Coombs and Gell classification

Typ
e

Comparison of hypersensitivity types

Often mentioned
Alternative names
Mediators
disorders

I Allergy (immediate)

Atopy

Anaphylaxis

Asthma

Description

Fast response
which occurs
in minutes
rather than
multiple
hours or days.
Free antigens
cross link the
IgE on mast
cells and
basophils
IgE and IgG4
which causes
a release of
vasoactive
biomolecules.
Testing can
be done via
skin test for
specific IgE.
[2]

II Cytotoxic, antibodydependent

Autoimmune
hemolytic anemia

Thrombocytopenia

Erythroblastosis
fetalis

Goodpasture's
syndrome

Membranous
nephropathy

Antibody
(IgM or IgG)
IgM or IgG
binds to
(Complement) antigen on
foreign cell
leading to
MAC
cellular
destruction
via the MAC.
Testing
includes both
the direct and
indirect
Coombs test.
[3]

Graves' disease
*see type V
explanation below

III

Immune complex
disease

Delayed-type
hypersensitivity[2][3]
(DTH), cell-mediated
IV
immune memory
response, antibodyindependent

Myasthenia Gravis
*see type V
explanation below

Serum sickness

Arthus reaction

Rheumatoid
arthritis

Post streptococcal
glomerulonephritis

Lupus Nephritis

Systemic lupus
erythematosus
(SLE)

Extrinsic allergic
alveolitis
(Hypersensitivity
pneumonitis)

Contact dermatitis

Mantoux test

Metal joint
replacement

Chronic transplant
rejection

Multiple sclerosis

Antibody
(IgG) binds
to antigen on
foreign cell
leading to
IgG
cellular
destruction
(Complement)
via
neutrophils
Neutrophils and the
subsequent
release of
lysosomal
enzymes.[4]

T-cells

[6]

[5]

Autoimmune disease,
V receptor mediated (see
below)

T cells find
antigen and
activate
macrophages.

Graves' disease

IgM or IgG

Myasthenia Gravis

(Complement)

Autoimmunity
Autoimmunity is the failure of an organism in recognizing its own constituent parts as self,
thus leading to an immune response against its own cells and tissues. Any disease that results
from such an aberrant immune response is termed an autoimmune disease. Prominent
examples include Celiac disease, diabetes mellitus type 1 (IDDM), Sarcoidosis, systemic
lupus erythematosus (SLE), Sjgren's syndrome, Churg-Strauss Syndrome, Hashimoto's
thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's Disease,
rheumatoid arthritis (RA), Polymyositis (PM), Dermatomyositis (DM), and allergies.
Autoimmune diseases are very often treated with steroids[citation needed].
The misconception that an individual's immune system is totally incapable of recognizing self
antigens is not new. Paul Ehrlich, at the beginning of the twentieth century, proposed the
concept of horror autotoxicus, wherein a "normal" body does not mount an immune response
against its own tissues. Thus, any autoimmune response was perceived to be abnormal and
postulated to be connected with human disease. Now, it is accepted that autoimmune
responses are an integral part of vertebrate immune systems[citation needed] (sometimes termed
"natural autoimmunity"), normally prevented from causing disease by the phenomenon of
immunological tolerance to self-antigens[citation needed]. Autoimmunity should not be confused
with alloimmunity.
Low-level autoimmunity

While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually
be beneficial. First, low-level autoimmunity might aid in the recognition of neoplastic cells
by CD8+ T cells, and thus reduce the incidence of cancer.

Second, autoimmunity may have a role in allowing a rapid immune response in the early
stages of an infection when the availability of foreign antigens limits the response (i.e., when
there are few pathogens present). In their study, Stefanova et al. (2002) injected an anti-MHC
Class II antibody into mice expressing a single type of MHC Class II molecule (H-2b) to
temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells (those that have not
encountered any antigens before) recovered from these mice 36 hours post-anti-MHC
administration showed decreased responsiveness to the antigen pigeon cytochrome C peptide,
as determined by Zap-70 phosphorylation, proliferation, and Interleukin-2 production. Thus
Stefanova et al. (2002) demonstrated that self-MHC recognition (which, if too strong may
contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when
foreign antigens are absent.[1] This idea of autoimmunity is conceptually similar to playfighting. The play-fighting of young cubs (TCR and self-MHC) may result in a few scratches
or scars (low-level-autoimmunity), but is beneficial in the long-term as it primes the young
cub for proper fights in the future.
Immunological tolerance

Pioneering work by Noel Rose and Ernst Witebsky in New York, and Roitt and Doniach at
University College London provided clear evidence that, at least in terms of antibodyproducing B lymphocytes, diseases such as rheumatoid arthritis and thyrotoxicosis are
associated with loss of immunological tolerance, which is the ability of an individual to
ignore "self", while reacting to "non-self". This breakage leads to the immune system's
mounting an effective and specific immune response against self determinants. The exact
genesis of immunological tolerance is still elusive, but several theories have been proposed
since the mid-twentieth century to explain its origin.
Three hypotheses have gained widespread attention among immunologists:

Clonal Deletion theory, proposed by Burnet, according to which selfreactive lymphoid cells are destroyed during the development of the
immune system in an individual. For their work Frank M. Burnet and Peter
B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine
"for discovery of acquired immunological tolerance".

Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or Bcells become inactivated in the normal individual and cannot amplify the
immune response.[2]

Idiotype Network theory, proposed by Jerne, wherein a network of

antibodies capable of neutralizing self-reactive antibodies exists naturally
within the body.[3]

In addition, two other theories are under intense investigation:

Clonal Ignorance theory, according to which autoreactive T cells that

are not represented in the thymus will mature and migrate to the
periphery, where they will not encounter the appropriate antigen because

it is inaccessible tissues. Consequently, auto-reactive B cells, that escape

deletion, cannot find the antigen or the specific helper T-cell. [4]

Suppressor population or Regulatory T cell theory, wherein

regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others)
function to prevent, downregulate, or limit autoaggressive immune
responses in the immune system.

Tolerance can also be differentiated into "Central" and "Peripheral" tolerance, on whether or
not the above-stated checking mechanisms operate in the central lymphoid organs (Thymus
and Bone Marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where selfreactive B-cells may be destroyed). It must be emphasised that these theories are not mutually
exclusive, and evidence has been mounting suggesting that all of these mechanisms may
actively contribute to vertebrate immunological tolerance.
A puzzling feature of the documented loss of tolerance seen in spontaneous human
autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by
B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and
where there is evidence for an abnormal T cell response it is usually not to the antigen
recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc
but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to
DNA, which cannot evoke a T cell response, and limited evidence for T cell responses
implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue
transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has
led to the idea that human autoimmune disease is in most cases (with probable exceptions
including type I diabetes) based on a loss of B cell tolerance which makes use of normal T
cell responses to foreign antigens in a variety of aberrant ways.[5]
Immunodeficiency and autoimmunity

