Overlooked non-motor symptoms in myasthenia gravis
- 1Department of Neurology, Keio University School of Medicine, Tokyo, Japan
- 2Department of Neurology, Hanamaki General Hospital, Iwate, Japan
- Correspondence to Dr Shigeaki Suzuki, Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;
- Received 27 September 2012
- Revised 22 October 2012
- Accepted 25 October 2012
- Published Online First 22 November 2012
Patients with myasthenia gravis (MG) may have various non-motor symptoms in addition to fatigability and weakness of skeletal muscles. Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells. Thymomas are found in 15–25% of patients with MG and are associated with severe symptoms. We suggest that non-motor symptoms are based on the autoimmune disorders probably owing to an abnormal T cell repertoire from thymomas. Using previously reported cases and cases from our multicentre cooperative study, we review the clinical characteristics of patients with thymoma-associated MG who have non-motor symptoms. CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles lead to the development of pure red cell aplasia, immunodeficiency and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and the related molecules can evoke various neurological and cardiac disorders. About 25% of patients with thymoma-associated MG have at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad spectrum of disease, ranging from the impairment of quality of life to lethal conditions. Since relatively little attention is paid to non-motor symptoms in patients with thymoma-associated MG, the symptoms may be overlooked by many physicians. Early diagnosis is important, since non-motor symptoms can be treatable. A complete understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.
Autoimmune myasthenia gravis (MG) is an organ-specific autoimmune disorder characterised by dysfunctional neuromuscular junctions of skeletal muscles targeted by pathogenic autoantibodies to acetylcholine receptor (AChR) or muscle-specific receptor tyrosine kinase.1 ,2 In addition to fatigability and weakness of skeletal muscles, patients with MG may have various non-motor symptoms.
The non-motor symptoms comprise a broad spectrum. Patients with MG sometimes have psychiatric symptoms such as depression and anxiety which impair their quality of life (QoL). However, these symptoms are not principally immune mediated. Moreover, 8–15% of patients with MG have additional autoimmune disorders. Graves’ disease, Hashimoto disease, rheumatoid arthritis and lupus erythematosus are often seen in early-onset MG without thymoma. The clinical manifestations of these diseases are also regarded as non-motor symptoms. Genetic factors and abnormalities of immune regulation may increase the development of the concomitant autoimmune disorders that occur in some patients with MG and their relatives. However, the autoimmune mechanisms underlying the association between MG and these disorders are not fully understood.
Thymomas are thymic epithelial tumours, generally characterised by indolent growth, with local invasion.3 Tumour stage, extent of surgical resection and histology are associated with the prognosis. It is accepted that around 30–44% of patients with thymomas have MG.4 Pathogenic T cell clones generated from thymomas lead to various autoimmune disorders, including MG. In this review, we clarify the suggestion that non-motor symptoms are based on the autoimmune disorders attributed to abnormal T cell clones from thymomas. Since less attention is paid to non-motor symptoms in patients with thymoma-associated MG, these symptoms may be overlooked by many physicians.
The affected age is usually 30–60 years, with an equal prevalence in men and women.
Patients with thymoma-associated MG have severe manifestations and high frequencies of bulbar involvement and crisis compared with patients with MG without thymomas.
The WHO type B2 and B3 thymomas are most commonly found in patients with MG and they are associated with severe symptoms of MG and advanced stage of thymomas.
MG sometimes appears several years after the complete removal of a thymoma.
All patients have anti-AChR, but not anti-muscle-specific receptor tyrosine kinase antibodies.
Thymoma-associated MG is often accompanied by striational antibodies targeted to titin, ryanodine receptor and muscular voltage-gated potassium channel (VGKC), Kv1.4.
Patients with MG occasionally require additional adjuvant treatment with radiotherapy, chemotherapy and re-operation.
Many autoimmune haematological, neurological and skin diseases may develop in the clinical course of MG.
Thymomas should be considered potentially malignant tumours requiring prolonged follow-up.
