PseudovasculitidesMikhail ValivachPavlodar 2015

Vasculitis-like disorders

• Viral endotheliitis (EBV, HSV, etc.). • Microembolism (atheroembolism, septic

embolism, etc.). • Thrombophilic disorders (DIC syndrone, APS,

etc.).• Metabolic angiopathies (diabetes,

homocysteinemia, calciphilaxis).

Vasculitides and pseudovasculitides have identical

clinical manifestations• If you are not familiar with manifestations of

vasculitides I would refer you to my presentation “Manifestations of vasculitides and pseudovasculitides”.

• You can find this persentation through yahoo.com using key words Valivach Manifestations of vasculitides and pseudovasculitides.

• We shall use many illustrations in this presentation.• You will be asked “What this could be?”• Think, what disease could cause these symptoms?• In addition, try to find out which size vessels are

affected?• Signs of different size vessel damages you can find in

Table 2 of “Diagnosis of vasculitides and pseudovasculitides. A quick reference guide. ”. You can find this guide through yahoo.com using key words valivach vasculitis quick reference guide

What this could be?

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calciphylaxis

Calciphylaxis of small vessels is revealed by histology, and medium vessels by x-ray

Causes of calciphylaxis

• Causes of calciphylaxis are not clearly understood, because in most patients with the same disorders calcifilaxis does not develop:

• - Chronic renal failure;• - Hyperparathyroidism;• - Overdosage of vitamin D3;• - Calcium overdosage;• - Sugar diabetes;• - Probably other causes.

Principles of diagnosis

• Overdosage of vitamin D3 :• Long lasting vitamin high dosage D3 intake.

Principles of diagnosis

• Hyperparathyroidism:• Can be suspected in osteoporosis, asthenia,

polyuria, thirst, nausea, nephrolithiasis, hypercalciemia, etc.

• Diagnosis confirmation: High blood parathormone level.

• Further treatment by endocrinologist.

Principles of diagnosis

• Calciphylaxis in sugar diabetes. • Can be suspected in the patients with high

blood glucose level.• Further treatment by endocrinologist.

Thrombosis and hemorrages of retinal arteries in homocysteinemia

Homocysteinemia• Homocysteinemia – increased blood

homocysteine level.• Homocysteinemia is due to a genetic

predisposition. Nutritional and environmental factors, as well as specific medications, may worsen this abnormality and provoke symptoms.

• These factors include chronic renal failure, hypothyroidism, malignancies, metotrexat and oral contraceptives intake, smoking.

Homocysteinemia• Homocysteinemia causes endothelial damage and

promotes arterial and venous thrombosis and atherosclerosis.

• Homocysteinemia is associated with such thrombotic events as myocardial infarction, stroke, miscarriage, etc.

• High risk of thrombosis after surgical intervention.• For more information refer to

http://emedicine.medscape.com/article/1952251-overview#a1

What you think this could be?

What you think this could be?

• Discoid lupus erythematosus?

• No. This patient has diabetic angiopathy.

Diabetic angiopathy • Diabetic angiopathy can cause as follows:• Nephropathy• Retinopathy• Dermopathy• Polyneuropathy, mononeuropathy, multiple

mononeuropathy• Encephalopathy• Peripheral gangrene • Cardiovascular disorders

Diabetic dermopathy

Diabetic dermopathy

Diabetic dermopathy

Diabetic dermopathy

Diabetic dermopathy

• Cited from http://www.slideshare.net/dnad07/diabetic-retinopathy-39333348

Diabetic nephropathy

• Cited from https://iwandahnial.wordpress.com/2010/10/10/diabetic-kidney-disease/

Diabetic nephropathy

Early diagnosis of diabetic nephropathy

• Microalbuminuria is an early sign of diabetic nephropathy

• 24-hour urine collection. Macroalbuminuria >300 mg/day

• Microalbumin. Normal value <150 mg/day.

What this could be?

What this could be?

Cited from http://www.medivisuals1.com/ttp-thrombotic-thrombocytopenic-purpura-506015-05x.aspx

Thrombotic Thrombocytopenic Purpura (TTP)

• TTP is a rare disorder characterized by clotting and a low platelet count.

• Blood clots form in small blood vessels throughout the body.• Hemolytic anemia is another characteristic sign of TTP. As

red blood cells travel through damaged vessels, they are fragmented resulting in intravascular hemolysis (microangiopathic anemia).

• Microangiopathic anemia is identified by the finding of anemia and schistocytes on microscopy of the blood film.