There are a large number of immunodeficiency syndromes that present clinical and laboratory
characteristics of autoimmunity. The decreased ability of the immune system to clear
infections in these patients may be responsible for causing autoimmunity through perpetual
immune system activation.[6]
One example is common variable immunodeficiency (CVID) where multiple autoimmune
diseases are seen, e.g. inflammatory bowel disease, autoimmune thrombocytopenia and
autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal
recessive primary immunodeficiency, is another example. Pancytopenia, rashes,
lymphadenopathy and hepatosplenomegaly are commonly seen in these patients. Presence of
multiple uncleared viral infections due to lack of perforin are thought to be responsible. In
addition to chronic and/or recurrent infections many autoimmune diseases including arthritis,
autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked
agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic
inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well.
CGD is a caused by decreased production of nicotinamide adenine dinucleotide phosphate

(NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with
midline granulomatous disease; an autoimmune disorder that is commonly seen in patients
with granulomatosis with polyangiitis (Wegeners disease) and NK/T cell lymphomas.
Wiskott-Aldrich syndrome (WAS) patients also present with eczema, autoimmune
manifestations, recurrent bacterial infections and lymphoma. In autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and
infections coexist: organ-specific autoimmune manifestations (e.g. hypoparathyroidism and
adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also
sometimes associated with the development of autoimmune and atopic phenomena.
Genetic factors

Certain individuals are genetically susceptible to developing autoimmune diseases. This

susceptibility is associated with multiple genes plus other risk factors. Genetically
predisposed individuals do not always develop autoimmune diseases.
Three main sets of genes are suspected in many autoimmune diseases. These genes are
related to:

Immunoglobulins

T-cell receptors

The major histocompatibility complexes (MHC).

The first two, which are involved in the recognition of antigens, are inherently variable and
susceptible to recombination. These variations enable the immune system to respond to a
very wide variety of invaders, but may also give rise to lymphocytes capable of selfreactivity.
Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong
evidence to suggest that certain MHC class II allotypes are strongly correlated with

HLA DR2 is strongly positively correlated with Systemic Lupus

Erythematosus, narcolepsy[7] and multiple sclerosis, and negatively
correlated with DM Type 1.

HLA DR3 is correlated strongly with Sjgren's syndrome, myasthenia

gravis, SLE, and DM Type 1.

HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1

diabetes mellitus, and pemphigus vulgaris.

Fewer correlations exist with MHC class I molecules. The most notable and consistent is the
association between HLA B27 and ankylosing spondylitis. Correlations may exist between
polymorphisms within class II MHC promoters and autoimmune disease.

The contributions of genes outside the MHC complex remain the subject of research, in
animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD
mouse), and in patients (Brian Kotzin's linkage analysis of susceptibility to SLE).
Recently, PTPN22 has been associated with multiple autoimmune diseases including Type I
diabetes, rheumatoid arthritis, systemic lupus erythematosis, Hashimotos thyroiditis, Graves
disease, Addisons disease, Myasthenia Gravis, vitiligo, systemic sclerosis juvenile idiopathic
arthritis, and psoriatic arthritis.
Sex
Ratio of female/male incidence
of autoimmune diseases
Hashimoto's thyroiditis

10/1[8]

Graves' disease

7/1[8]

Multiple sclerosis (MS)

2/1[8]

Myasthenia gravis

2/1[8]

Systemic lupus erythematosus (SLE)

9/1[8]

Rheumatoid arthritis

5/2[8]

Primary sclerosing cholangitis

1/2

A person's sex also seems to have some role in the development of autoimmunity; that is,
most autoimmune diseases are sex-related. Nearly 75%[8] of the more than 23.5 million
Americans who suffer from autoimmune disease are women, although it is less-frequently
acknowledged that millions of men also suffer from these diseases. According to the
American Autoimmune Related Diseases Association (AARDA), autoimmune diseases that
develop in men tend to be more severe. A few autoimmune diseases that men are just as or
more likely to develop as women, include: ankylosing spondylitis, type 1 diabetes mellitus,
Wegener's granulomatosis, Crohn's disease, Primary sclerosing cholangitis and psoriasis.
The reasons for the sex role in autoimmunity are unclear. Women appear to generally mount
larger inflammatory responses than men when their immune systems are triggered, increasing
the risk of autoimmunity.[8] Involvement of sex steroids is indicated by that many
autoimmune diseases tend to fluctuate in accordance with hormonal changes, for example,
during pregnancy, in the menstrual cycle, or when using oral contraception.[8] A history of
pregnancy also appears to leave a persistent increased risk for autoimmune disease.[8] It has
been suggested that the slight exchange of cells between mothers and their children during
pregnancy may induce autoimmunity.[9] This would tip the gender balance in the direction of
the female.

Another theory suggests the female high tendency to get autoimmunity is due to an
imbalanced X chromosome inactivation.[10] The X-inactivation skew theory, proposed by
Princeton University's Jeff Stewart, has recently been confirmed experimentally in
scleroderma and autoimmune thyroiditis.[11] Other complex X-linked genetic susceptibility
mechanisms are proposed and under investigation.[8]
References to the original scientific literature would be helpful here.
Environmental factors

An interesting inverse relationship exists between infectious diseases and autoimmune

diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are
quite rarely seen. The reverse, to some extent, seems to hold true. The hygiene hypothesis
attributes these correlations to the immune manipulating strategies of pathogens. Whilst such
an observation has been variously termed as spurious and ineffective, according to some
studies, parasite infection is associated with reduced activity of autoimmune disease.[12][13][14]
The putative mechanism is that the parasite attenuates the host immune response in order to
protect itself. This may provide a serendipitous benefit to a host that also suffers from
autoimmune disease. The details of parasite immune modulation are not yet known, but may
include secretion of anti-inflammatory agents or interference with the host immune signaling.
A paradoxical observation has been the strong association of certain microbial organisms
with autoimmune diseases. For example, Klebsiella pneumoniae and coxsackievirus B have
been strongly correlated with ankylosing spondylitis and diabetes mellitus type 1,
respectively. This has been explained by the tendency of the infecting organism to produce
super-antigens that are capable of polyclonal activation of B-lymphocytes, and production of
large amounts of antibodies of varying specificities, some of which may be self-reactive (see
below).
Certain chemical agents and drugs can also be associated with the genesis of autoimmune
conditions, or conditions that simulate autoimmune diseases. The most striking of these is the
drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the
symptoms in a patient.
Cigarette smoking is now established as a major risk factor for both incidence and severity of
rheumatoid arthritis. This may relate to abnormal citrullination of proteins, since the effects
of smoking correlate with the presence of antibodies to citrullinated peptides.
Pathogenesis of autoimmunity

Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases,

against a backdrop of genetic predisposition and environmental modulation. It is beyond the
scope of this article to discuss each of these mechanisms exhaustively, but a summary of
some of the important mechanisms have been described:

T-Cell Bypass A normal immune system requires the activation of Bcells by T-cells before the former can produce antibodies in large
quantities. This requirement of a T-cell can be bypassed in rare instances,
such as infection by organisms producing super-antigens, which are
capable of initiating polyclonal activation of B-cells, or even of T-cells, by
directly binding to the -subunit of T-cell receptors in a non-specific
fashion.

