and the resulting reduced oxygen-carrying capacity. The petechiae and bleeding are from the lack of platelets, inhibiting the ability of the blood to clot. Patients with leukemia are susceptible to serious infections due to the lack of normal WBCs. Finally, the markedly elevated numbers of leukemic cells can clog small blood vessels and result in strokes, retinal vein occlusion, and pulmonary infarction.
Chromosomal deletions, duplications, and translocations have been identified in leukemias. One such genetic abnormality is the so-called Philadelphia chromosome, a balanced translocation of chromosomes 9 and 22, that is commonly found in chronic myelogenous leukemia (CML). This translocation results in a fusion gene, bcr-abl, which encodes a kinase that phosphorylates key proteins involved in cell growth. Targeted therapies that inhibit the enzymatic function of the bcr-abl kinase by competing with the ATP-binding site, induce remissions in most patients in chronic phases of CML.
The most likely cause of anemia in this patient is iron deficiency. Iron deficiency anemia is the most common form of anemia. In developed nations, it is primarily the result of iron loss, almost always through blood loss. In men and in postmenopausal women, blood is most commonly lost from the GI tract, as in this case. In premenopausal women, menstrual blood loss is the major cause of iron deficiency.
In this man, there are no symptoms of significant bleeding from the gut as would be manifested by gross blood (hematochezia) or metabolized blood in the stool (melena, usually described as black-colored stool), and he has no GI complaints. This makes some of the benign GI disorders such as peptic ulcer, arteriovenous malformations, and angiodysplasias less likely. He has no symptoms of inflammatory bowel disease such as diarrhea or abdominal pain. Concern is thus aroused about possible malignancy, particularly colon cancer.
When no source of bleeding is uncovered, GI malabsorption should be considered as a possible cause of iron deficiency anemia. Such malabsorption occurs in patients with celiac disease, H pylori infection, partial gastrectomy, or gastric bypass surgery. Other mechanisms of iron deficiency anemia include intravascular hemolysis (paroxysmal nocturnal hemoglobinuria or cardiac valvular disease) and response to erythropoietin treatment.
Blood loss results in anemia via a reduction in heme synthesis. With loss of blood comes loss of iron, the central ion in the oxygen-carrying molecule, heme. When there is iron deficiency, the final step in heme synthesis, during which ferrous iron is inserted into protoporphyrin IX, is interrupted, resulting in inadequate heme synthesis. Globin biosynthesis is inhibited by heme deficiency through a heme-regulated translational inhibitor (HRI). Elevated HRI activity (a result of heme deficiency) inhibits a key transcription initiation factor for heme synthesis, eIF2. Thus, there are both less heme and fewer globin chains available in each red cell precursor. This directly causes anemia, a decrease in the hemoglobin concentration of the blood.
In this symptomatic man, the peripheral blood smear is likely to be significantly abnormal. As the hemoglobin concentration of individual red blood cells falls, the cells take on the classic picture of microcytic (small), hypochromic (pale) erythrocytes. There is also apt to be anisocytosis (variation in size) and poikilocytosis (variation in shape), with target cells. The target cells occur because of the relative excess of red cell membrane compared with the amount of hemoglobin within the cell, leading to “bunching up” of the membrane in the center.
Laboratory tests may be ordered to confirm the diagnosis. The most commonly ordered test is serum ferritin, which, if low, is diagnostic of iron deficiency. Results may be misleading, however, in acute or chronic inflammation and severe illness. Because ferritin is an acute-phase reactant, it can rise in these conditions, resulting in a normal ferritin level. Serum iron and transferrin levels can also be misleading because these levels can fall not only in anemia but also in many other illnesses. Typically in iron deficiency, however, serum iron levels are low, whereas total iron-binding capacity (TIBC) is elevated. The ratio of serum iron to TIBC is less than 20% in uncomplicated iron deficiency. Serum (soluble) transferrin receptor (TfR), released by erythroid precursors, is elevated in iron deficiency. A high ratio of TfR to ferritin may predict iron deficiency when ferritin is not diagnostically low. Though helpful, this test has seen limited use in clinical practice.
Occasionally, when blood tests are misleading, a bone marrow biopsy is performed to examine for iron stores. Iron is normally stored as ferritin in the macrophages of the bone marrow and is stained blue by Prussian blue stain. A decrease in the amount of iron stores on bone marrow biopsy is diagnostic of iron deficiency. More commonly, however, the response to an empiric trial of iron supplementation is used to determine the presence of iron deficiency in complicated cases.
