What Is Vasculitis – Causes, Symptoms, Diagnosis, Treatment

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Vasculitis is a heterogeneous group of pathologie inflammation of blood vessels (which include the veins, arteries, and capillaries) that carry blood throughout the body leading to tissue destruction with or without organ damage. Small vessel vasculitis can be seen secondary to systemic vasculitides such as Anti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (Microscopic polyangiitis, Granulomatosis with polyangiitis or Eosinophilic granulomatosis with polyangiitis), Behçet’s disease, and Cogan’s syndrome. Immune complex-mediated small vessel vasculitis can be seen in rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, Hypocomplementemic urticarial vasculitis, Erythema elevatum diutinum, and cutaneous leukocytoclastic angiitis, formerly known as hypersensitivity vasculitis.  Vasculitis can affect blood vessels of any type, size, or location.  The inflammation can cause the walls of blood vessels to weaken, stretch, thicken, and develop swelling or scarring, which can narrow the vessel and slow or completely stop the normal flow of blood.  This reduced blood flow can permanently damage organs and tissues, including the brain, spinal cord (the central nervous system, or CNS), and peripheral nervous system (PNS, which transmits information from the brain and central nervous system to other parts of the body).  In some cases, the weakened vessel can burst, causing bleeding into surrounding tissues.  In the brain, the inflammation can cause headaches and stroke-like symptoms, or even death.

Vasculitides is a heterogeneous disease entity of variable causes in which immunologically mediated inflammatory reaction of the blood vessel wall leads to vessel wall damage and weakening (aneurysm, rupture) or obstruction of lumen, leading to infarction of tissue.[]

Vasculitis (also called angiitis) can affect anyone, although some types occur more often in people who have autoimmune disorders (disorders that occur when the immune attacks healthy body cells) such as lupus and rheumatoid arthritis, or infectious disorders such as hepatitis B or C.  Some forms of vasculitis affect a particular organ, while others may affect many organs at the same time.  Vasculitis affecting only the brain and spinal cord that is not the result of another systemic disorder is called primary angiitis of the central nervous system.  In some instances, the vasculitis may improve without treatment, while other times, it requires medications.

What causes vasculitis?

Vasculitis occurs when the immune system attacks blood vessels in the body by mistake.  In most instances, the cause of the attack isn’t known.  In other instances, an ongoing or recent infection, other disease of the immune system, an allergic reaction to medications or toxins, and certain blood cancers (such as lymphoma and leukemia) can trigger an immune system reaction and cause damaging inflammation.

How does vasculitis affect the nervous system?

Vasculitis can cause problems in the central and peripheral nervous systems, where it affects the blood vessels that nourish the brain, spinal cord, and peripheral nerves.  Nervous system complications from vasculitis include:

  • headaches, especially a headache that doesn‚Äôt go away
  • cerebral aneurysms (a weak spot on a blood vessel in the brain that balloons out) can burst and spill blood into surrounding tissue (called a hemorrhagic stroke)
  • blood in the inflamed blood vessel can clot (thrombosis), blocking blood flow and causing ischemic stroke
  • confusion or forgetfulness leading to dementia
  • abnormal sensations or a loss of sensations
  • muscle weakness and paralysis, usually in the arms and legs
  • pain
  • swelling of the brain
  • vision problems
  • seizures and convulsions
  • trouble speaking or understanding.

Symptoms of vasculitis generally include fever, a sick feeling, weight loss, unusual rashes or skin discoloration, and damage to virtually any organ system.

How are these syndromes diagnosed in the nervous system?

Diagnosing vasculitis can be difficult, as some diseases have similar symptoms of vasculitis.  It is especially difficult to distinguish from non-inflammatory causes of vasoconstriction (a decrease in the diameter of a blood vessel due to a muscle contraction in the vessel wall).  The diagnosis of a CNS or PNS vasculitis disorder will depend upon the number of blood vessels involved, their size, and their location as well as the types of other organs involved.  A doctor who suspects CNS or PNS vasculitis will review the person’s medical history, perform a physical exam to confirm signs and symptoms, and order diagnostic tests and procedures, including:

  • blood and urine tests to look for signs of inflammation (such as abnormal levels of certain proteins, antibodies and blood cells)
  • analysis of the fluid that surrounds the brain and spinal cord (cerebrospinal fluid) to check for infection and signs of inflammation
  • biopsy of brain or nerve tissue (involving removal of a small piece of tissue that is studied under a microscope)
  • diagnostic imaging using computed tomography (CT) and magnetic resonance imaging (MRI) scans that produce two- and three-dimensional images of the brain, nerves, and other organs, and tissues.¬† Scans are performed before and after injection of a contrast agent to determine if the contrast agent leaks from the weakened vessels.
  • Angiogram (x-ray imaging using a special dye that is released into the bloodstream) to detect the degree of narrowing of the blood vessel in the brain, head, or neck
  • ultrasound to produce high-resolution images of the blood vessel walls and to measure blood flow velocity.
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How is vasculitis treated?