Neuromyotonia and limbic encephalitis
Various neurological manifestations are seen in patients with MG and thymomas.3 ,4 ,7 ,10 Neuromyotonia, first described by Isaacs in 1961, is characterised by hyperexcitability of peripheral motor nerves, leading to intermittent or continuous muscle contractions, cramps and myokymia.11 ,12 Limbic encephalitis is characterised by subacute development of short-term memory loss, behavioural change and seizure involving the temporomedial lobes and the amygdalae, with variable evidence of cerebrospinal fluid inflammation and neuronal antibodies.13 Antineuronal VGKC antibodies are likely to be pathogenic for both neuromyotonia and limbic encephalitis.12 ,13 In addition to neuromyotonia and limbic encephalitis, neuronal VGKC autoimmunity is now known to have a broader spectrum of neurological manifestations than was previously recognised.14 Tan et al14 reported that the coexistence of MG was not found in 72 patients with antineuronal VGKC antibodies, suggesting that the combination of thymomatous MG and neuromyotonia is not common.
It has been established that antibodies immunoprecipitating neuronal VGKC extracted from mammalian brain do not target the VGKC itself, as originally thought.12 Targeted autoantigens are mainly leucine-rich glioma-inactivated protein (LGI1) or contactin-associated protein 2 (CASPR2), which are tightly associated with VGKC.13 LGI1 antibodies are found almost exclusively in patients with limbic encephalitis without tumour, whereas antibodies to CASPR2 are found in patients with neuromyotonia and thymoma. In addition, Morvan's syndrome, recognised as a rare constellation of neuromyotonia, dysautonomia and limbic encephalopathy, is also associated with anti-CASPR2 antibodies.15 Of 29 patients with Morvan's syndrome from a number of countries, nine had a history of MG with thymomas.
We treated a 67-year-old man with thymoma-associated MG positive for antineuronal VGKC antibody. He developed marked myokymia, especially in his legs, spontaneously at rest and during movement (see the online supplemental video). Electromyographic findings showed myokymic discharge and fasciculation. Serum hyponatraemia (<120 mEq/l) was also found. He claimed neuropathic pain rather than myokymia or muscle cramp and immunotherapy was not effective for his neuropathic pain.
Since neuronal VGKC antibodies define neurological conditions that are usually responsive to immunotherapy, severe painful muscle cramps can be successfully treated with plasma exchange.13 Neuromyotonia is a transient disease, with a florid phase of 2–3 months, after which symptoms slowly subside.3 However, muscle cramps and neuropathic pain may require the administration of antiepileptic agents including phenytoin or carbamazepine and they are sometimes resistant to drugs. Although over 15 years have passed since the discovery of antineuronal VGKC antibodies, they are, unfortunately, not routinely available in most hospitals. This may create a predisposition among physicians to underestimate neuromyotonia in patients with MG.
Pure red cell aplasia
Pure red cell aplasia (PRCA) is a syndrome characterised by a severe normocytic anaemia, reticulocytopenia and absence of erythroblasts from otherwise normal bone marrow.16 Acquired PRCA is associated with various drugs, viral infections (parvovirus B19), immune disorders, ABO-incompatible haematopoetic stem cell transplantation and tumours. A small minority of PRCA cases are associated with thymomas (usually <10%). Abnormal CD8 T cell clones in bone marrow are believed to be involved in the development of PRCA associated with thymomas.
Since the first published case in 1954, about 40 cases of coexisting MG and PRCA have been reported in English publications.17–19 All cases were thymoma-associated MG except for one case with thymic hyperplasia.20 The mean age at PRCA onset was 60 years, with women predominantly affected. In 70% of the patients, PRCA developed after thymomectomy and MG onset even when the thymomas had been completely removed.17–19 The length of time between thymomectomy and PRCA onset ranged from 9 months to 21 years (7 years on average). Sine type AB thymomas were generally associated with the PRCA and the severity of MG was relatively mild. The reported cases showed that the MG was generally well controlled when the PRCA was diagnosed. The clinical features and prevalence of PRCA in thymoma-associated MG were similar among various ethnic patient populations.17–19
Since dyspnoea and fatigue due to anaemia may be regarded simply as symptoms of MG, a routine check of blood cell counts is encouraged to avoid a delay in diagnosis. Other types of autoimmune anaemia such as haemolytic anaemia and pernicious anaemia should be differentiated, since these disorders are also accompanied by MG. When blood cell counts show pancytopenia, the possibility of aplastic anaemia must be considered, although it is less frequently associated with thymomatous MG.