Fatigue, weakness, and shortness of breath are the direct results of decreased oxygen-carrying capacity, which leads to decreased oxygen delivery to metabolically active tissues, causing this patient’s symptoms. He is pale because there is less oxygenated hemoglobin per unit of blood, and oxygenated hemoglobin is red, giving color to the skin. Pallor results also from a compensatory mechanism whereby superficial blood vessels constrict, diverting blood to more vital structures.
The probable cause of this woman’s anemia is vitamin B12 (cobalamin) deficiency, which is characterized by anemia, glossitis, and neurologic impairment. Vitamin B12 deficiency results in anemia via effects on DNA synthesis. Cobalamin is a crucial cofactor in the synthesis of deoxythymidine from deoxyuridine. Cobalamin accepts a methyl group from methyltetrahydrofolate, leading to the formation of methylcobalamin and reduced tetrahydrofolate. Methylcobalamin is required for the production of the amino acid methionine from homocysteine. Reduced tetrahydrofolate is required as the single-carbon donor in purine synthesis. Thus, cobalamin deficiency depletes stores of tetrahydrofolate, lowering purine production and impairing DNA synthesis. Impaired DNA synthesis results in decreased production of red blood cells. It also causes megaloblastic changes in the blood cells in the bone marrow. These cells are subsequently destroyed in large numbers by intramedullary hemolysis. Both processes result in anemia.
The peripheral blood smear varies depending on the duration of cobalamin deficiency. In this patient, because she is profoundly symptomatic, we would expect a full-blown megaloblastic anemia. The peripheral smear would have significant anisocytosis and poikilocytosis of the red cells as well as hypersegmentation of the neutrophils. In severe cases, morphologic changes in peripheral blood cells may be difficult to differentiate from those seen in leukemia.
Other laboratory tests that may be ordered include a lactate dehydrogenase (LDH) level and indirect bilirubin determination. Both should be elevated in cobalamin deficiency, reflecting the intramedullary hemolysis that occurs in vitamin B12 deficiency. Serum vitamin B12 would be expected to be low. Yet there remain high rates of both false-positive and false-negative tests due to the fact that only 20% of total measured serum B12 is bound to the cellular delivery protein, transcobalamin; the rest is bound to haptocorrin, which is not available for cells to utilize. Antibodies to intrinsic factor are usually detectable. Concurrent elevations of both serum methylmalonic acid and serum homocysteine are highly predictive of B12 deficiency.
The various causes of megaloblastic anemia can often be differentiated by a Schilling test. This test measures the oral absorption of radioactively labeled vitamin B12 with and without added intrinsic factor, thereby directly evaluating the mechanism of the vitamin deficiency. It must be performed after cobalamin stores have been replenished.
Pernicious anemia is caused by autoimmune destruction of the gastric parietal cells, which are responsible for production of stomach acid and intrinsic factor. Autoimmune destruction of these cells leads to achlorhydria (loss of stomach acid), which is required for release of cobalamin from foodstuffs. The production of intrinsic factor decreases. Intrinsic factor is required for the effective absorption of cobalamin by the terminal ileum. Together these mechanisms result in vitamin B12 deficiency.
The evidence that parietal cell destruction is autoimmune in nature is strong. Pathologically, patients with pernicious anemia demonstrate gastric mucosal atrophy with infiltrating lymphocytes, predominantly antibody-producing B cells. Furthermore, more than 90% of patients with this disease demonstrate antibodies to parietal cell membrane proteins, primarily to the proton pump. More than half of patients also have antibodies to intrinsic factor or to the intrinsic factor–cobalamin complex. These patients also have an increased risk of other autoimmune diseases.
The patient’s tachycardia is probably a reflection of profound anemia. Unlike many other causes of anemia, pernicious anemia often leads to very severe decreases in the hemoglobin concentration. This results in a marked decrease in the oxygen-carrying capacity of the blood. The only way to increase oxygenation to metabolically active tissues is to increase cardiac output. This is accomplished by raising the heart rate. Over time, the stresses this puts on the heart can result in high-output heart failure.