Schistocytes

• Cited from http://imgarcade.com/1/schistocyte/

Thrombotic Thrombocytopenic Purpura.When to suspect?

• Vasculitis-like symptoms• Low platelet count • Anemia with schistocytes and reticulocytes. • High d-dimer in active disease

Diagnosis of TTP

• Only a small proportion of patients has classical pentad.

• To start treatment it is enough to find microangiopathic anemia (schistocytes and reticulocytes) and low platelets. Note: DIC should be excluded.

Hemolytic uremic syndrome(HUS)

Hemolytic uremic syndrome(HUS)• HUS has much in common with PPT in its

clinical picture and laboratory.• One of the differences is predominant

damages of CNS in PPT, and kidneys in HUS.• HUS is more common in children. • Some cases of HUS are due to Shiga toxin-

producing Escherichia coli (STEC) and less frequently from Shigella dysenteriae type 1 infection.

Disseminated intravascular blood coagulation

• Disseminated intravascular blood coagulation is an acquired thrombohemorrhagic disorder caused by excessive production of thrombin and plasmin in peripheral blood.

DIC causes

• Any kind of shock,• Blood loss,• Intoxication,• Sepsis,• Rhesus- conflict pregnancy,• Sudden cardiac failure,• Gestosis,• Malignancies, • Other

Cited from http://medicalpicturesinfo.com/disseminated-intravascular-coagulation/

Disseminated intravascular blood coagulation

Disseminated intravascular blood coagulation

Disseminated intravascular blood coagulation

Disseminated intravascular blood coagulation

Disseminated intravascular blood coagulation

Diagnostic algorithm for DIC, proposed by the ISTH

• gg

1. Assess the risk of DIC:Does the patient have a disorder known to be associated with DIC?• If yes: calculate the clinical score using this algorithm;• If no: do not use this algorithm

2. Request global coagulation tests: platelet count, prothrombin time, fibrinogen, and fibrin monomers (FM) or fibrin degradation products (FnDP).

3. Score each result of the global coagulation tests:• Platelet count:> 100 G/L = 0; ≤ 100 G/L = 1; ≤ 50 G/L = 2• Elevated fibrin-related marker (e.g. FM or FDP)no increase = 0; moderate increase = 2; strong increase = 3• Prolonged prothrombin time:< 3 sec. = 0; ≥ 3 sec. but < 6 sec. = 1; ≥ 6 sec. = 2• Fibrinogen level:> 1.0 g/L = 0; ≤ 1.0 g/L = 1

4. Add the scores together

5. Analyse the final score:• If ≥ 5: compatible with overt DIC. In this case, repeat the tests and scoring daily• If < 5: suggestive (but not affirmative) for non-overt DIC. In this case, repeat the tests and scoring for the next 1 or 2 days.Cited from http://www.stago.com/haemostasis/tests-clinical-applications/disseminated-intravascular-coagulation/how-to-diagnose-disseminated-intravascular-coagulation/

Acute and chronic DIC-syndrome

• In acute DIC syndrome one can simultaneously see bleeding and thrombotic disorders.

• Chronic DIC demonstrates only thrombosis that makes clinical diagnosis difficult.

• Chronic DIC can develop even in indolent course of malignancies and inflammatory diseases.

Paraneoplastic hypercoagulation

• Paraneoplastic hypercoagulation is a variant of chronic DIC syndrome.

• It can develop in different malignancies.• Diagnosis is difficult when thrombotic disorders

develop before clinical manifestaions of tumor.• Any thrombophilic disorder requires exclusion of

cancer.

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Antiphospholipid syndrome

• Antiphospholipid antibodies can be found in systemic lupus erythematosus or in the absence of any other related disease.

• These antibodies interact with thrombocytes and promote coagulation.

• Antiphospholipid syndrome manifests with venous and arterial thrombosis, and repeated miscarriages.

Criteria for the Classification of the Antiphospholipid Syndrome (APS)

• Clinical Criteria• Vascular thrombosis• One or more clinical episodes of arterial, venous, or small-vessel thrombosis, occurring within any tissue or organ• Complications of pregnancy• One or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation; or• One or more premature births of morphologically normal neonates at or before the 34th week of gestation; or• Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation• Laboratory Criteria• Anticardiolipin antibodies• Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on two or more occasions at

least six weeks apart• Lupus anticoagulant antibodies• Lupus anticoagulant antibodies detected in the blood on two or more occasions at least six weeks apart, according

to the guidelines of the International Society on Thrombosis and Hemostasis• A diagnosis of definite antiphospholipid syndrome requires the presence of at least one of the clinical criteria and at

least one of the laboratory criteria. No limits are placed on the interval between the clinical event and the positive laboratory findings.