The association of PRCA with thymomas is relatively rare and its optimal treatment is not well established. Corticosteroids are the preferred treatment for PRCA with thymomas. However, ciclosporins are the leading drugs for the treatment of PRCA in Japan, with a response rate of 65–87%.16 Relapses of PRCA are occasional and the long-term use of immunosuppressive agents is usually required. Red cell transfusion can be given as necessary.
Alopecia areata, characterised by a sudden and patchy loss of the scalp hair, is a T cell mediated autoimmune disorder that targets hair follicles.21 The hair loss may resolve completely, become chronic, or progress to a total loss of hair, termed ‘alopecia totalis’. Immunohistochemical analyses of skin biopsy specimens have shown that lymphocytes, which infiltrate into the peribulbar area, are predominantly CD8 T cells rather than CD4 T cells (see the online supplementary figure).
Muller and Winkelmann22 first pointed out in 1963 that alopecia areata was found in patients with MG with thymoma. To date, clinical information is available from about 20 patients with both MG and alopecia areata,23 ,24 most of whom are Japanese. The prevalence of alopecia areata in patients with MG is probably higher in Japanese people than in Caucasians.7 ,23 ,24 This ethnic difference may be explained by differences in the immunogenetic background.24 Alopecia areata in patients with MG was reported to be generally associated with thymomas; 15% of patients with MG and alopecia areata had no thymomas with a younger disease onset. Noguchi et al25 described a 4-year-old boy with both MG and alopecia totalis. However, the mean age at the onset of alopecia areata in thymoma-associated MG cases is 44 years, with a similar prevalence in men and women. Alopecia areata appeared after thymomectomy and MG in 70% of the cases. The interval between the MG and alopecia areata was 1–18 years (5.7 years on average, but most cases within 3 years).23 ,24 Since most of these patients had type B2 or B3 thymomas, MG was generally severe with advanced-stage, invasive thymomas.
Although the diagnosis of alopecia areata may appear easy, close inspection is sometimes necessary since many patients will hide or downplay their alopecia areata at a medical visit. In addition, a clinician may conclude that alopecia areata is a side effect of irradiation or chemotherapy for an invasive thymoma, or the result of acute emotional stress from disease. It should be kept in mind that alopecia areata is a serious cosmetic problem and it may have devastating effects on a person's QoL and self-esteem.21 Interestingly, patients with MG with alopecia totalis tend to have an additional (third) autoimmune disease such as PRCA, immunodeficiency or myocarditis.24 Other autoimmune skin disorders including vitiligo and pemphigus are sometimes seen in patients with MG and alopecia areata.
The treatment of alopecia areata is difficult. The best-tested immunosuppressive treatment consists of intradermal injections of triamcinolone acetonide. Topical glucocorticoids are also widely used, especially in children and in adults with less than 50% loss of scalp hair.21 When alopecia areata occurs together with MG, oral prednisolone potentially alleviates both the MG and alopecia areata,23 but overall, the treatments for alopecia totalis have been disappointing.
Immunodeficiency associated with thymoma (Good's syndrome) is a rare cause of combined B and T cell dysfunction in adults, first described by Good in 1954.26 Hypogammaglobulinaemia induced by low numbers of, or absent, B cells in the peripheral blood is the most striking finding. The pathogenesis of this disorder is unknown, although there is some evidence that the basic defect may be in the bone marrow.27 We had a 58-year-old male patient with thymoma-associated MG and immunodeficiency; he completely lacked any CD19 B cells and had no IgG autoantibodies reactive with B cells in peripheral blood.28 Kelesidis and Yang27 reviewed 127 cases with immunodeficiency associated with thymoma. Immunodeficiency results in opportunistic infections linked to various pathogens, including bacterial, fungal, viral and parasitic infections related to both humoral and cell-mediated immune deficiencies. Concomitant with other autoimmune disorders, PRCA in 35% and MG in 16% of the 127 cases suggest that the serious and complicated imbalance of the immune response leads to both immunodeficiency and autoimmunity.