The neurologic manifestations—paresthesias and impaired proprioception—seen in this patient are caused by demyelination of the peripheral nerves and posterolateral spinal columns, respectively. The lack of methionine caused by vitamin B12 deficiency appears to be at least partly responsible for this demyelination, but the exact mechanism is unknown. Demyelination eventually results in neuronal cell death. Therefore, neurologic symptoms may not be improved by treatment of the vitamin B12 deficiency.
Classic, childhood-onset cyclic neutropenia results from mutations in the gene for a single enzyme, neutrophil elastase. Most cases reflect an autosomal dominant inheritance; however, sporadic adult cases also occur, and these are associated with neutrophil elastase mutations as well.
Studies of neutrophil kinetics in affected patients reveal that the gene defect results in abnormal production—rather than abnormal disposition—of neutrophils. In cyclic neutropenia, it is hypothesized that the mutant neutrophil elastase may have an overly inhibitory effect, causing prolonged trough periods and inadequate storage pools to maintain a normal peripheral neutrophil count. This production defect affects other cell lines as well, resulting in cyclic depletion of all storage pools. Because development of neutrophils from progenitor stage to maturity takes 2 weeks and the life span is only 12 days, depletion of the neutrophil cell line becomes clinically apparent. The other cell lines have longer life spans, and although they too undergo cyclic decreases in production, these decreases do not become clinically apparent.
The exact cause of the relationship between the cyclic waves of maturation and the neutrophil elastase mutation is not known. Because multiple cell lines are seen to cycle, it is believed that neutrophil elastase mutations accelerate the process of apoptosis (programmed cell death) in early progenitor cells unless they are “rescued” by granulocyte colony-stimulating factor (G-CSF). Some evidence suggests that neutrophil elastase can antagonize G-CSF action, but the relationship of mutated neutrophil elastase to G-CSF action in cyclic neutropenia is not well understood.
Clinically, administration of pharmacologic doses of G-CSF (filgrastim) to affected individuals has three interesting effects that partially overcome the condition. First, although cycling continues, mean neutrophil counts increase at each point in the cycle, such that patients are rarely neutropenic. Second, cycling periodicity decreases immediately from 21 days to 14 days. Third, other cell line fluctuations change in parallel; their cycle periodicity also decreases to 14 days, suggesting that an early progenitor cell is indeed at the center of this illness. However, the fact that cycling does not disappear demonstrates that there are other abnormalities yet to be discovered. It also suggests that there may be an inherent cycling of all stem cells in normal individuals, which is modulated by multiple cytokines in the marrow.
The periodic neutropenia with spontaneous remission seen in this patient is characteristic of cyclic neutropenia. In this disease, patients develop a drop in neutrophil count approximately every 3 weeks (19–22 days), with nadirs (low neutrophil counts) lasting 3–5 days. Patients are generally well during periods when the neutrophil cell count is normal and become symptomatic as the counts drop below 250/μL. Neutrophils are responsible for a significant portion of the immune system’s response to both bacterial and fungal infections. Thus, the primary clinical manifestation of cyclic neutropenia is recurrent infection. Each nadir is usually characterized by symptoms of fever and malaise. Cervical lymphadenopathy and oral ulcers, as seen in this patient, are also common. Life-threatening bacterial and fungal infections are uncommon but can occur, particularly as a result of infection from endogenous gut flora. More commonly, however, patients develop skin infections and chronic gingivitis.
The peripheral blood smear should be normal except for a paucity of neutrophils. Those neutrophils present would be normal in appearance. The bone marrow, however, would be expected to show increased numbers of myeloid precursors such as promyelocytes and myelocytes. Mature neutrophils would be rare. If marrow examination were repeated in 2 weeks—after neutrophil counts have improved—the results would be normal.
The most likely diagnosis in this patient is drug-associated immune thrombocytopenia. Many drugs—but most commonly heparin—have been associated with this phenomenon. There is a 10-fold increased risk for heparin-induced thrombocytopenia (HIT) in patients receiving unfractionated heparin (UFH) compared with those receiving low-molecular-weight heparin (LMWH). Cardiac or orthopedic surgery patients have a higher risk for clinical HIT (1–5%) than medical or obstetric patients (0.1–1%) when receiving UFH. Women have twice the risk for HIT as men.