Treatment for vasculitis typically depends on the organ(s) affected and involves drugs aimed at suppressing abnormal immune system activity and reducing inflammation.  Duration of treatment depends on the type of vasculitis but usually, long-term treatment is needed. Medications used to treat vasculitis include:

  • Glucocorticoid drugs – (‚Äústeroids‚ÄĚ) such as prednisone.¬† These drugs, which are often the primary treatment for vasculitis, have anti-inflammatory effects and are generally quick-acting.¬† They may be given in combination with other immunosuppressive drugs. Glucocorticoids are the first-line treatment for patients with vasculitis used with or without immunosuppressive agents. The type of vasculitis guides the choice of immunosuppressive agents.¬†Once the condition is in remission, slow, downward glucocorticoid titration should commence, to maintain control of disease activity and minimize the risks of drug toxicity. Patients and physicians should know the short-term and long-term toxic side effects of therapeutic agents for monitoring.
  • Corticosteroid – Initial treatment for GCA includes steroids, starting at doses 40 to 60 mg a day, as single or divided doses. Glucocorticoid treatment should initiate without delay in patients with a strong suspicion for GCA. Intravenous pulse steroids are an option in patients with recent vision loss. After remission, steroid should be slowly tapered off. Methotrexate and azathioprine can serve as steroid-sparing agents. Tocilizumab has been approved recently for treatment of GCA
  • Rituximab – a type of medication called ‚Äúmonoclonal antibody,‚ÄĚ works by attaching to certain abnormally functioning immune cells (B cells) and killing them.¬† It has been shown not only to be effective in stopping inflammation but also for maintenance therapy to prevent flare-ups. Rituximab 0.5-1 gm every 6 months is a viable option to maintain remission and prevent relapses. Duration of maintenance therapy is highly individualized. Co-trimoxazole has been employed in GPA which prevents respiratory infection-induced relapses and also as prophylaxis in pneumocystis pneumonia. avacopan (CCX168) is an oral small molecule C5a receptor (C5aR) antagonist that blocks neutrophil activation. Avacopan 30 mg, twice daily dosage, can replace high-dose glucocorticoids effectively and safely.[,,,]
  • Cyclophosphamide (CYC) – is a time-tested standard drug which suppresses B cell. Rituximab (RTX) has specific activity against B cells and is quite effective. Both agents induce prolonged remission in the majority of the patients. Opportunistic infections are equally common both with CYC and RTX. RTX is supposed to be effective in inducing remission in patients with relapse.

Cryoglobulinemic vasculitis (CV)

  • In Hep C-induced CV, treatment with ribavirin 200-1400 mg/d, combined with sofosbuvir 400 mg/d not only bring down viral load but also lessens the production of cryoglobulins.[] Steroids and immunosuppressants have a role only in severe diseases like mononeuritis, CNS involvement. In Hep C negative patients, rituximab scores over steroids, however, both are used in conjunction, along with CYC, azathioprine as far as efficacy is concerned, especially in patients with severe GN, skin necrosis, multiple neuritides, and in patients with life-threatening complications.[,]

Hypersensitivity vasculitis

  • Basic investigations include CBC, ESR, CRP, RFT, LFT – and urinalysis. Skin biopsy for histopathology and DIF is mandatory to look for immune-mediated disease. Advanced investigations are anti-streptolysin O titers, Hep B and C panels, HIV serology, ANA, and complement levels. Up to 10% of patients may have chronic disease lasting between 2 and 4 years. Mild cases may respond to rest, leg elevation, and antihistamines. If not, one may need to start oral prednisolone 1-2 mg/kg tapered over a period of 8-12 weeks. Colchicine may be a good option: the usual dose is 0.5-1.5 mg/day as needed or as tolerated.[,,]
  • Dapsone – is an often-used option for those with cutaneous disease. The dose range varies from 50 to 150 mg/day in adults. Precautions include a screening G6PD test, starting at a lower dose (25-50 mg/day for adults) and frequent monitoring (weekly until the maximum tolerated dose, then monthly for 3 months, and eventually quarterly for maintenance). Hydroxychloroquine may be of value in patients not responding or intolerant to dapsone or colchicine. A standard dose of 200-400 mg/day (adults) is used; baseline eye examination and yearly (retinal) examinations are recommended.
  • Prednisolone – is still the most often used drug for those patients with more symptoms or more severe cutaneous disease. The dose is typically 0.5-1.0 mg/kg/day until the cutaneous lesions improve and then slowly tapered over several weeks to months.

