Which Lung Nodules Need Follow-up?

A 65 year old man who is a lifelong smoker undergoes low dose CT scan of the chest given recent onset cough and night sweats. The scan picks up a 8 mm nodule in the right upper lobe. Thoracic lymph nodes are not enlarged and there are no other lesions. How does one follow up?

The incidentally discovered solitary lung nodule must be one of the commonest problems faced by clinicians. Further, in the USA in particular, there is insurance coverage for low dose CT scannning of current smokers or ex-smokers aged 50-75 who have quit within the last 15 years, who have at least a 30-pack year smoking history. Studies have shown that such screening reduces lung cancer related mortality by 20%.

But which nodules do you ignore and which do you follow-up?

Studies conducted in smokers show that several factors predict risk of a cancerous lung nodule. Size is probably the most important. Nodules less than 5 mm carry <1% risk of cancer. This risk rises to 50% with nodules greater than 20 mm. A lesion bigger than 30 mm is classified as a "mass" rather than as a nodule. Other factors which increase risk of a nodule being cancerous are older age, female gender, family history of lung cancer, location in the upper lobe, emphysema, a part-solid rather than pure solid or ground glass (also called sub-solid) nodule and spiculation. The likelihood of cancer decreases when the number of nodules crosses four. Other factors also influence the likelihood of cancer being present. While most patterns of calcification are thought to favour a benign nodule, eccentric calcification increases the risk that the nodule is cancerous. Popcorn calcification is characteristic of hamartomas, while central calcification is usually benign. Peri-fissural nodules are almost always benign. Nodules which have been shown to grow on successive CT scans are clearly suspicious. However, the pace of growth matters. Most cancerous nodules have a "tumour-doubling time" between 20 and 400 days. Nodules which double in less than 20 days are likely to be infective. While most nodules taking more than 400 days to double in diameter on CT are likely to be benign, this does not apply to ground glass (subsolid) or part solid nodules. These lesions, particularly the subsolid nodules can only be picked up on CT, but not on chest Xray. Subsolid or part solid nodules can represent in situ adenocarcinoma, minimally invasive adenocarcinoma, lepidic adenocarcinoma, or carcinoid, are particularly common in non-smokers, and take longer to increase in size, with a tumour doubling time of up to 800 days. While solid nodules need only be followed up for 2 years, subsolid or part solid nodules need follow-up for 3 years. There is an on-line resource, available from Brock University, Canada, based on the Pan Can study which was then validated in a British Colombian cohort, which incorporates the above factors into a risk model. http://www.uptodate.com/contents/calculator-solitary-pulmonary-nodule-malignancy-risk-brock-university-cancer-prediction-equation?source=see_link&utdPopup=true Using the calculator, subjects are classified into 3 groups in terms of the likelihood that lung cancer is present <5% 5-65% >65%

With the lowest risk group, it is only necessary to do surveillance CT scans at algorithm determined intervals. The intermediate risk group should have a PET scan to assess the likelihood of cancer (>2.5 SUV being suspicious), while the highest risk group would have a direct non-surgical or surgical biopsy.

Normally, nodules less than 5 mm need no further follow-up unless they are part-solid. Larger solid nodules less than 8mm (called sub-centimetre nodules although the threshold is 8 mm rather than 1 cm), would need follow up up to 2 or 3 years depending on whether they are solid or subsolid. Nodules larger than 8 mm would ordinarily be scanned after 3-6 months, with repeat scans in 9-12 months and 18-24 months. If the nodule has grown more than 50% between scans or by more than 20% in two dimensions, it will need a biopsy.

Any lymph node involvement would mandate a biopsy straightaway.

Just a word of caution. These guidelines were designed for smokers and have not been validated in non-smokers. The predominant cancer in non-smokers is adenocarcinoma, which tend to be peripherally located ground glass nodules. Small cell cancers are solid nodules, also peripherally located, while squamous cell cancers are usually central lesions.

Endocarditis Is Not Always Infective

A 31 year old lady presents to you with a history of recent recurrent "bruising". Although she has no active lesions at the moment and looks quite well, pictures taken on her mobile phone show a substantial dark area on the left ring finger and larger, incomplete dark circular lesions on her upper shins. The GP has checked her ANA. It's negative. Inflammatory parameters are normal. She has two healthy children.