The first patient with MG and Good's syndrome was described by Velde et al in 1966.29 We have evaluated eight patients with MG (four men, four women) with immunodeficiency associated with thymomas based on previous reports and our experience.27–29 The onset ages of MG and immunodeficiency were 48 and 55 years on average, respectively. Type AB thymomas were most common and the severity of MG was mild (including one ocular type). Although the serum IgG levels of these patients were markedly reduced at 147–380 mg/dl (290 mg/dl on average), anti-AChR antibodies were detectable. Opportunistic infections included respiratory tract infections in most patients, followed in frequency by diarrhoea, candidiasis and tuberculosis.
In patients with thymoma-associated MG, recognition of hypogammaglobulinaemia is important, since this disorder has a significant death rate. The major causes of death include serious infections and haematological complications. Intravenous immunoglobulin can reduce the risk of infection. Excess administration of antibiotics and hospitalisation should be considered when immunodeficiency is demonstrated.27 When immunosuppressive agents are used for MG there is a risk that infection will deteriorate. Repeated measurement of serum IgG values is necessary in patients with MG before and after thymomectomy.
Autoimmunity is an important cause of myocarditis because it is a potentially fatal condition but treatable by immunotherapy. About 20 cases showing a unique syndrome of giant-cell myocarditis and myositis, MG and thymoma have been reported.30 ,31 Most patients deteriorated rapidly with lethal arrhythmias and severe heart failure and died despite intensive treatments. Their autopsies showed massive lymphocyte infiltration with widespread giant cells in the heart and skeletal muscles (see the online supplemental figure).
A survey of inflammatory myopathy in patients with MG found this fatal condition in only one patient; seven other patients showed only myocarditis or myositis with a good prognosis.32 Myositis mainly affects limbs and paraspinal muscles, in addition to transmission failure at the neuromuscular junction. The muscle weakness of myositis is not improved by anticholinesterase agents and response to immunotherapy is delayed. This condition may be the same myasthenic myopathy.33 The possible involvement of myositis in patients with MG should be evaluated by serum creatine kinase and electromyography before the start of treatment.
Myocarditis, accompanied by thymoma and MG is a more lethal condition and should be paid special attention. Fatigue, shortness of breath and exercise intolerance may be misdiagnosed as symptoms of MG.34 Respiratory failure attributed to severe heart failure also resembles myasthenic crisis. In addition, lethal arrhythmias, including ventricular tachycardia, sick sinus syndrome and atrial ventricular block, may cause sudden death.8 It has been reported that sudden death is often seen in patients with thymoma-associated MG.3 The management of a patient with myocarditis requires admission to an intensive care unit and the start of treatment as soon as possible. For patients with MG who have cardiac symptoms an electrocardiogram is necessary to avoid overlooking myocarditis.
A focal collection of mononuclear cells is found in the skeletal muscles of patients with MG.34 This subclinical phenomenon, known as lymphorrhages, does not cause clinically defined myopathy. We speculate that the autoantibody-mediated injury is necessary to develop myocarditis or myositis in patients with MG, although the exact mechanism is not yet understood. Thus, over 85% of patients with inflammatory myopathies and MG have at least one of the striatal antibodies.32 Anti-Kv1.4 antibodies, in particular, are closely associated with myocarditis in patients with thymoma-associated MG.6 ,8 In contrast, myositis-specific autoantibodies—detected in 40% of patients with polymyositis or dermatomyositis—are not seen in patients with MG with inflammatory myopathies, suggesting a different disease entity from that defined by striational antibodies.32
Taste is the sensory system which primarily carries out a quality check of food to be ingested.35 Although aided by smell and visual inspection, the final recognition relies on chemoreceptors in the taste buds. Taste disorders disturb the QoL of humans and are also seen in patients with MG. Iseki et al36 first pointed out that taste disorders are one of the non-motor symptoms.
A multicentre cooperative study in Japan surveyed taste disorders in patients with MG.37 We found nine patients with MG who had taste disorders which, after exclusion of other causes, were found to be associated with MG. The average of onset age of MG in these patients was 44 years. Type B2 thymomas were most common and associated with advanced stage and severe involvement of MG. Four of nine patients noticed their taste disorders several months before the onset of their MG. It was noted that their sweet-taste ability was selectively impaired. Seven patients experienced their taste disorders in correlation with the disease activity of their MG. After immunotherapy for MG the taste disorders improved or were eliminated in five patients. However, four patients had a relapse of the taste disorder when their thymoma recurred.