Heparin leads to thrombocytopenia via two distinct mechanisms, both involving antibodies. It appears that heparin can bind to a platelet-produced protein, platelet factor 4 (PF4), which is released by platelets in response to activation. The heparin-PF4 complex acts as an antigenic stimulus, provoking the production of IgG. IgG can then bind to the complex, forming IgG-heparin-PF4. The new complex can bind to platelets via the Fc receptor of the IgG molecule or via the PF4 receptor. This binding can lead to two distinct phenomena. The first is platelet destruction by the spleen. Antibody adherence to the platelets changes their shape, causing the spleen to recognize them as abnormal and destroy them. This leads to simple thrombocytopenia, with few sequelae.
The second phenomenon is platelet activation, which can lead to more significant sequelae. After formation of an IgG-heparin-PF4 complex, both IgG and PF4 can bind to platelets. The platelets can become cross-linked, leading to platelet aggregation. This decreases the number of circulating platelets, leading to thrombocytopenia. However, it may also lead to the formation of thrombus, or “white clot.”
Even though the platelet count in drug-associated immune thrombocytopenia may be very low, significant bleeding is unusual. Most commonly, the primary manifestation is easy bruising, and, at platelet counts less than 5000/μL, petechiae may be seen on the skin or mucous membranes. When actual bleeding does occur, it is generally mucosal in origin, such as nosebleed, gingival bleeding, or GI blood loss.
As noted, when thrombocytopenia is due to heparin, paradoxical clotting may occur instead of bleeding. Thrombus formation often occurs at the site of previous vascular injury or abnormality and can present as either arterial or venous thrombosis.
The Virchow triad consists of three possible contributors to the formation of a clot: decreased blood flow, blood vessel injury or inflammation, and changes in the intrinsic properties of the blood. This patient has no history of immobility or other cause of decreased blood flow. She does, however, have a history of blood vessel injury (ie, deep vein thrombosis). Despite the absence of symptoms of a lower extremity thrombus, this is still the most likely site of origin of the pulmonary embolus. Finally, the recurrence now of thrombus formation along with the family history of clots is suggestive of a change in the intrinsic properties of the blood, as seen in the inherited hypercoagulable states.
The most common hypercoagulable states include activated protein C resistance (factor V Leiden), protein C deficiency, protein S deficiency, antithrombin III deficiency, and hyperprothrombinemia (prothrombin gene mutation). Except for hyperprothrombinemia, each of these results in clot formation because of a lack of adequate anticoagulation rather than overproduction of procoagulant activity; hyperprothrombinemia is caused by excess thrombin generation.
The most common site of the problem in the coagulation cascade is at factor Va, which is required for the formation of the prothrombinase complex with factor Xa, which leads to the thrombin burst and fibrin generation during hemostasis. Protein C is the major inhibitor of factor Va. It acts by cleaving factor V into an inactive form, thereby slowing the activation of factor X. The negative effect of protein C is enhanced by protein S. Quantitative or qualitative reduction in either of these two proteins thus results in the unregulated procoagulant action of factor Xa.
Activated protein C resistance is the most common inherited hypercoagulable state. It results from a mutation in the factor V gene. This mutation alters the three-dimensional conformation of the cleavage site within factor Va, where protein C usually binds. Protein C is then unable to bind to factor Va and is, therefore, unable to inactivate it. Coagulation is not inhibited.
Antithrombin inhibits the coagulation cascade at an alternative site. It inhibits the serine proteases: factors II, IX, X, XI, and XII. Deficiency of antithrombin results in an inability to inactivate these factors, allowing the coagulation cascade to proceed unrestrained at multiple coagulation steps.
Hyperprothrombinemia is the second most common hereditary hypercoagulable state and the only one so far recognized as being due to overproduction of procoagulant factors. It is caused by a mutation of the prothrombin gene that leads to elevated prothrombin levels. The increased risk of thrombosis is thought to be due to excess thrombin generation when the Xa-Va-Ca2+-PL complex is activated.
This patient may be evaluated by various laboratory tests for the presence of an inherited hypercoagulable state. Quantitative evaluation of the relative amounts of protein C, protein S, and antithrombin can be performed. Qualitative tests that assess the ability of these proteins to inhibit the coagulation cascade can be measured via clotting assays. The presence of the specific mutation in factor V Leiden can be assessed via polymerase chain reaction testing.