T-Cell-B-Cell discordance A normal immune response is assumed to

involve B and T cell responses to the same antigen, even if we know that B
cells and T cells recognise very different things: conformations on the
surface of a molecule for B cells and pre-processed peptide fragments of
proteins for T cells. However, there is nothing as far as we know that
requires this. All that is required is that a B cell recognising antigen X
endocytoses and processes a protein Y (normally =X) and presents it to a
T cell. Roosnek and Lanzavecchia showed that B cells recognising IgGFc
could get help from any T cell responding to an antigen co-endocytosed
with IgG by the B cell as part of an immune complex. In coeliac disease it
seems likely that B cells recognising tissue transglutamine are helped by T
cells recognising gliadin.

Aberrant B cell receptor-mediated feedback A feature of human

autoimmune disease is that it is largely restricted to a small group of
antigens, several of which have known signaling roles in the immune
response (DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin
receptor(PNAR)). This fact gave rise to the idea that spontaneous
autoimmunity may result when the binding of antibody to certain antigens
leads to aberrant signals being fed back to parent B cells through
membrane bound ligands. These ligands include B cell receptor (for
antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like
receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR.
More indirect aberrant activation of B cells can also be envisaged with
autoantibodies to acetyl choline receptor (on thymic myoid cells) and
hormone and hormone binding proteins. Together with the concept of Tcell-B-cell discordance this idea forms the basis of the hypothesis of selfperpetuating autoreactive B cells.[15] Autoreactive B cells in spontaneous
autoimmunity are seen as surviving because of subversion both of the T
cell help pathway and of the feedback signal through B cell receptor,
thereby overcoming the negative signals responsible for B cell selftolerance without necessarily requiring loss of T cell self-tolerance.

Molecular Mimicry An exogenous antigen may share structural

similarities with certain host antigens; thus, any antibody produced
against this antigen (which mimics the self-antigens) can also, in theory,
bind to the host antigens, and amplify the immune response. The idea of
molecular mimicry arose in the context of Rheumatic Fever, which follows
infection with Group A beta-haemolytic streptococci. Although rheumatic
fever has been attributed to molecular mimicry for half a century no
antigen has been formally identified (if anything too many have been
proposed). Moreover, the complex tissue distribution of the disease (heart,
joint, skin, basal ganglia) argues against a cardiac specific antigen. It
remains entirely possible that the disease is due to e.g. an unusual
interaction between immune complexes, complement components and
endothelium.

Idiotype Cross-Reaction Idiotypes are antigenic epitopes found in the

antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and
Oldstone presented evidence that autoimmunity can arise as a result of a
cross-reaction between the idiotype on an antiviral antibody and a host
cell receptor for the virus in question. In this case, the host-cell receptor is
envisioned as an internal image of the virus, and the anti-idiotype
antibodies can react with the host cells.

Cytokine Dysregulation Cytokines have been recently divided into two

groups according to the population of cells whose functions they promote:
Helper T-cells type 1 or type 2. The second category of cytokines, which
include IL-4, IL-10 and TGF- (to name a few), seem to have a role in
prevention of exaggeration of pro-inflammatory immune responses.

Dendritic cell apoptosis immune system cells called dendritic cells

present antigens to active lymphocytes. Dendritic cells that are defective
in apoptosis can lead to inappropriate systemic lymphocyte activation and
consequent decline in self-tolerance.[16]

Epitope spreading or epitope drift when the immune reaction

changes from targeting the primary epitope to also targeting other
epitopes.[17] In contrast to molecular mimicry, the other epitopes need not
be structurally similar to the primary one.

Epitope modification or Cryptic epitope exposure this mechanism

of autoimmune disease is unique in that it does not result from a defect in
the hematopoietic system. Instead, disease results from the exposure of
cryptic N-glycan (polysaccharide) linkages common to lower eukaryotes
and prokaryotes on the glycoproteins of mammalian non-hematopoietic
cells and organs[18] This exposure of phylogenically primitive glycans
activates one or more mammalian innate immune cell receptors to induce
a chronic sterile inflammatory state. In the presence of chronic and
inflammatory cell damage, the adaptive immune system is recruited and
selftolerance is lost with increased autoantibody production. In this form
of the disease, the absence of lymphocytes can accelerate organ damage,
and intravenous IgG administration can be therapeutic. Although this
route to autoimmune disease may underlie various degenerative disease
states, no diagnostics for this disease mechanism exist at present, and
thus its role in human autoimmunity is currently unknown.

The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells,
T-cells in the pathogenesis of autoimmune disease are under investigation.
Classification

Autoimmune diseases can be broadly divided into systemic and organ-specific or localised
autoimmune disorders, depending on the principal clinico-pathologic features of each disease.

Systemic autoimmune diseases include SLE, Sjgren's syndrome,

sarcoidosis, scleroderma, rheumatoid arthritis, and dermatomyositis.
These conditions tend to be associated with autoantibodies to antigens
which are not tissue specific. Thus although polymyositis is more or less

tissue specific in presentation, it may be included in this group because

the autoantigens are often ubiquitous t-RNA synthetases.

Local syndromes which affect a specific organ or tissue:

o

Endocrinologic: Diabetes mellitus type 1, Hashimoto's thyroiditis,

Addison's disease

Gastrointestinal: Coeliac disease, Crohn's Disease, Pernicious

anaemia

Dermatologic: Pemphigus vulgaris, Vitiligo

Haematologic: Autoimmune haemolytic anaemia, Idiopathic

thrombocytopenic purpura

Neurological: Myasthenia gravis

Using the traditional organ specific and non-organ specific classification scheme, many
diseases have been lumped together under the autoimmune disease umbrella. However, many
chronic inflammatory human disorders lack the telltale associations of B and T cell driven
immunopathology. In the last decade it has been firmly established that tissue "inflammation
against self" does not necessarily rely on abnormal T and B cell responses.
This has led to the recent proposal that the spectrum of autoimmunity should be viewed along
an immunological disease continuum, with classical autoimmune diseases at one extreme
and diseases driven by the innate immune system at the other extreme. Within this scheme,
the full spectrum of autoimmunity can be included. Many common human autoimmune
diseases can be seen to have a substantial innate immune mediated immunopathology using
this new scheme. This new classification scheme has implications for understanding disease
mechanisms and for therapy development (see PLoS Medicine article.
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030297).
Diagnosis

Diagnosis of autoimmune disorders largely rests on accurate history and physical

examination of the patient, and high index of suspicion against a backdrop of certain
abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several
systemic disorders, serological assays which can detect specific autoantibodies can be
employed. Localised disorders are best diagnosed by immunofluorescence of biopsy
specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of
autoantibodies are measured to determine the progress of the disease.
Treatments

Treatments for autoimmune disease have traditionally been immunosuppressive, antiinflammatory (steroids), or palliative.[4] Non-immunological therapies, such as hormone
replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat outcomes of the

autoaggressive response, thus these are palliative treatments. Dietary manipulation limits the
severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of
many diseases. IVIG is used for CIDP and GBS. Specific immunomodulatory therapies, such
as the TNF antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6
receptor tocilizumab and the costimulation blocker abatacept have been shown to be useful in
treating RA. Some of these immunotherapies may be associated with increased risk of
adverse effects, such as susceptibility to infection.
Helminthic therapy is an experimental approach that involves inoculation of the patient with
specific parasitic intestinal nematodes (helminths). There are currently two closely related
treatments available, inoculation with either Necator americanus, commonly known as
hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs.[19][19][20][21][22][23]
T cell vaccination is also being explored as a possible future therapy for auto-immune
disorders.