A 71 year old man presents with transient dark lesions on his fingers. On his second visit, you are lucky enough to catch sight of some of these dark areas on the fingers. They are tender. The patient is well and apyrexial without audible murmurs. You diagnose Osler's nodes and ask for blood cultures and echo.

All perfectly reasonable. Except that it may not be enough.

The prospect of embolic lesions from the heart valves is terrifying, but not all such cases are infective endocarditis. There are other possibilities.

Young women with SLE often have Libman Sacks lesions on left sided heart valves, particularly the mitral valve. This is three times more common in those with anti-phospholipid antibodies, which can exist independently of lupus. Although subjects with SLE and Libman Sack's lesions tend to have active lupus, often associated with lupus nephritis, subjects with aPL alone may have been hitherto asymptomatic. While it is important to dip the urine for blood and protein to screen for lupus nephritis, immune glomerulonephritis in infective endocarditis can cause an active urinary sediment.

In fact, Glomerulonephritis is one of the four immune manifestations of infective endocarditis, the other three being Osler's nodes, Roth spots and a false positive Rheumtoid factor (aid memoire GORR).

Treatment would be immunosuppression and anticoagulation, although there are no RCTs that support the use of the former in Libman Sacks endocarditis.

The old man with "Osler nodes" may have cancer, with thrombotic, non infective endocarditis. Clots, present on the heart valves (again more common on the left), are thought to be due to hypercoagulability. Such patients may often have occult DVTs or pulmonary emboli. Gastric or pancreatic cancers may have associated portal or mesenteric vein thrombosis. Apart from treatment of the underlying cancer, these patients need clexane. Warfarin would be ineffective.

Cancer and infective endocarditis can co-exist due to Streptococcus bovis septicaemia. These patients often have underlying colon cancer. Others have cirrhosis.

Subjects with left atrial myxoma can present exactly like subacute bacterial endocarditis with fever, lassitude, murmurs and embolic phenomena. Echo may pick up pedunculated lesions on the mitral valve.

A final non-infective cause of cardiac emboli is eosinophilia. Regardless of the underlying cause of eosinophilia, prolonged or high eosinophil counts go through three phases- cardiac microabscesses, a flabby, poorly contractile myocardium and endomyocardial fibrosis. It is in the second stage that clots build up, often in the left ventricle, which can then embolise and cause strokes, renal or splenic infarcts, just like infective endocarditis.

Eosinophilia can also occur secondarily in subjects with cholesterol emboli, usually from the aorta. These often present in the elderly with renal impairment and livedo in the lower limbs following an invasive procedure such as cardiac catheterisation. There are reports of cholesterol emboli occurring after anticoagulation.

It is important to consider these non-infective causes of endocarditis in subjects with cardiac vegetations on echo, who are culture negative and do not have the expected response to antibiotics.

Shoshin Beriberi: An Underappreciated Cause of Severe Heart Failure

Severe heart failure, often with cardio-renal syndrome, is a despairing condition to treat. Rescue therapies such as LVAD are not widely available and cardiac transplantation is rarely used, even in developed countries. Subjects may be on optimum medical treatment and may have already been fitted with CRT-D in cases associated with LBBB.

Certain hidden aetiologies deserve mention.

Correcting iron deficiency, through IV iron infusion, can help.

Alcoholics deserve special mention. Heart failure in alcoholics is often confused with anasarca caused by cirrhosis. Many of these subjects have alcoholic cardiomyopathy, and in refractory, newly diagnosed heart failure, a history of alcohol abuse must always be sought.

Beri-beri is now considered very infrequently. First described in Japan in subjects consuming polished rice, cases seen in the West mainly comprise alcoholics. However, severe thiamine deficiency occurs quickly in subjects with persistent vomiting, after bariatric surgery, after parenteral nutrition, and in cancer patients or other subjects with poor nutrition. Refeeding increases thiamine requirements, as does dextrose infusion.

Dry beri-beri is due to peripheral neuropathy, usually presenting with burning pain the feet and a glove and stocking distribution of patchy sensory loss. Wet beri-beri in its classic form is considered to be a phenotype of hyperdynamic, mainly right sided failure associated with peripheral vasodilatation. The left heart is largely spared.