The most common form of motor neuron disease in adults is amyotrophic lateral sclerosis (ALS), in which mixed upper and lower motor neuron deficits are found in limb and bulbar muscles. In 80% of patients, the initial symptoms are due to weakness of limb muscles. Complaints are often bilateral but asymmetric. Involvement of bulbar muscles causes difficulty with swallowing, chewing, speaking, breathing, and coughing. Neurologic examination reveals a mixture of upper and lower motor neuron signs. There is usually no involvement of extraocular muscles or sphincters. The disease is progressive and generally fatal within 3–5 years, with death usually resulting from pulmonary infection and respiratory failure.
In ALS, there is selective degeneration of motor neurons in the primary motor cortex and the anterolateral horns of the spinal cord. Many affected neurons show cytoskeletal disease with accumulations of intermediate filaments in the cell body and in axons. There is only a subtle glial cell response and little evidence of inflammation.
There are several theories concerning the molecular pathogenesis of ALS. Glutamate is the most abundant excitatory neurotransmitter in the CNS and functions to generate an excitatory postsynaptic potential and raise the concentration of free intracellular Ca2+ in the cytosol of the postsynaptic neuron. This Ca2+ signal activates calcium-sensitive enzymes and is quickly terminated by removal of glutamate from the synapse and by mechanisms for calcium sequestration and extrusion in the postsynaptic cell. In 60% of patients with sporadic ALS, there is a large decrease in glutamate transport activity in the motor cortex and spinal cord, but not in other regions of the CNS. This has been associated with a loss of the astrocytic glutamate transporter protein excitatory amino acid transporter 2 (EAAT2), perhaps resulting from a defect in splicing of its messenger RNA. In cultured spinal cord slices, pharmacologic inhibition of glutamate transport induces motor neuron degeneration.
About 10% of ALS cases are familial and 20% of these familial cases are due to missense mutations in the cytosolic copper-zinc superoxide dismutase (SOD1) gene on the long arm of chromosome 21. SOD1 catalyzes the formation of hydrogen peroxide from superoxide anion. Hydrogen peroxide is then detoxified by catalase or glutathione peroxidase to form water. Not all mutations reduce SOD1 activity, and the disorder is typically inherited as an autosomal dominant trait, suggesting that familial ALS results from a gain of function rather than a loss of function of the SOD1 gene product. One hypothesis suggests that the mutant enzyme has an altered substrate specificity catalyzing the reduction of hydrogen peroxide to yield hydroxyl radicals and utilizing peroxynitrite to produce nitration of tyrosine residues in proteins.
A role for neurofilament dysfunction in ALS is supported by the finding that neurofilamentous inclusions in cell bodies and proximal axons are an early feature of ALS pathology. In addition, mutations in the heavy chain neurofilament subunit (NF-H) have been detected in some patients with sporadic ALS, suggesting that NF-H variants may be a risk factor for ALS.
An exciting discovery of the protein transactive response DNA-binding protein 43 (TDP 43) may offer new clues to the etiology of this disorder. This newly discovered protein is the major component of the ubiquitinated, tau-negative inclusions that are the pathological hallmark of sporadic and familial ALS and frontotemporal dementia (FTD). It is also found in some cases of Alzheimer disease and Parkinson disease. Mutations in this gene, which is located on chromosome 1, co-segregate with disease in familial forms of ALS and FTD and are not found in SOD1 familial ALS. FTD and ALS overlap in approximately 15–25% of cases, and these disorders are starting to be referred to as “TDP-43 proteinopathies.” Several other genes and gene regions have been identified to cause both FTD and ALS such as TARDBP on chromosome 1p36.2, MAPT on chromosome 7q21, and DCTN1 on chromosome 2p13.
The major genetic cause of ALS and/or FTD was recently discovered. Two independent groups identified hexanucleotide repeats in an intron of C9ORF72 on chromosome 9 in 34% of familial ALS cases, 6% of sporadic ALS cases, 26% of familial FTD cases, and 5% of sporadic FTD cases. The protein is of unknown function. These mutations likely induce a gain-of-function mutation similar to other noncoding repeat-expansion disorders. This discovery of another disorder caused by nucleotide repeats provides an additional rationale for the development of one or more new drugs focused on decreasing expression of these toxic repeats.
This patient has parkinsonism. The resting tremor (which improves with activity), “cog-wheeling” rigidity, and difficulty with gait (especially with initiation of walking and with changing direction) are all characteristic of parkinsonism. While there are many causes of parkinsonism, including toxins, head trauma, drugs, encephalitis, and other degenerative diseases, the most common cause is Parkinson disease, an idiopathic degenerative neurological disorder.