Nutrition and Autoimmunity

Vitamin D/Sunlight

Because most human cells and tissues have receptors for vitamin D,
including T and B cells, adequate levels of vitamin D can aid in the
regulation of the immune system.[24]

Omega-3 Fatty Acids

Studies have shown that adequate consumption of omega-3 fatty

acids counteracts the effects of arachidonic acids, which contribute
to symptoms of autoimmune diseases. Human and animal trials
suggest that omega-3 is an effective treatment modality for many
cases of Rheumatoid Arthritis, Inflammatory Bowel Disease,
Asthma, and Psoriasis.[25]

While major depression is not necessarily an autoimmune disease,

some of is physiological symptoms are inflammatory and
autoimmune in nature. Omega-3 may inhibit production of
interferon gamma and other cytokines which cause the
physiological symptoms of depression. This may be due to the fact
that an imbalance in omega-3 and omega-6 fatty acids, which have
opposing effects, is instrumental in the etiology of major
depression.[25]

Probiotics/Microflora

Various types of bacteria and microflora present in fermented dairy

products, especially Lactobacillus casei, have been shown to both
stimulate immune response to tumors in mice and to regulate
immune function, delaying or preventing the onset of nonobese

diabetes. This is particularly true of the Shirota strain of L. casei

(LcS). Unfortunately, the LcS strain is mainly found in yogurt and
similar products in Europe and Japan, and rarely elsewhere. [26]

Anti-Oxidants

It has been theorized that free radicals contribute to the onset of

type-1 diabetes in infants and young children, and therefore that
the risk could be reduced by high intake of anti-oxidant substances
during pregnancy. However, a study conducted in a hospital in
Finland from 1997-2002 concluded that there was no statistically
significant correlation between anti-oxidant intake and diabetes risk.
[27]
It should be noted that this study involved monitoring of food
intake through questionnaires, and estimated anti-oxidant intake on
this basis, rather than by exact measurements or use of
supplements.

Graves' disease
Graves' disease (or Basedow-Graves disease) is an autoimmune disease. It most commonly
affects the thyroid, frequently causing it to enlarge to twice its size or more (goiter), become
overactive, with related hyperthyroid symptoms such as increased heartbeat, muscle
weakness, disturbed sleep, and irritability. It can also affect the eyes, causing bulging eyes
(exophthalmos). It affects other systems of the body, including the skin, heart, circulation and
nervous system.
It affects up to 2% of the female population, sometimes appears after childbirth, and has a
female:male incidence of 5:1 to 10:1.[citation needed] Hereditary factors are the major risk factor
for the development of Graves disease, with "79% of the liability to the development of
GD ... attributable to genetic factors".[1] Smoking and exposure to second-hand smoke is
associated with the eye manifestations but not the thyroid manifestations.
Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be
useful, particularly to monitor treatment.[2]
Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease
are variant stylings for the same term.

Signs and symptoms

Main article: Symptoms and signs of Graves' disease

Graves' disease symptoms

The signs and symptoms of Graves' disease virtually all result from the direct and indirect
effects of hyperthyroidism, with main exceptions being Graves' ophthalmopathy, goitre, and
pretibial myxedema (which are caused by the autoimmune processes of the disease).
Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity,
hair loss, excessive sweating, shaking hands, itching, heat intolerance, weight loss despite
increased appetite, diarrhea, frequent defecation, palpitations, muscle weakness, and skin
warmth and moistness.[3] Further signs that may be seen on physical examination are most
commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive
lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus
tachycardia, atrial fibrillation and premature ventricular contractions, and hypertension.[3]
People with hyperthyroidism may experience behavioral and personality changes including:
psychosis, mania, anxiety, agitation, and depression.[4]
Cause

The Immunoglobulin G antibody recognizes and binds to the thyrotropin receptor (TSH
receptor). It mimics the TSH to that receptor and activates the secretion of thyroxine (T4) and
triiodothyronine (T3), and the actual TSH level will decrease in the blood plasma. The TSH
levels fall because the hypothalamus-pituitary-thyroid negative feedback loop is working.
The result is very high levels of circulating thyroid hormones and the negative feedback
regulation will not work for the thyroid gland.[citation needed]
The trigger for auto-antibody production is not known. There appears to be a genetic
predisposition for Graves' disease, suggesting that some people are more prone than others to

develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially
DR3) appears to play a significant role.[5]
Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in
life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react
with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some
cases of type I diabetes).[citation needed]
One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the
agent of bubonic plague). However, although there is indirect evidence for the structural
similarity between the bacteria and the human thyrotropin receptor, direct causative evidence
is limited.[5] Yersinia seems not to be a major cause of this disease, although it may contribute
to the development of thyroid autoimmunity arising for other reasons in genetically
susceptible individuals.[6] It has also been suggested that Y. enterocolitica infection is not the
cause of auto-immune thyroid disease, but rather is only an associated condition; with both
having a shared inherited susceptibility.[7] More recently the role for Y. enterocolitica has been
disputed.[8]
Emotional stress has been posited as a possible cause of Graves' disease as well, based largely
on anecdotal evidence. While there are theoretical mechanisms by which stress could cause
an aggravation of the autoimmune response that leads to Graves' disease, more robust clinical
data are needed for a firm conclusion.[9]
Diagnosis

Graves' disease may present clinically with one of the following characteristic signs:

exophthalmos (protuberance of one or both eyes)

fatigue, weight loss with increased appetite, and other symptoms of

hyperthyroidism/thyrotoxicosis

rapid heart beats

muscular weakness

The two signs that are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid
conditions) are exophthalmos and non-pitting edema (pretibial myxedema). Goitre is an
enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse
goitre may be seen with other causes of hyperthyroidism, although Graves' disease is the
most common cause of diffuse goitre. A large goitre will be visible to the naked eye, but a
small goitre (mild enlargement of the gland) may be detectable only by physical exam.
Occasionally, goitre is not clinically detectable but may be seen only with CT or ultrasound
examination of the thyroid.

Another sign of Graves' disease is hyperthyroidism, i.e., overproduction of the thyroid

hormones T3 and T4. Normothyroidism is also seen, and occasionally also hypothyroidism,
which may assist in causing goitre (though it is not the cause of the Graves' disease).
Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism,
by measuring elevated blood levels of free (unbound) T3 and T4.
Other useful laboratory measurements in Graves' disease include thyroid-stimulating
hormone (TSH, usually low in Graves' disease due to negative feedback from the elevated T3
and T4), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be
detected serologically.
Biopsy to obtain histiological testing is not normally required but may be obtained if
thyroidectomy is performed.
Differentiating two common forms of hyperthyroidism such as Graves' disease and Toxic
multinodular goiter is important to determine proper treatment. Measuring TSH-receptor
antibodies with the h-TBII assay has been proven efficient and was the most practical
approach found in one study.[10]
Eye disease
Further information: Graves' ophthalmopathy

Thyroid-associated ophthalmopathy is one of the most typical symptoms of Graves' disease.