However, there is another form of beriberi, called "Shoshin beriberi" which may not be widely known. ("Sho" means acute in Japanese, while "shin" denotes heart). This can cause acute bi-ventricular heart failure and if untreated, can be fatal within hours in advanced cases. In the two cases described by Wolf and Levin in The New England Journal of Medicine in 1960, subjects had striking peripheral cyanosis affecting the extremeties, tachycardia, cardiomegaly, hypotension, and pulmonary oedema. Both were alcoholics and one hadn't eaten for six days, subsisting on wine. There was striking improvement with IV thiamine in one patient, while the other case was only diagnosed at autopsy.

Another under-appreciated sign of thiamine deficiency in such subjects is lactic acidosis. This acidosis often drives severe tachypnoea and thus such subjects may have a paradoxically normal oxygen saturation, despite striking peripheral cyanosis. Thus, an alcoholic or otherwise malnourished subject presenting in acute pulmonary oedema, associated with anxiety, restlessness, dyspnoea and often central chest discomfort, with lactic acidosis on venous blood gas often upto 6-7 mmol/l, should be considered to have Shoshin beriberi. Intravenous thiamine may be lifesaving in such cases, and should be administered without delay even if a history of alcohol abuse is not immediately forthcoming. Whole blood thiamine or erythrocyte transketolase levels should be sent off concurrently.

It is well recognised that loop diuretics cause increased loss of thiamine in the urine. However, there is disagreement on whether this has the potential to worsen heart failure.

For some reason, Wernicke's encephalopathy and beri-beri do not co-exist very often. These disparate signs of severe thiamine deficiency are therefore rarely seen together.

The Striking Gender Bias of Hepatic Lesions

For unfathomable reasons, most hepatic lesions have striking gender bias.

Amoebic liver abscess is 9 times more common in men, and almost always present in the right lobe of the liver. It is almost always single. Coexistent amoebic colitis is rare and occurs in only 10% of cases. Serology is an excellent test.

Pyogenic abscesses are usually multiple. No gender bias.

Hepatocellular carcinoma occurs in a shrunken, cirrhotic liver, usually in the right lobe. It is 3 times more common in men, occurs in older subjects (usually >60) and is associated with a rise in serum alpha-fetoprotein in 70% cases.

Metastatic liver cancers are 30-times more common than primary hepatocellular cancer.

Fibrolamellar hepatocellular carcinoma occurs in much younger subjects- mean age 25. It accounts for 10% of primary liver cancers, and is not associated with a rise in alpha-fetoprotein. Distribution is equal between men and women, and between right and left lobes of liver. Prognosis is good, and if resected before metastasising , this cancer is associated with more than 60% 5-year survival. It occurs in a normal appearing liver (not cirrhotic) and has a central scar. Lesions are usually >10 cm, and can present with subcostal pain, intermittent pyrexia and weight loss over years.

Also with a central scar is focal nodular hyperplasia. It is usually solitary, discovered incidentally, is <5 cm in size, much more common in females and occurs in 3rd to 5th decades of life. Hepatic adenomas are almost exclusively seen in young women on oral contraceptives. When they occur in men, a history of anabolic steroid abuse must be sought. Cholangiocarcinomas are only slightly more common in men, but much more so when associated with sclerosing cholangitis, which is 9-times more common in men. Cholangiocarcinomas are often associated with a rise in serum Ca-19-9. However, this antigen is only present in subjects who have the Duffy blood group antigen. Gallbladder cancer is 2-6 times more common in women. Choledochal cysts are 3-4 times more common in women.

Random X Chromosome Inactivation as a Marker of Clonality

A female subject inherits two X-chromosomes, one from each parent. Shortly after conception, each somatic cell randomly inactivates (turns off) one of the X chromosomes. All daughter cells arising subsequently will therefore carry the same pair of inactive and active X chromosome. Since the process is random, the likelihood is that there will be a roughly equal split between inactivation of the paternal or maternal X chromosome.

The process by which this inactivation occurs is by methylation of the genes present on the inactivated X chromosome. Methylation silences the gene, an example of epigenetic modification.

The phenomenon of random X-inactivation can be used to determine the clonality of haematopoetic cells, when these cells are suspected to be neoplastic.