Immunosuppressant or cytotoxic drugs.  These medications include methotrexate, azathioprine, and cyclophosphamide.  These agents stop or decrease the function of immune system cells.

  • Azathioprine – may be used as a monotherapy or as a steroid-sparing agent. Dose is most often 50-100 mg/day. A baseline thiopurine methyltransferase (TPMT) enzyme activity level is desirable as well as periodic monitoring of blood cell counts and liver function tests.
  • Mycophenolate mofetil – is a good choice for patients who have become steroid-resistant or dependent. The adult dose is most often 500-2500 mg/day in two divided doses. Methotrexate has been reported to be effective as a steroid-sparing agent in some cases but is not used as often as azathioprine. Oral dose ranges from 5 to 25 mg/week. Adding folic acid 1 mg/day is recommended. Cyclosporin A has been effective in patients either intolerant of prednisolone or in those in whom prednisolone is contraindicated. It is used most often in the early stage of disease and tapered in weeks. Dose range in adults is 2.5-5 mg/kg/day given in two divided doses.
  • Intravenous immune globulin (IVIG) – has been used uncommonly because of the cost and non-availability. It is recommended when the disease is severe and where infection or immune deficiency may be present. Precautions in the use of IVIG include checking for IGA deficiencies and the doses are titrated depending upon the renal status.
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Henoch Schonlein purpura (IgA vasculitis)

Investigations include CBC, ESR, CRP, and urinalysis. Thrombocytosis is seen and hematuria, proteinuria indicate renal pathology. Skin biopsy with DIF will help in the diagnosis with the demonstration of IgA1 and C3 deposits in the postcapillary venules.[] Renal biopsy will reveal IgA deposits in glomeruli.[]

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Prednisolone is given in patients with severe cutaneous and joint disease, pulmonary hemorrhage, stroke, nephritic syndrome, and gastrointestinal hemorrhage in the dose of 1-2 mg/kg/day tapered over 8-12 weeks. The steroid is also combined with oral cyclophosphamide 100-200 mg/day for a period of 6-12 months.[]

Plasmapheresis

It is reserved for patients with progressive nephropathy, not responding to steroids and other immunosuppressives. It should be started within 2 weeks of onset of renal complications.[] Cutaneous and joint manifestations are managed by NSAIDs and dapsone and steroids. Renal involvement is treated by steroid + CYC, mycophenolate mofetil, rituximab, plasmapheresis, dialysis and finally renal transplant in that sequence.\

Urticarial vasculitis (UV)

CBC, ESR, CRP, and urinalysis are the initial investigations. C3, C4, C1q, anti C1q antibodies, CH50, ANA, ds DNA are also carried out if facilities are available.[,] Skin biopsy with DIF will demonstrate IgG and C3 at basement membrane zone if associated SLE is present. RFT, chest x-ray, ECG, and eye examination will reveal renal, pulmonary, cardiac, and ocular involvement, respectively. UV can disclose purpuric dots or globules in a patchy orange-brown background dermatoscopically corresponding to extravasation and degradation of red blood cells due to leukocytoclastic vasculitis.

Treatment of Normocomplementemic UV (NUV) and Hypocomplementemic UV (HUV) includes using prednisone and colchicine which can be effective to gain control of the disease. The use of glucocorticoids combined with dapsone, colchicine, or hydroxychloroquine to aid in their systemic disease have proven to be beneficial during the initial stages in patients who have mild to moderate disease.[,,] Additionally, biological agents that interrupt the IL-1 pathway may also be of benefit. These include anakinra (monoclonal recombinant IL-1 receptor antagonist protein. Canakinumab (monoclonal antibody against IL-1ő≤) has also been shown to be beneficial.[] Rituximab (monoclonal antagonist directed against the CD20 molecule on B lymphocytes) will be an exciting option.