Parkinson disease results from selective degeneration of the monoamine-containing neurons in the basal ganglia and brainstem, particularly the pigmented dopaminergic neurons of the substantia nigra. This region is involved in regulation of movement, particularly in initiating and stopping actions. In addition to the degeneration of the dopaminergic neurons, scattered neurons elsewhere contain eosinophilic cytoplasmic inclusion bodies, called Lewy bodies.
Through studies of familial cases of Parkinson disease as well as parkinsonism produced by toxins, some of the molecular processes involved have been discovered. One cause of parkinsonism is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that was once a contaminant in illicit opioid drugs. It caused parkinsonism by being metabolized to N-methyl-4-phenylpyridinium (MPP+), which was taken up through dopamine uptake sites on dopamine nerve terminals and concentrated in mitochondria. This led to disturbed mitochondrial function and ultimately to cell death.
In familial cases of Parkinson disease, there have been several mutations identified involving genes encoding several proteins: parkin, alpha-synuclein, DJ-1, ubiquitin, and PTEN-induced kinase. Mutations in the glucocerebrosidase (GCase) enzyme account for 3% of sporadic Parkinson disease cases and 25% of juvenile-onset Parkinson disease cases. This enzyme is involved in lysosomal processing. The enzyme activity is reduced by 58% in the substantia nigra of heterozygous patients and 33% lower in sporadic Parkinson disease patients. Inhibiting this enzyme leads to accumulation of α-synuclein, which leads to further inhibition of this enzyme. These mutations are being studied to find clues about the molecular mechanisms involved in the pathogenesis of Parkinson disease.
The most likely diagnosis in this patient is myasthenia gravis, a disease characterized by fluctuating fatigue and weakness of muscles with small motor units, particularly the ocular muscles. Myasthenia gravis is an autoimmune disorder resulting in simplification of the postsynaptic region of the neuromuscular end plate.
Patients with this disease have lymphocytic infiltration at the end plate plus antibody and complement deposition along the postsynaptic membrane. Circulating antibodies to the receptor are present in 90% of patients, blocking acetylcholine binding and activation. The antibodies can cross-link the receptor molecules, leading to receptor internalization and degradation. They also activate complement-mediated destruction of the postsynaptic region, resulting in simplification of the end plate.
Many patients who lack antibodies to the acetylcholine receptor instead have autoantibodies against the muscle-specific receptor tyrosine kinase, which is an important mediator of acetylcholine receptor clustering at the end plate. These antibodies inhibit clustering of receptors in muscle cell culture. Thus, patients with myasthenia gravis have impaired ability to respond to acetylcholine release from the presynaptic membrane.
Referred to as double-sero-negative patients, some myasthenia gravis patients have no antibodies for either acetylcholine receptor antibodies or MuSK. Recently, a new antibody has been found in 50% of these patients. Antibodies to lipoprotein-related protein 4 (LRP4), which is the agrin-binding receptor of the MuSK complex, disrupt agrin-induced acetylcholine receptor clustering, causing the disease symptoms. The clinical presentation of these patients is similar to that of patients with acetylcholine receptor myasthenia gravis without thymoma.
Muscles with small motor units are most affected in myasthenia gravis. The ocular muscles are most frequently affected; oropharyngeal muscles, flexors and extensors of the neck and proximal limbs, and erector spinae muscles are next most commonly involved. In severe cases and without treatment, the disease can progress to involve all muscles, including the diaphragm and intercostal muscles, resulting in respiratory failure.
Normally, the number of quanta of acetylcholine released from the nerve terminal decreases with repetitive stimuli. There are usually no clinical consequences of this decrease because a sufficient number of acetylcholine receptor channels are opened despite the reduced amount of neurotransmitter. In myasthenia gravis, however, there is a deficiency in the number of acetylcholine receptors. Therefore, as the number of quanta released decreases, there is a decremental decline in neurotransmission at the neuromuscular junction. This is manifested clinically as muscle fatigue with sustained or repeated activity.
Myasthenia gravis is associated both with a family history of autoimmune disease and with the presence of coexisting autoimmune diseases. Hyperthyroidism, rheumatoid arthritis, systemic lupus erythematosus, and polymyositis are all seen with increased frequency in these patients. These patients also have a high incidence of thymic disease; most demonstrate thymic hyperplasia and 10–15% have thymomas.