Determining clonality is easy for B cells and T cells. Each B cell experiences an isotype switch from IgM to IgG, IgA, or IgE during its development. B cells then rearrange their immunoglobulin heavy chains and express only the kappa or lambda light chain. Thus a lymphoma arising from a B cell clone will carry a rearranged mu, gamma, alpha or epsilon heavy chain and either kappa or lambda light chain.

T cells don't express cell surface immunoglobulins, but do carry T cell receptors. Just like B cells, they rearrange these receptors upon exposure to their cognate antigen. T cells carry alpha/beta and gamma/delta receptors, although only one of these pairs is expressed. It is easier to test for rearrangement of gamma receptors, because they have less polymorphisms.

However, such unique receptors or cell surface immunoglobulins do not exist for other haematopoetic cells, such as natural killer cells, macrophages or eosinophils. (Yes, they do express generic receptors, but these are not unique for each cell, unlike in T or B cells, which have to recognise specific antigens)

In females, as long there is heterozygosity, inactivation of a gene present on the X chromosome can be used to determine clonality in these haematopoetic cells. Such genes include phosphoglycerate kinase (PGK), hypoxanthine guanine phosphoribosyl transferase and human androgen receptor. Such analysis cannot be done if a both alleles of the gene are the same, i.e. with a state of homozygosity.

PGK has been used, but carries the drawback that there is only 40% heterozygosity in the population for this gene. Most such analyses are now done with the Human Androgen Receptor gene (HUMARA), as the prevalence of heterozygosity is very high- around 90%.

Restriction endonucleases which are methylation sensitive, are used to digest the DNA on each allele. The methylated (inactivated) allele will not be broken down, while the unmethylated (active) allele will be. All daughter cells arising from a single (clonal) cell will carry either the unmethylated (cleaved) or methylated (uncleaved) DNA, but not both. In homozygotes, since the paternally and maternally inherited alleles would be identical, it would not be possible to tell whether the paternal or maternal allele of the gene was present in the cells under consideration.

Males carry only one X-chromosome, hence the phenomenon of random X inactivation cannot be used to determine clonality in men.

Natural Killer Cell Alloreactivity in Haplo-identical Stem Cell Transplantation

Only 30% of subjects needing haematopoetic stem cell transplantation (HSCT) will find HLA identical donors. In the case of related donors, the requirement is to match all 6 alleles at HLA A, B and DRB1, while, for unrelated donors, matching needs to be 8/8, i.e. at HLA A, B, C and DRB1.

An alternative to fully matched donors, is using a haplo-identical donor. This could be a parent, an offspring, a sibling or half-sibling. It is estimated that there is a mean of 2.7 haplo-identical donors available for every subject needing HSCT. These donors are naturally highly motivated, being related donors. Unlike cord blood donations, haplo-identical donors will be available for further infusions of stem cells or lymphocytes at a later date for graft failure or infections respectively if needed.

However, samples of bone marrow or peripheral blood obtained from haplo-identical donors have large numbers of T-cells, giving a much higher risk of GVHD. There is severe bidirectional alloreactivity, also increasing the risk of graft failure. This can be mitigated by depleting the T-lymphocytes in the donor sample with pre-treatment with anti-thymocyte globulin and drugs such as cyclophosphamide or busulfan, and by reducing the risk of GVHD with medthotrexate and cyclosporin or tacrolimus.

Children tend to do better when they receive a haplo-identical graft from the mother rather than the father. Similarly, when receiving the graft from a sibling, they do better if the haplotype mismatch applies to the maternal antigens rather than paternal ones. This is due to the effect of non-inherited maternal antigens (NIMA). It is thought that exposure to maternal antigens in utero, even if those antigens have not been inherited, tolerizes the child's immune system to NIMA. The same does not apply to paternal antigens. Mismatch for paternal antigens carries a worse outcome.

In 2002, Ruggeri and colleagues from Perugia, Italy published a seminal work of research in Science that was to unleash a decade long quest to investigate the role of Natural Killer Cells (NK cells) in transplantation. The role of NK cells, as a part of innate immunity, is to find and destroy cancer cells and infected cells before the adaptive immune system is called into play. They do this by recognising the absence of cognate HLA Class I receptors on the surface of their target cells. If such receptors are detected, the NK cells do not kill them, while if the "self" receptors are absent or not recognised, cytolysis occurs.