• Cited from http://www.medicalcriteria.com/criteria/reu_aps.htm

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Septic embolism• Bacteria and their aggregates can embolize small and medium

vessels.• Any organ can be affected.• These bacteria can interact with antibodies and form immune

conplexes. Then they can cause immune complex type reaction. • They can activate coagulation leading to development of

thrombosis.• A metastatic infection can develop in the site of thrombosis.

Causes of septic embolism

• Septic endocarditis• Fungal endocarditis• Abscesses and purulent infection of any

location• Septicemia

Diagnosis of septic embolism • The first symptoms of embolism can be

connected with occlusion of small and medium size vessels.

• At this stage it is difficult to make differencial diagnosis between septic embolism and other vasculitidis and pseudovasculirides.

• Later characteristic metastatic infection develops.

• Search for primary septic source is mandatory.

Brain abscess due to septic embolism

Cited from oconorlaw.com

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Myxoma is the most common primary tumor of the heart and arises from the endocardium as a polypoid and often pedunculated mass extending into the chamber. Myxoma is a frequent cause of embolism.

Embolism from atrial myxoma

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Atheroembolism

• Atheroembolism (cholesterol embolism) means an embolism of lipid debris from an ulcerated atheromatous deposit from aorta or a large artery to its small branches.

• This results in numerous occlusions of distal medium and small size vessels of different organs with such disorders as:

• - blue toe syndrome• - retinal ischemia• - renal failure• - livedo reticularis• - intestinal infarction• - various other disorders. • Atheroembolism can be triggered by endovascular intervention and

anticoagulant therapy. Atheroembolism can also develop spontaneously.

Classical triad of massive atheroembolism

• Livedo reticularis.• Acute renal failure.• Eosinophilia.• Note: As far as only the most distant arteries are affected,

atheroembolism can be compensated for a long time due to collateral supply. Accumulation of occlusions finally leads to ischemic lesions.

• During this “hidden” period patients can have unexplained fever, weight loss, myalgia, poor appetite, eosinophilia, acute phase blood changes.

Manifestations• Myocardial infarction• Brain infarction • Hemiparesis and paraplegia, mental confusion• Arterial hypertension, oliguria, acute renal failure • Livedo, purpura, ulcers and peripheral necroses • GI hemorrhages, abdominal pains, intestinal infarction,

pancreatitis, ischemic cholecystitis• Myalgia • Lungs not affected

Direct and indirect signs of atheroembolism

• Histological detection of intravascular cholesterol emboli is a direct evidence.

• Biopsy should be deep and multiple. Otherwise chances to find emboli are very low.

• Hollenhorst plaques in retinal arteries are another direct evidence of atheroembolism. Diagnostic sensitivity of this symptom is low because atheroemboli affect mostly lower part of the body.

• Indirect diagnosis based on clinical picture is easier when disorders developed after endovascular intervention or anticoagulants.

• Imaging of unstable atherosclerotic plaques in aorta is another indirect method of diagnosis.

Atheroembolism. Cholesterol clefts.

• Hollenhorst plaques

• (retinal cholesterol emboli)

Diagnosis of atheroembolism

• Diagnosis is difficult. It is easier in certain situations:• 1. Direst detection of cholesterol crystals by histology or

ophtalmoscopy.• 2. Symptoms developed after endovascular intervention

or antigoagulants.• 3. Imaging of unstable atherosclerotic plaques in aorta. • 4. Age > 50 y.o.• 4. Classical variants of clinical picture.

Classical variants of clinical picture• In patients with evident atherosclerosis• First variant• Livedo reticularis.• Acute renal failure.• Eosinophilia.• Second variant• Age > 50 y.o.• Excruciating lower extremity pain • Livedo reticularis • Palpable peripheral pulses

Endothelial infections (endotheliitis)

• Endotheliites caused by HSV, VZ, CMV, and EBV are mostly described by ophthalmologists.

• Reports on endotheliites with other locations are very rare.

• It is still a question if this is because such endotheliites are rare or our diagnostic approaches have low sensitivity.

Corneal endotheliitis

• Corneal endotheliitis is characterized by:• corneal edema, • keratic precipitates, • mild to moderate anterior chamber

inflammation.• Among causes HSV, VZ, CMV, and EBV.• Reported good effect of combination of

antiviral agents with topical steroids.