It is known by a variety of terms, the most common being Graves' ophthalmopathy. Thyroid
eye disease is an inflammatory condition, which affects the orbital contents including the
extraocular muscles and orbital fat. It is almost always associated with Graves' disease but
may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer.
The ocular manifestations that are relatively specific to Graves' disease include soft tissue
inflammation, proptosis (protrusion of one or both globes of the eyes), corneal exposure, and
optic nerve compression. Also seen, if the patient is hyperthyroid, (i.e., has too much thryoid
hormone) are more general manifestations, which are due to hyperthyroidism itself and which
may be seen in any conditions that cause hyperthyroidism (such as toxic multinodular goitre
or even thyroid poisoning). These more general symptoms include lid retraction, lid lag, and
a delay in the downward excursion of the upper eyelid, during downward gaze.
It is believed that fibroblasts in the orbital tissues may express the Thyroid Stimulating
Hormone receptor (TSHr). This may explain why one autoantibody to the TSHr can cause
disease in both the thyroid and the eyes.[11]

For mild disease - artificial tears, steroids (to reduce chemosis)

For moderate disease - lateral tarsorrhaphy

For severe disease - orbital decompression or retro-orbital radiation

Classification

Mnemonic: "NO SPECS":[12]

Class 0: No signs or symptoms

Class 1: Only signs (limited to upper lid retraction and stare, with or
without lid lag)

Class 2: Soft tissue involvement (oedema of conjunctivae and lids,

conjunctival injection, etc.)

Class 3: Proptosis

Class 4: Extraocular muscle involvement (usually with diplopia)

Class 5: Corneal involvement (primarily due to lagophthalmos)

Class 6: Sight loss (due to optic nerve involvement)

Pathophysiology

Histopathological image of diffuse hyperplasia of the thyroid gland (clinically

presenting as hyperthyroidism)

Graves' disease is an autoimmune disorder, in which the body produces antibodies to the
receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the
thyroid hormones T3 and T4 may also be produced.)
These antibodies cause hyperthyroidism because they bind to the TSH receptor and
chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid
gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an
abnormally high production of T3 and T4. This in turn causes the clinical symptoms of
hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.
The infiltrative exophthalmos that is frequently encountered has been explained by
postulating that the thyroid gland and the extraocular muscles share a common antigen which

is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause
swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin,
causing an inflammatory reaction and subsequent fibrous plaques.
There are 3 types of autoantibodies to the TSH receptor currently recognized:

TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly IgG)

act as LATS (Long Acting Thyroid Stimulants), activating the cells in a
longer and slower way than TSH, leading to an elevated production of
thyroid hormone.

TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the

TSH receptor and have been implicated in the growth of thyroid follicles.

TBII, Thyrotrophin Binding-Inhibiting Immunoglobulins: these antibodies

inhibit the normal union of TSH with its receptor. Some will actually act as
if TSH itself is binding to its receptor, thus inducing thyroid function. Other
types may not stimulate the thyroid gland, but will prevent TSI and TSH
from binding to and stimulating the receptor.

Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased

excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if
the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the
blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired
kidney function.[13]
Management

Treatment of Graves' disease includes antithyroid drugs which reduce the production of
thyroid hormone; radioiodine (radioactive iodine I-131); and thyroidectomy (surgical
excision of the gland). As operating on a frankly hyperthyroid patient is dangerous, prior to
thyroidectomy preoperative treatment with antithyroid drugs is given to render the patient
"euthyroid" (i.e. normothyroid).
Treatment with antithyroid medications must be given for six months to two years to be
effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side
effects of the antithyroid medications include a potentially fatal reduction in the level of
white blood cells. Therapy with radioiodine is the most common treatment in the United
States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan,
and most of the rest of the world.
-blockers (such as propranolol) may be used to inhibit the sympathetic nervous system
symptoms of tachycardia and nausea until such time as antithyroid treatments start to take
effect. Pure beta blockers do not inhibit lid-retraction in the eyes, which is mediated by alpha
adrenergic receptors.

Antithyroid drugs

The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and
propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines.
The most dangerous side-effect is agranulocytosis (1/250, more in PTU). Others include
granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic
anemia. Patients on these medications should see a doctor if they develop sore throat or fever.
The most common side effects are rash and peripheral neuritis. These drugs also cross the
placenta and are secreted in breast milk. Lygole is used to block hormone synthesis before
surgery.
A randomized control trial testing single dose treatment for Graves' found methimazole
achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on
methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).[14]
A study has shown no difference in outcome for adding thyroxine to antithyroid medication
and continuing thyroxine versus placebo after antithyroid medication withdrawal. However
two markers were found that can help predict the risk of recurrence. These two markers are a
positive Thyroid Stimulating Hormone receptor antibody (TSHR-Ab) and smoking. A
positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to
90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug
treatment is associated with a 78% chance of remaining in remission. Smoking was shown to
have an impact independent to a positive TSHR-Ab.[15]

Radioiodine

Scan of affected thyroid before and after radioiodine therapy.

Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt
General Clinical Research Center. This modality is suitable for most patients, although some
prefer to use it mainly for older patients. Indications for radioiodine are: failed medical
therapy or surgery and where medical or surgical therapy are contraindicated.
Hypothyroidism may be a complication of this therapy, but may be treated with thyroid
hormones if it appears. The rationale for radioactive iodine is that it accumulates in the
thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total
radiation being emitted by the beta (electron) particles. The most common method of iodine131 treatment is to administer a specified amount in microcuries per gram of thyroid gland
based on palpation or radiodiagnostic imaging of the gland over 24 hours.[16] Patients who
receive the therapy must be monitored regularly with thyroid blood tests to ensure that they
are treated with thyroid hormone before they become symptomatically hypothyroid. For some
patients, finding the correct thyroid replacement hormone and the correct dosage may take
many years and may be in itself a much more difficult task than is commonly understood.
[citation needed]

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can

aggravate thyroid eye disease), solitary nodules.
Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring
eventual thyroid hormone supplementation in the form of a daily pill(s). The radio-iodine
treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves'
disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a
relapse rate that depends on the dose of radioiodine which is administered.
Surgery
Further information: Thyroidectomy

This modality is suitable for young patients and pregnant patients. Indications are: a large
goitre (especially when compressing the trachea), suspicious nodules or suspected cancer (to
pathologically examine the thyroid) and patients with ophthalmopathy.
Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy
on one side and partial lobectomy on other side) are possible.
Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the
recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands),
hematoma (which can be life-threatening if it compresses the trachea) and scarring. Removal
of the gland enables complete biopsy to be performed to have definite evidence of cancer
anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of
the thyroid). No further treatment of the thyroid is required, unless cancer is detected.
Radioiodine uptake study may be done after surgery, to ensure that all remaining (potentially
cancerous) thyroid cells (i.e., near the nerves to the vocal chords) are destroyed. Besides this,
the only remaining treatment will be Synthroid, or thyroid replacement pills to be taken for
the rest of the patient's life.
Disadvantages are as follows. A scar is created across the neck just above the collar bone line.
However, the scar is very thin, and can eventually recede and appear as nothing more than a
crease in the neck. The patient may spend a night in hospital after the surgery, and endure the
effects of total anesthesia (i.e., vomiting), as well as sore throat, raspy voice, cough from
having a breathing tube stuck down the windpipe during surgery.[citation needed]
Eye disease

Mild cases are treated with lubricant eye drops or non steroidal antiinflammatory drops.
Severe cases threatening vision (Corneal exposure or Optic Nerve compression) are treated
with steroids or orbital decompression. In all cases cessation of smoking is essential. Double
vision can be corrected with prism glasses and surgery (the latter only when the process has
been stable for a while).
Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to
enable full, deep sleep.