To this end, NK cells carry two types of receptors, the NKG2D/CD94 hetero-dimeric receptor which is inhibitory, and a much larger group of receptors called Killer Cell Immunoglobulin-like receptor (KIR), which is comprised of some 15 genes. KIR receptors are broadly of 2 types- A & B. Type A KIR receptors do not have a great deal of antigenic heterogeneity, and are mostly inhibitory. Type B KIR receptors are much more diverse and include both inhibitory and activating receptors. The inhibitory receptors have the suffix L (e.g. KIR2DL. KIR3DL) while activating receptors end with a S (e.g. KIR2DS).

After HSCT, NK cells are usually the first to be repopulated, before T-cells have had time to recover. It is probably stating the obvious to mention that T-cells account for the bulk of graft versus leukaemia (GVL) effect, but increase the risk of GVHD.

Ruggeri and his colleagues found that in T-cell depleted stem cell transplants, when there was mismatch between the recepient's and donor's KIR ligands (the receptors for KIR), GVL effect was better, leukaemia free progression (LFP) was longer and GVHD occurred less often. It is easy to understand why NK cells would attack leukemia cells, but how do you explain a reduced incidence of acute GVHD? It is thought that NK cells do this through allo-reactivity against the recipient's antigen presenting cells (mismatched for KIR ligands).

This effect was not replicated in T-cell replete grafts, presumably because T-cells would increase the risk of GVHD and thus nullify the effect of NK cells.

It is now clear that it is not just the host characteristics that influence graft survival. Unrelated donors who have at least one KIR-B haplotype (KIR B/x, as opposed to KIR A/A), display greater GVL effect, even in T-cell replete grafts. There may therefore be a case or deliberately selecting donors whose NK cells carry KIR-B. KIR-B alleles lying in the centromeric rather than telomeric position appear to provide greater GVL effect. There is also a dose response effect, with greater number of KIR B alleles providing more efficacy.

Further, recipients who are homozygous for HLA-C2 benefit less than those heterozygous or homozygous for HLA-C1. It appears that the activating receptor KIR2DS1, whose cognate receptor is the HLA Class C molecule, will only destroy leukaemia cells that carry HLA-C1, but is tolerized by HLA-C2. Fortunately only 15% of subjects with acute leukaemia are homozygous for HLA-C2.

Finally, mismatch for HLA-Class C antigen between donor and recipient increases the benefits offered by NK cells in terms of GVL effect and LFP through alloreactivity.

It is worth mentioning that these salutary effects of NK cells in haplo-identical and unrelated-donor HSCT are only seen for recipients with AML, but not with ALL.

Hence, if multiple haplo-identical or unrelated, otherwise matched donors are under consideration for a recipient with AML, it is worth selecting the donor with KIR B alleles over a donor who is homozygous for KIR A. There is less agreement over whether to select donors who are deliberately mismatched for KIR ligands to increase NK cell alloreactivity in haploidentical transplants, as some studies have shown a higher risk of GVHD.

References:

1. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A: Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.

2. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, Marsh SG, Geraghty D, Spellman S, Haagenson MD, Ladner M,Trachtenberg E, Parham P, Miller JS: Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 2010; 116: 2411–2419.

Differentiating Neuropsychiatric Lupus from Anti-Phospholipid syndrome

We've all been there. An elderly woman with obvious cognitive dysfunction, otherwise well and apyrexial, but with high ESR/CRP, is screened for "autoimmunity". The screen comes back as strongly positive. The patient is positive for ANA, dsDNA, C3, C4, lupus anticoagulant and IgG antibodies to beta-2 glycoprotein I. A question is asked. Does this patient have "cerebral lupus?" Do we give steroids, anticoagulation, or both?

Even experts find it difficult to make such determinations. There is too much soft research, nonspecific tests and grey areas passed off as "evidence" in the literature that confuses rather than resolves the issue. However, there are some hard facts that can be relied on. One must take care to ask the right questions.

1. Lupus vasculitis as a cause of neuro-psychiatric lupus (NP lupus) is uncommon~3% of all cases of NP lupus. Most patients with lupus vasculitis present with fever, severe headache and confusion and may progress to coma. A true emergency. The focus is on ruling out infection and TTP, and immunosuppressing ASAP with high dose steroids and cyclophosphamide.

2. Most cases of dementia related to lupus have stable, non-progressive disease and do not need to be immunosuppressed. Aspirin and statins are the order of the day.