There are two basic strategies for treating this disease: decreasing the immune-mediated destruction of the acetylcholine receptors and increasing the amount of acetylcholine available at the neuromuscular junction. As noted previously, many patients with myasthenia gravis demonstrate disease of the thymus gland. The thymus is thought to play a role in the pathogenesis of myasthenia gravis by supplying helper T cells that are sensitized to thymic nicotinic receptors. Removal of the thymus in patients with generalized myasthenia gravis can improve symptoms and even induce remission. Plasmapheresis, corticosteroids, and immunosuppressant drugs can all be used to reduce the levels of antibody to acetylcholine receptors, thereby suppressing disease. Increasing the amount of acetylcholine available at the neuromuscular junction is accomplished by the use of cholinesterase inhibitors. Cholinesterase is responsible for the breakdown of acetylcholine at the neuromuscular junction. By inhibiting the breakdown of acetylcholine, cholinesterase inhibitors can compensate for the normal decline in released neurotransmitter during repeated stimulation and thus decrease symptoms.
The characteristic pathologic finding in Alzheimer disease (AD) is the finding of neuritic plaques, made of a dense amyloid core surrounded by dystrophic neuritis, reactive astrocytes, and microglia. There are also neurofibrillary tangles, synaptic loss, and neuronal loss. Interestingly, the severity of disease does not correlate with plaque number.
In neurological disorders, the location of the lesion predicts what function will be affected. In AD, the neuritic plaques are most prominent in the hippocampus, entorhinal cortex, association cortex, and basal forebrain. These are areas involved in memory and higher order cortical functions such as judgment and insight. This explains why memory loss, poor judgment, and denial are such common presenting symptoms. In contrast, the motor and sensory cortexes are not prominently affected, and thus loss of motor and sensory function is not present until much later in the course of the disease.
The major protein in neuritic plaques is amyloid beta-peptide. This is a protein derived from beta-amyloid precursor protein (APP) that is encoded by a gene on chromosome 21. Increased production of APP results in increased amyloid beta-peptide, which is known to be toxic to cultured neurons. Individuals who produce excess APP, such as people with trisomy 21 or families with inherited mutations of the APP gene, develop early onset AD.
Currently, there is no role for genetic testing for AD. Only about 10% of the cases of AD are familial, and in these cases, several different mutations have been identified in affected families. It has also been recognized that individuals with a subtype 4 of apolipoprotein E have an increased risk of developing AD. However, 15% of the population carries this subtype, and most cases of AD develop in people who do not carry this subtype. Even among carriers, many never develop AD. Therefore, testing for it is not recommended.
Generalized tonic-clonic seizures are characterized by sudden loss of consciousness followed rapidly by tonic contraction of the muscles, causing extension of the limbs and arching of the back. This phase lasts approximately 10–30 seconds and is followed by a clonic phase of limb jerking. The jerking builds in frequency, peaking after 15–30 seconds, and then gradually slows over another 15–30 seconds. The patient may remain unconscious for several minutes after the seizure. This is generally followed by a period of confusion lasting minutes to hours.
Recurrent seizures are in many cases idiopathic, particularly those seen in children. Seizures may also be due to brain injury from trauma, stroke, mass lesion, or infection. Finally, one must consider metabolic causes such as hypoglycemia, electrolyte abnormalities, and alcohol withdrawal. The cause of this patient’s seizure is unknown because of the lack of an available history. However, because he has focal neurologic findings, with decreased movement of his left side, one must suspect an underlying brain lesion in the right cerebral hemisphere.
Seizures occur when neurons are activated synchronously. The kind of seizure depends on the location of the abnormal activity and the pattern of spread to different parts of the brain. The formation of a seizure focus in the brain may result from disruption of normal inhibitory circuits. This disruption may occur because of alterations in ion channels or from injury to inhibitory neurons and synapses. Alternatively, a seizure focus may be formed when groups of neurons become synchronized by reorganization of neural networks after brain injury. After formation of a seizure focus, local discharge may then spread. This spread occurs by a combination of mechanisms. After synchronous depolarization of abnormally excitable neurons—known as the paroxysmal depolarizing shift—extracellular potassium accumulates, depolarizing nearby neurons. Increased frequency of depolarization then leads to increased calcium influx into nerve terminals. This increases neurotransmitter release at excitatory synapses by a process known as posttetanic potentiation, whereby normally quiescent voltage-gated and N
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