Although the mechanisms are unknown, we suspect that taste disorders in patients with thymomas may be immune mediated, based on the distinct clinical features. Taste disorders may be unrecognised or misjudged as a side effect of drugs used for chemotherapy and immunotherapy. They should be recognised as one of the important non-motor symptoms.
Many researchers have attempted to elucidate the autoimmune mechanisms of anti-AChR antibody production. However, the relationships between thymomas, MG and the characteristic autoimmune responses are complicated and not fully established. The pathogenesis of other autoimmune diseases associated with thymomas is also unknown. We propose the hypothesis of an association between thymomas, MG and other autoimmune disorders based on previous studies (figure 1).38–42
Pathogenesis in thymomas
Thymomas contain abundant immature thymocytes and developing CD4 and CD8 T cells.4 These T cells may be actively selected or immunised against self-antigens including AChR, VGKC and other molecules. These autoantigens, probably partial fragments including pathogenetic peptides, are expressed in thymic epithelial cells. Thymomas fail to delete, or randomly generate and export, non-tolerant T cells in association with decreased function of the autoimmune regulator (AIRE) gene and regulatory T cells (Treg). The AIRE gene plays a crucial role in the expression of tissue-specific self-antigens within the thymus, and the defective AIRE expression of thymic epithelial cells results in spontaneous autoimmunity.38 It was also demonstrated that thymomas export many autoreactive CD4 T cells that are accompanied by a reduced number of Treg in thymomas.39 Both CD4 and CD8 T cells move to the periphery where they can persist, potentially stimulating autoantibody production and subsequent autoimmune disease.
To test this hypothesis, Buckley et al40 evaluated T cell receptor excision circles (TRECs). TRECs in peripheral lymphocytes reflect the balance between the thymic export of T cells and their persistence and rate of proliferation in the periphery. TRECs were significantly raised in both the CD4 and CD8 peripheral blood compartment of patients with thymoma-associated MG. It was also reported that TRECs remained detectable for at least 20 years after thymomectomy.40 These results suggested that significant numbers of both CD4 and CD8 T cells exported from thymomas could persist in peripheral sites. In addition, Nagvekar et al41 established pathogenetic T cell clones which were autoreactive to pathogenetic AChR peptides from the thymoma cells of patients with thymoma-associated MG.
Pathogenesis in peripheral sites
Autoreactive T cells exported from thymomas need to encounter self-antigens in the periphery, in some cases at a later time, in order to maintain or initiate an autoimmune response.42 CD8 T cells recognise epitopes presented by target organs, perhaps after tissue damage or inflammation, with the upregulation of human leucocyte antigen (HLA)-class I and/or accessory molecules. CD8 T cell-mediated cytotoxicity is closely associated with autoimmune responses in bone marrow and skin. Moreover, cytotoxicity results in the release of other antigens, leading to uptake and presentation by HLA-class II-positive antigen-presenting cells, including antigen-specific B cells.42 Only when antigens, HLA-class II-restricted T cells and the specific B cells are present together—probably in local lymph nodes—can autoantibodies be produced.
The activity of autoantibodies targeted at AChR on the neuromuscular junction results in the development of MG. In contrast, VGKC has several types of subunits, including neuronal VGKC (Kv1.1, Kv1.2 and Kv1.6) and muscular VGKC (Kv1.4). True targeted molecules may be not VGKC but rather the associated molecules. Importantly, autoantibodies to the several types of VGKC and the related molecules can evoke various neurological and cardiac autoimmune disorders.6 ,12 ,14 ,32 Taste disorders may be induced by undetermined antibodies associated with thymomas and targeted against molecules of the sweet-taste cells.35
In contrast, CD8 T cell cytotoxicity against haematopoietic precursor cells in bone marrow and unidentified autoantigens in hair follicles result in the development of PRCA, immunodeficiency and alopecia areata.16 ,21 ,27 Mature and long-lived CD8 T cells from thymomas are associated with the later development of PRCA.40 Taken together, both MG and non-motor symptoms are strongly associated with abnormal CD4 and CD8 T cell clones exported from thymomas.