3. Two-thirds of neuro-psychatric manifestations in lupus are due to non-lupus causes. Consider infections, medications (e.g. aseptic meningitis caused by NSAIDs and azathioprine, CVA caused by steroids), posterior reversible encephalopathy syndrome in those with very high BP and visual disturbances, TTP, atherosclerosis (risk factors diabetes, BP, hyperlipidaemia and smoking- all treatable causes), obstructive sleep apnoea (causing headache and fatigue).

4. Lumbar puncture is one of the most useful tests in NP lupus. Neutrophilia and high CSF protein indicates vasculitis (if bacterial meningitis can be ruled out). Anti-phospholipid (APL) syndrome is associated with raised protein but no pleocytosis. Presence of raised protein and mild lymphocytic pleocytosis indicates non-vasculitic active NP lupus (raised protein more common than pleocytosis). Hypoglycorrhachia indicates infection, with the exception of transverse myelitis, where CSF sugar is often low.

5. CSF IgG levels, IgG index, and CSF oligoclonal bands are really useful tests. CSF IgG levels are raised in over 2/3 of patients with NP lupus and a CSF IgG level> 6mg/dl is virtually pathognomonic of active NP lupus, although present in only 40% of cases. A raised CSF IgG index and CSF oligoclonal bands are seen in ~80% of cases with active NP lupus, particularly those with diffuse manifestations such as encephalopathy and psychosis. IgG index and oligoclonal bands will be normal/absent in those with focal symptoms such as hemiparesis caused by APL syndrome or chorea. CSF Q-albumin is not an useful test as it'd be raised in any aetiology that causes breakdown of the blood brain barrier such as stroke.

(IgG index is the ratio of two ratios- CSF IgG/CSF albumin divided by serum IgG/serum albumin. Normal IgG index is less than 0.66)

(Q-albumin is simply the ratio between CSF albumin and serum albumin).

6. Demographics are really important. Lupus patients with chorea and transverse myelitis tend to be young women. Always check ANA in a young woman who develops chorea. A positive ANA makes it more likely than not that she has lupus. APL is overrepresented in these two conditions, and in those with seizures.

7. Always check NMO-IgG in a lupus or Sjogren's patient who develops optic neuritis or transverse myelitis. The antibody is present in 75% of subjects with neuromyelitis optica, and carries an adverse prognosis, with multiple recurrences. Anti-Ro antibodies are often associated.

8. Large vessel stroke in SLE is bad news. Can be caused by APL, hypertension or TTP, the typical patient is 35 years old, 86% have active SLE at the time of stroke, and 40% will die in the short term. Thirteen percent will have recurrent stroke.

9. Recurrent TIAs with small infarcts is more characteristic of APL.

10. MRI is overrated. Although it is the preferred imaging procedure in picking up lesions of NP lupus, these typically appear as small white matter lesions on T2 weighted MRI. These are non-specific and can be found in many subjects with lupus who do not have NP manifestations.

11. Studies on anti-neuronal antibodies, antibodies to NMDAR and anti-ribosomal P antibodies are simply too discordant for these tests to be useful, although the latter is reasonably specific for lupus with severe psychosis or depression.

12. The old adage about ESR and CRP in SLE is true. ESR tends to be raised in subjects with lupus, while CRP rises with infection or vasculitis. A subject with NP lupus with raised CRP should be suspected to have infection or vasculitis.

13. NP lupus typically occurs in subjects with active lupus, but less commonly, can be the first presentation of the condition.

14. Scan the heart in all patients with NP lupus. Non infective vegetations (Libman sacks endocarditis) on left sided valves can be a source of emboli for subjects with stroke or multi-infarct phenotypes. APL is overrepresented in such subjects.

15. Don't ignore investigations you'd otherwise perform in non-lupus subjects with stroke, young or otherwise. Thus, carotid dopplers in all patients, and serum homocysteine in young patients should be checked. Young patients with recurrent stroke should be screened for patent foramen ovale through bubble contrast echo.

16. Presence of livedo reticularis (Sneddon's syndrome), thrombocytopenia, adverse obstetric history, or a history of clots makes it more likely that APL is the cause. Subjects with arterial clots related to APL tend to have recurrent arterial clots, while those with venous clots tend to have recurrent VTE, albeit at different sites.