Case report• Cited from: E.J.Blackwood, D.M.Sharpe. Case Report: Meningomyelitis, cranial neuropathy and cerebral

vasculitis secondary to Epstein Barr virus and varicella zoster virus co-infection of the central nervous system. Posted in Case Reports on 27th Jan 2014. http://www.acnr.co.uk/2014/01/case-report-meningomyelitis-cranial-neuropathy-and-cerebral-vasculitis-secondary-to-epstein-barr-virus-and-varicella-zoster-virus-co-infection-of-the-central-nervous-system/

• A 20-year-old woman with a two-week history of sore throat and fevers. Enlarged cervical lymphnodes.

• Serous meningitis. PCR of CSF revealed EBV and VZ.• Visual acuity deteriorated to count fingers in the right eye

and hand movements in the left eye. Right sided lower motor neuron facial droop. Acute urinary retention.

• Intravenous methylprednisolone 1g/day followed by oral dexamethasone (2gms qid) with improvement on day 21.

• MRI. A. Sagittal T1 post-gadolinium MRI showing enhancement of optic nerve sheath.

• B. Right common carotid cerebral angiogram showing extensive beading and variation in calibre of cerebral arteries consistent with severe cerebral vasculitis.

• C. Sagittal T2 weighted spinal cord MRI with prolongation of T2 signal throughout the thoracolumbar cord.

• D. Diffusion weighted MRI from day 71 showing three acute infarcts.

• Day 36. Fever 38.5C, mild left lower limb weakness.

• Intravenous acyclovir added to treatment. • Day 37. A complete paraplegia. • Day 38. A bulbar palsy was noted with

dysarthria, dysphagia.• Then slow improvement.• In 20 months is stable with poor vision and

paraparesis.

Our own case

• January 9, 2012. Patient B., 1987 г.р.• Repeated episodes of “urticaria”, febril fever,

artralgia and slight swelling of joints (rheumatologist – “reactive artritis”).

• Disease onset in November 2011 with the same complaints. An infectionist once registered a “generalized lymphadenopathy”.

• “Fixed” urticaria-like rash (maculopapular rash)

• Repeated blood tests with differential count were normal excepting increased ESR = 35 mm/hour.

• Repeated urine tests were normal.• Chest x-ray was normal.• Blood biochemistry and d-dimer were normal.• Tests for ANA, ANCA, RF, cryoglobulins were negative. Plasma

electrophoresis found no monoclonal Ig.• Repeated serum ELISA for HIV was negative. • Blood PCR for EBV, HSV, VZ, CMV, HBV, HCV were negative.• Cardiac and aortal ultrasound exams were normal.• Provisional diagnosis: Undifferentiated connective tissue disease?

Lymphotropic viral infection with severe systemic manifestations?

• Skin histology.• Angiocentric

inflammatory infiltrate in upper and middle dermis: lymphocytes, histiocytes, eosinophils. With prevailing lymphocytes.

• Destruction of some small vessels.

Direct immunofluorescence for immune deposits

IgA – no staining. Granular staining of the

walls of small wessels for IgG, IgM, C1 and C3.

Conclusion: Immune deposits in small vessel walls.

• During examination the patient developed a subcutaneous node in the left periareolar area, 10 mm, mobile, moderately tender.

• Biopsy of the node was made.• Before formalin fixation some material was

taken for PCR for EBV, HSV, VZ, and CMV.• Histology was performed.

• Node histology:• Rudimentory

mammary gland with Tzank cells.

• Septal panniculitis.• Cytopathic changes

of endothelium with elongation and polymorphismn of nuclei, marginated and clumped chromatin.

• PCR revealed EBV.• Cytopathic viral effects were found in epithelium

and endothelium..• Conclusion: Endotheliitis caused by EBV.• This case was reported in Russian and is available

online http://health-kz.com/arhiv/6_17_avgust_2013/atipichnoe_protekanie_zatyazhnoj_epshtejnbarr_virusnoj_infekcii_s_vaskulitom_i_poliartritom/

On a practical approach to diagnosis of vasculitides and pseudovasculitides

• Diagnosis is difficult because one should keep in mind a huge number of various disease requiring differential diagnosis.

• I have created a “A quick reference guide. Diagnosis of vasculitides and pseudovasculitides. ”, which, I hope, can be useful for practical doctors.

• You can find this guide through yahoo.com using key words valivach vasculitis quick reference guide

• Dear colleagues, with questions and suggestions you can address to Mikhail Valivach valivach@mail.ru

Thank you for attention!