Two different pathogeneses
There are clear differences in pathogenesis among non-motor symptoms; autoantibody-mediated damage; and CD8 T cell cytotoxicity. Neuromyotonia, limbic encephalitis, myocarditis and taste disorders are responsive to immunotherapy such as plasmapheresis or intravenous immunoglobulin. These conditions are usually synchronised with the disease activity of MG. The clinical findings suggest that these autoimmune disorders are autoantibody mediated. In contrast, PRCA, alopecia areata and immunodeficiency develop independently of the clinical course of MG and their response to immunotherapy is usually limited.
This distinction corresponds to central nervous system (CNS) autoimmune syndromes: diseases associated with intracellular antibodies (classical paraneoplastic CNS syndrome) and those with neuronal surface antibodies.13 It is generally accepted that intracellular antibodies (Hu, Yo, Ri, Ma2, etc) are markers for the immune-mediated process, but are not pathogenic. CD8 T cell cytotoxicity toward the same or other antigens is thought to be causative of classic paraneoplastic CNS syndrome.
Characteristics of non-motor symptoms
The frequencies of non-motor symptoms among Japanese patients with thymoma-associated MG in a multicentre cooperative study are shown in table 1. The frequencies ranged from <1% of the patients with limbic encephalitis to 12% for those with alopecia areata. About 25% of the patients with thymoma-associated MG had at least one non-motor symptom. Evoli et al7 reported that 16% of patients with thymoma-associated MG had paraneoplastic diseases. The characteristics of the non-motor symptoms are summarised as follows.
Autoimmunity targets various organs and results in various symptoms.
The disease impact of non-motor symptoms ranges from the impairment of QoL to lethal conditions.
Several non-motor symptoms may develop in the same patient (see online supplementary figure).
The activity of other autoimmune diseases does not parallel that of MG.
These diseases sometimes develop several years (occasionally up to 15 years) after thymomectomy, even when the thymoma was completely removed.
Non-motor symptoms are less common in patients with MG without thymoma.
Early diagnosis is important, since non-motor symptoms are potentially treatable.
Why are non-motor symptoms overlooked?
We suspect that non-motor symptoms in thymomas may be overlooked by physicians for the following reasons:
The number of patients with thymoma-associated MG followed up in a single institution is small.
Patients with thymoma may be followed up separately by a neurologist, surgeons, haematologists and/or dermatologist.
Since much attention is paid to the severe manifestation of MG alone, non-motor symptoms are disregarded.
Non-motor symptoms may be misdiagnosed as side effects of immunotherapy, radiotherapy or chemotherapy for MG or thymoma.
Long-term follow-up over 10 years is required, since the survival rate of patients with invasive thymomas has improved.
We emphasise that patients with MG with thymomas may have non-motor symptoms in addition to MG symptoms. In this review we have described only seven non-motor symptoms, but the spectrum of non-motor symptoms attributed to thymomas may be broader.3 ,4 Glomerulonephritis and ulcerative colitis are also listed as autoimmune diseases associated with thymomas and MG.3 ,4 ,7 To elucidate the clinical features of non-motor symptoms, multicentre research is recommended, since the clinical information available in a single hospital is insufficient. There may be ethnic differences in non-motor symptoms, although the clinical features of thymoma-associated MG are generally homogeneous in different countries. Moreover, further investigations are necessary to disclose the pathogenesis of these autoimmune disorders. A determination of the pathogenesis of autoimmunity will enable new and better treatments to be developed. A thorough understanding of non-motor symptoms is necessary for the management of patients with thymoma-associated MG.
We thank all patients, family members and cooperative physicians. This work was supported by a grant from the Japanese Ministry of Education, Science, Sports and Culture (No 23591255) and a neuroimmunological disease research committee grant from the Japanese Ministry of Health, Labour and Welfare.
Contributors All the authors made substantial contributions to the conception and design of this review article. They drafted the article together and revised it critically for important intellectual content. The version to be published was approved by all the authors.
Competing interests None.
Patient consent Obtained.
Ethics approval Institutional review boards of Keio University.
Provenance and peer review Commissioned; externally peer reviewed.