Orbital decompression can be performed to enable bulging eyes to retreat back into the head.
Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty
tissue to fall back into the skull.
Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of
Graves' on the eyelids. Eyelid muscles can become tight with Graves, making it impossible to
close eyes all the way. Eyelid surgery involves an incision along the natural crease of the
eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle
weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery
helps reduce or eliminate dry eye symptoms.
Prognosis

If left untreated, more serious complications could result, including birth defects in
pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves disease is
often accompanied by an increase in heart rate, which may lead to further heart complications
including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the
eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will
occur with a risk of a secondary corneal infection which could lead to blindness. Pressure on
the optic nerve behind the globe can lead to visual field defects and vision loss as well.
Epidemiology

The disease occurs most frequently in women (7:1 compared to men). It occurs most often in
middle age (most commonly in the third to fifth decades of life), but is not uncommon in
adolescents, during pregnancy, during menopause, or in people over age 50. There is a
marked family preponderance, which has led to speculation that there may be a genetic
component. To date, no clear genetic defect has been found that would point at a monogenic
cause.

Myasthenia gravis

Myasthenia gravis
Classification and external resources

Strabismus and ptosis in a person with

myasthenia gravis trying to open his eyes.

Myasthenia gravis (from Greek "muscle", "weakness", and Latin: gravis

"serious"; abbreviated MG) is an autoimmune neuromuscular disease leading to fluctuating
muscle weakness and fatigue. Muscle weakness is caused by circulating antibodies that block
acetylcholine receptors at the postsynaptic neuromuscular junction,[1] inhibiting the excitatory
effects of the neurotransmitter acetylcholine on nicotinic receptors at neuromuscular
junctions.
Myasthenia is treated medically with acetylcholinesterase inhibitors or immunosuppressants,
and, in selected cases, thymectomy. The disease incidence is 330 cases per million per year
and rising as a result of increased awareness.[2] MG must be distinguished from congenital
myasthenic syndromes that can present similar symptoms but do not respond to
immunosuppressive treatments.
Classification

The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis
Foundation of America Clinical Classification:[3]

Class I: Any eye muscle weakness, possible ptosis, no other evidence of

muscle weakness elsewhere

Class II: Eye muscle weakness of any severity, mild weakness of other
muscles

Class IIa: Predominantly limb or axial muscles

Class IIb: Predominantly bulbar and/or respiratory muscles

Class III: Eye muscle weakness of any severity, moderate weakness of

other muscles
o

Class IIIa: Predominantly limb or axial muscles

Class IIIb: Predominantly bulbar and/or respiratory muscles

Class IV: Eye muscle weakness of any severity, severe weakness of other
muscles
o

Class IVa: Predominantly limb or axial muscles

Class IVb: Predominantly bulbar and/or respiratory muscles (Can

also include feeding tube without intubation)

Class V: Intubation needed to maintain airway

Signs and symptoms

Blepharoptosis of the left eye

The hallmark of myasthenia gravis is fatigability. Muscles become progressively weaker

during periods of activity and improve after periods of rest. Muscles that control eye and
eyelid movement, facial expressions, chewing, talking, and swallowing are especially
susceptible. The muscles that control breathing and neck and limb movements can also be
affected. Often, the physical examination yields results within normal limits.[4]
The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of
myasthenia gravis may be delayed if the symptoms are subtle or variable.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others,
difficulty in swallowing and slurred speech may be the first signs. The degree of muscle
weakness involved in MG varies greatly among patients, ranging from a localized form that
is limited to eye muscles (ocular myasthenia), to a severe and generalized form in which
many muscles--sometimes including those that control breathing--are affected. Symptoms,
which vary in type and severity, may include asymmetrical ptosis (a drooping of one or both
eyelids), diplopia (double vision) due to weakness of the muscles that control eye
movements, an unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a
change in facial expression, dysphagia (difficulty in swallowing), shortness of breath and
dysarthria (impaired speech, often nasal due to weakness of the velar muscles).
In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted
ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may
be triggered by infection, fever, an adverse reaction to medication, or emotional stress.[5]
Since the heart muscle is regulated only by the autonomic nervous system, it is generally
unaffected by MG.
Pathophysiology

A neuromuscular junction: 1. Axon 2. Muscle cell membrane (sarcolemma) 3.

Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion

A juvenile thymus shrinks with age.

The nicotinic acetylcholine receptor

Myasthenia gravis is an autoimmune channelopathy: it features antibodies directed against

proteins that are naturally present in the body. While various similar diseases have been
linked to immunologic cross-reaction with an infective agent, there is no known causative
pathogen that could account for myasthenia. There is a slight genetic predisposition:
particular HLA types seem to predispose for MG (B8 and DR3 with DR1 more specific for
ocular myasthenia). Up to 75% of patients have an abnormality of the thymus; 10% have a

thymoma, a tumor (either benign or malignant) of the thymus, and other abnormalities are
frequently found. The disease process generally remains stationary after thymectomy
(removal of the thymus).
In MG, the autoantibodies most commonly act against the nicotinic acetylcholine receptor
(nAChR),[6] the receptor in the motor end plate for the neurotransmitter acetylcholine that
stimulates muscular contractions. Some forms of the antibody impair the ability of
acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by
complement fixation or by inducing the muscle cell to eliminate the receptors through
endocytosis.
The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into
plasma cells by T-helper cell stimulation. To carry out this activation, T-helpers must first be
activated themselves, which is done by binding of the T-cell receptor (TCR) to the
acetylcholine receptor antigenic peptide fragment (epitope) resting within the major
histocompatibility complex of antigen presenting cells. Since the thymus plays an important
role in the development of T-cells and the selection of TCR, myasthenia gravis is closely
associated with thymoma. The exact mechanisms are, however, not convincingly clarified,
although resection of the thymus (thymectomy) in MG patients without a thymus neoplasm
often have positive results.
In normal muscle contraction, cumulative activation of the nAChR leads to influx of sodium
ions, which in turn causes the depolarization of muscle cell and subsequent opening of
voltage-gated sodium channels. This ion influx then travels down the cell membranes via Ttubules and, via calcium channel complexes, leads to the release of calcium from the
sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high
enough will it contract. Decreased numbers of functioning nAChRs therefore impairs
muscular contraction by limiting depolarization. In fact, MG causes the motor neuron action
potential to muscular twitch ratio to vary from the nonpathological one to one ratio.
A second category of gravis is due to autoantibodies against the MuSK protein (muscle
specific kinase), a tyrosine kinase receptor which is required for the formation of the
neuromuscular junction. Antibodies against MuSK inhibit the signaling of MuSK normally
induced by its nerve-derived ligand, agrin. The result is a decrease in patency of the
neuromuscular junction, and the consequent symptoms of MG.
People treated with penicillamine can develop MG symptoms. Their antibody titer is usually
similar to that of MG, but both the symptoms and the titer disappear when drug
administration is discontinued.
MG is more common in families with other autoimmune diseases. A familial predisposition
found in 5% of the cases is associated with certain genetic variations, such as an increased
frequency of HLA-B8 and DR3. People with MG suffer from coexisting autoimmune
diseases at a higher frequency than members of the general population. Of particular mention

is coexisting thyroid disease, where episodes of hypothyroidism may precipitate a severe

exacerbation.
The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research into
which might eventually lead to new treatment options.[7]
Associated condition

Myasthenia gravis is associated with various autoimmune diseases,[8] including:

Thyroid diseases, including Hashimoto's thyroiditis and Graves' disease

Diabetes mellitus type 1

Rheumatoid arthritis

Lupus, and

Demyelinating CNS diseases

Seropositive and "double-seronegative" patients often have thymoma or thymic hyperplasia.

However, anti-MuSK positive patients do not have evidence of thymus pathology.
In pregnancy

In the long term, pregnancy does not affect myasthenia gravis. The mothers themselves suffer
from exacerbated myasthenia in a third of cases, and in those for whom it does worsen, it
usually occurs in the first trimester of pregnancy. Signs and symptoms in pregnant mothers
tend to improve during the second and third trimesters. Complete remission can occur in
some mothers.[9] Immunosuppressive therapy should be maintained throughout pregnancy, as
this reduces the chance of neonatal muscle weakness, as well as controls the mother's
myasthenia.[10]
Up to 10% of infants with parents affected by the condition are born with transient (periodic)
neonatal myasthenia (TNM), which generally produces feeding and respiratory difficulties.[10]
TNM usually presents as poor suckling and generalized hypotonia (low muscle tone). Other
reported symptoms include a weak cry, facial diplegia (paralysis of one part of the body) or
paresis (impaired or lack of movement) and mild respiratory distress. A child with TNM
typically responds very well to acetylcholinesterase inhibitors. Very rarely, an infant can be
born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness.
This is due to maternal antibodies that target an infant's acetylcholine receptors. In some
cases, the mother remains asymptomatic.[10]
Diagnosis

MG can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from
both normal variants and other neurological disorders.[4] A thorough physical examination can
reveal easy fatigability, with the weakness improving after rest and worsening again on repeat

of the exertion testing. A good response to medication can also be considered a sign of
autoimmune pathology.
Three types of myasthenic symptoms in children can be distinguished:[11]
1. Neonatal: In 12% of the pregnancies with a mother with MG, she passes
the antibodies to the infant through the placenta, causing neonatal
myasthenia gravis. The symptoms will start in the first two days and
disappear within a few weeks after birth. With the mother, it is not
uncommon for the symptoms to even improve during pregnancy, but they
might worsen after labor.
2. Congenital: Children of a healthy mother can, very rarely, develop
myasthenic symptoms beginning at birth, congenital myasthenic
syndrome or CMS. Other than myasthenia gravis, CMS is not caused by an
autoimmune process, but due to synaptic malformation, which in turn is
caused by genetic mutations. Thus, CMS is a hereditary disease. More than
11 different mutations have been identified, and the inheritance pattern is
typically autosomal recessive.
3. Juvenile myasthenia gravis: myasthenia occurring in childhood, but after
the peripartum period

The congenital myasthenias cause muscle weakness and fatigability similar to those of MG.
The symptoms of CMS usually begin within the first two years of life, although in a few
forms, patients can develop their first symptoms as late as the seventh decade of life. A
diagnosis of CMS is suggested by the following:

Onset of symptoms in infancy or childhood

Weakness which increases as muscles tire

A decremental EMG response, on low frequency, of the compound muscle

action potential (CMAP)

No anti-AChR or MuSK antibodies

No response to immunosuppressant therapy

Family history of symptoms which resemble CMS

The symptoms of CMS can vary from mild to severe. It is also common for patients with the
same form, even members of the same family, to be affected to differing degrees. In most
forms of CMS, weakness does not progress, and in some forms, the symptoms may diminish
as the patient gets older. Only rarely do symptoms of CMS become worse with time.
Physical examination

Muscle fatigability can be tested for many muscles.[11] A thorough investigation includes:

looking upward and sidewards for 30 seconds: ptosis and diplopia

looking at the feet while lying on the back for 60 seconds

keeping the arms stretched forward for 60 seconds

ten deep knee bends

walking 30 steps on both the toes and the heels

five situps, lying down and sitting up completely

"Peek sign": after complete initial apposition of the lid margins, they
quickly (within 30 seconds) start to separate and the sclera starts to
show[4]

Blood tests

If the diagnosis is suspected, serology can be performed in a blood test to identify certain
antibodies:

One test is for antibodies against the acetylcholine receptor.[4] The test has
a reasonable sensitivity of 8096%, but in MG limited to the eye muscles
(ocular myasthenia) the sensitivity falls to 50% (negative in up to 50%
who have MG).

A proportion of the patients without antibodies against the acetylcholine

receptor have antibodies against the MuSK protein.[12]

In specific situations (decreased reflexes which increase on facilitation,

coexisting autonomic features, suspected presence of neoplasm,
especially of the lung, presence of increment or facilitation on repetitive
EMG (electromyography) testing) testing is performed for Lambert-Eaton
syndrome, in which other antibodies (against a voltage-gated calcium
channel) can be found.

Electrodiagnostics

Muscle fibers of patients with MG are easily fatigued, and thus do not respond as well as
muscles in healthy individuals to repeated stimulation. By stimulating a nerve-muscle motor
unit with short sequences of rapid, regular electrical impulses, before and after exercising the
motor unit, the fatiguability of the muscle can be measured. This is called the repetitive nerve
stimulation test. In single fiber electromyography (SFEMG), which is considered to be the
most sensitive (although not the most specific) test for MG,[4] a thin needle electrode is
inserted into different areas of a particular muscle to record the action potentials from several
samplings of different individual muscle fibers. Two muscle fibers belonging to the same
motor unit are identified and the temporal variability in their firing patterns are measured.
Frequency and proportion of particular abnormal action potential patterns, "jitter" and
"blocking," are diagnostic. Jitter refers to the abnormal variation in the time interval between
action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the
failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same
motor unit.[13]

Ice test

Applying ice to weak muscle groups characteristically leads to improvement in strength of

those muscles. Applying ice for 5 minutes to the muscles reportedly has a sensitivity and
specificity of 76.9% and 98.3%, respectively, for the identification of MG. It is thought that
acetylcholinesterase is inhibited at the lower temperature and that this is the basis for this
diagnostic test.[14]
Edrophonium test

Photograph of a patient showing right partial ptosis (left picture), the left lid
shows compensatory pseudo lid retraction because of equal innervation of the
levator palpabrae superioris (Hering's law of equal innervation). Right picture:
after an edrophonium test, note the improvement in ptosis.

The "edrophonium test" is infrequently performed to identify MG; its application is limited to
those situations in which other investigations have failed to yield a conclusive diagnosis. This
test requires the intravenous administration of edrophonium chloride (Tensilon, Reversol) or
neostigmine (Prostigmin), drugs that block the breakdown of acetylcholine by cholinesterase
(acetylcholinesterase inhibitors) and temporarily increases the levels of acetylcholine at the
neuromuscular junction. In people with myasthenia gravis involving the eye muscles,
edrophonium chloride will briefly relieve weakness.[15]
Imaging

A chest CT-scan showing a thymoma (red circle)

A chest X-ray is frequently performed; it may point towards alternative diagnoses (e.g.,
Lambert-Eaton syndrome due to a lung tumor) and comorbidity. It may also identify
widening of the mediastinum suggestive of thymoma, but computed tomography (CT) or
magnetic resonance imaging (MRI) are more sensitive ways to identify thymomas and are
generally done for this reason.[16] MRI of the cranium and orbits may also be performed to
exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.[17]

Pulmonary function test

Spirometry (lung function testing) may be performed to assess respiratory function if there
are concerns about breathing adequacy. The forced vital capacity may be monitored at
intervals to detect increasing muscular weakness. Acutely, negative inspiratory force may be
used to determine adequacy of ventilation. Severe myasthenia may cause respiratory failure
due to exhaustion of the respiratory muscles.[18]
Pathological findings

Muscle biopsy is only performed if the diagnosis remains in doubt and clinical suspicion of
MG persists. Immunofluorescence shows IgG antibodies on the neuromuscular junction. (The
antibody which causes myasthenia gravis does not fluoresce, but rather a secondary antibody
directed against it.) Muscle electron microscopy shows receptor infolding and loss of the tips
of the folds, together with widening of the synaptic clefts. Both these techniques are currently
used for research rather than diagnostically.[7]
Management

Treatment is by medication and/or surgery. Medication consists mainly of

acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant
drugs to reduce the autoimmune process. Thymectomy is a surgical method to treat MG. For
emergency treatment, plasmapheresis or IVIG can be used as a temporary measure to remove
antibodies from the blood circulation.
Medication

Neostigmine, chemical structure.

Acetylcholinesterase inhibitors: neostigmine and pyridostigmine can

improve muscle function by slowing the natural enzyme cholinesterase
that degrades acetylcholine in the motor end plate; the neurotransmitter
is therefore around longer to stimulate its receptor. Usually, doctors will
start with a low dose, e.g. 3x20mg pyridostigmine, and increase until the
desired result is achieved. If taken 30 minutes before a meal, symptoms
will be mild during eating. Side effects, such as perspiration and diarrhea,
can be countered by adding atropine. Pyridostigmine is a short-lived drug,
with a half-life of about four hours.

Azathioprine, chemical structure

Immunosuppressive drugs: prednisone, cyclosporin, mycophenolate and

azathioprine may be used. Patients are commonly treated with a
combination of these drugs with an acetylcholinesterase inhibitor.
Treatments with some immunosuppressives take weeks to months before
effects are noticed. Other immunomodulating substances, such as drugs
that prevent acetylcholine receptor modulation by the immune system,
are currently being researched.[19]

Plasmapheresis and IVIG

If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the
putative antibodies from the circulation. Also, intravenous immunoglobulins (IVIGs) can be
used to bind the circulating antibodies. Both of these treatments have relatively short-lived
benefits, typically measured in weeks.[20]
Surgery
Main article: thymectomy

Thymectomy, the surgical removal of the thymus, is essential in cases of thymoma in view of
the potential neoplastic effects of the tumor. However, the procedure is more controversial in
patients who do not show thymic abnormalities. Although some of these patients improve
following thymectomy, some patients experience severe exacerbations and the highly
controversial concept of "therapeutic thymectomy" for patients with thymus hyperplasia is
disputed by many experts, and efforts are underway to unequivocally answer this important
question.

There are a number of surgical approaches to the removal of the thymus gland: transsternal
(through the sternum, or breast bone), transcervical (through a small neck incision), and
transthoracic (through one or both sides of the chest). The transsternal approach is most
common and uses the same length-wise incision through the sternum (breast bone) used for
most open-heart surgery. The transcervical approach, a less invasive procedure, allows for
removal of the entire thymus gland through a small neck incision. There has been no
difference in success in symptom improvement between the transsternal approach and the
minimally invasive transcervical approach.[21] For patients with a thymoma, though, complete
tissue removal is important, as thymic tissue can regrow. Thymomas can be malignant and
are thought to be the onset of other diseases, as well, so many surgeons will only recommend
the full sternotomy approach to a thymectomy.
Thymoma is relatively rare in younger (<40) patients, but especially younger patients with
generalized MG without thymoma benefit, paradoxically, from thymectomy. Resection is also
indicated for those with a thymoma, but it is less likely to improve the MG symptoms.
Physical activity

Patients with MG should be educated regarding the fluctuating nature of their symptoms,
including weakness and exercise-induced fatigue. Exercise participation should be
encouraged with frequent bouts of rest.[22]
Inspiratory muscle therapy

In patients with generalized MG, there is some evidence that a partial home program
including training in diaphragmatic breathing, pursed lip breathing, and interval based IMT
may improve respiratory muscle strength, chest wall mobility, respiratory pattern, and
respiratory endurance.[23]
Prognosis

With treatment, patients have a normal life expectancy, except for those with a malignant
thymoma (whose lesser life expectancy is on account of the thymoma itself and is otherwise
unrelated to the myasthenia). Quality of life can vary depending on the severity and the
cause. The drugs used to control MG either diminish in effectiveness over time
(acetylcholinesterase inhibitors) or cause severe side effects of their own
(immunosuppressants). About 10% of MG patients are found to have tumors in their thymus
glands, in which case a thymectomy is a very effective treatment with long-term remission.
However, most patients need treatment for the remainder of their lives, and their abilities vary
greatly. MG is not usually a progressive disease; the symptoms may fluctuate, but do not
always get worse as the patient ages. For some, the symptoms decrease after a span of three
to five years.
Epidemiology

Myasthenia gravis occurs in all ethnic groups and both sexes. It most commonly affects
women under 40 and people from 50 to 70 years old of either sex, but it has been known to

occur at any age. Younger patients rarely have thymoma. The prevalence in the United States
is estimated at 20 cases per 100,000.[24] Risk factors are the female sex with ages 20 40,
familial myasthenia gravis, D-penicillamine ingestion (drug-induced myasthenia), and having
other autoimmune diseases.