Mycophenolate mofetil has also been shown to be beneficial. Methotrexate used as steroid-sparing is also effective. Azathioprine in combination with prednisone has shown to have significant improvement in patients with nephropathy and well as skin involvement in patients with HUV. Cyclosporine has also been effective in treating HUV especially in patients suffering from pulmonary and renal involvement and used to taper patients off glucocorticoids.

Kawasaki disease

The most effective regimen includes a

high dosage (2 g/kg) of intravenous immunoglobulin (IVIG) infusion with aspirin (80-100 mg/kg/day) to achieve the anti-inflammatory and antiplatelet effect.[] IVIG should be infused slowly over 8-12 hours and repeated if fever persists 36-48 hours after the first infusion.[] High dosage aspirin is recommended during the first 48 hours. Later, aspirin dosage (5 mg/kg/day) is indicated until long-term follow-up is completed.[,]

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Baseline echocardiographic coronary evaluation helps to stratify the coronary risk and also determines the antithrombotic treatment schedule. Z scores <2 imply no coronary artery lesions and low dosage aspirin for 4-6 weeks is given, with repeated echocardiographic evaluations in 2 weeks and 6-8 weeks after the onset of illness.[,] Z scores >2.5 has higher coronary risks with dilated coronary artery diameters need a lifelong follow-up for surveillance of worsening aneurysms and antithrombotic treatment based on their coronary risk.[,]

What are some of the nervous system vasculitis syndromes?

A vasculitis syndrome may begin suddenly or develop over time. Symptoms include:

  • headaches, especially a headache that doesn‚Äôt go away
  • fever
  • malaise (feeling out-of-sorts)
  • rapid weight loss
  • confusion or forgetfulness leading to dementia
  • aches and pains in the joints and muscles
  • pain while chewing or swallowing
  • paralysis or numbness, usually in the arms or legs
  • visual disturbances, such as double vision, blurred vision, or blindness
  • seizures, convulsions
  • stroke or transient ischemic attack (TIA, sometimes also called a ‚Äúmini-stroke‚ÄĚ)
  • unusual rashes or skin discoloration
  • problems with the kidneys or other organs

What are some of these syndromes called and how are they treated?

There are many forms of vasculitis that can affect the brain, spinal cord, and nerves, including:

Giant cell arteritis (also called temporal arteritis or cranial arteritis)

Giant cell arteritis is a type of vasculitis that affects the aorta and its primary branches.  The temporal artery (found on both sides of the head and running across the temple) and the ophthalmic artery that supplies the eyes are often affected.  A biopsy of the temporal artery is often performed to confirm the diagnosis.  Giant cell arteritis typically occurs in people age 50 and older. Symptoms of giant cell arteritis are:

  • new, severe headache
  • visual problems, including blurred or double vision, or sudden vision loss
  • pain in the jaw or tongue when chewing or swallowing
  • tenderness in the temporal arteries or the scalp.

Fever, weight loss, and neck or muscle pain can occur, usually in the early phase of the disease. Individuals may also have joint pain, fatigue, and discomfort in the neck/shoulders/hip regions known as polymyalgia rheumatic.  Vision loss is a feared complication of giant cell arteritis.  Untreated temporal arteritis can cause strokes and even death.  Although giant cell arteritis was traditionally thought to affect the arteries of the head and neck region, many individuals with giant cell arteritis can have inflammation in the large arteries within the chest, abdomen, and pelvis.

Primary angiitis of the CNS (or granulomatous angiitis)

The symptoms of this rare disorder typically develop slowly and include headache, dementia, behavioral changes, pain, sensory abnormalities, and tremors.  Stroke, transient ischemic attack, multiple mini-strokes, and seizures can occur.  A definitive diagnosis may require a brain biopsy.  The disorder can affect anyone of any age but peaks about age 50, and is most often seen in males.  It is fatal if left untreated.

Takayasu’s arteritis

This disease affects large arteries such as the aorta, which brings blood to the arms, legs, and head.  Takayasu’s arteritis usually first occurs in women under the age of 40.  The main symptoms are headaches, dizziness, a feeling of cold or numbness in the limbs, problems with memory and thinking, and visual disturbances.  It may also cause strokes, heart attacks, and damage to the intestines. The disorder can cause partial to complete disability and can be fatal if left untreated. Imaging studies to evaluate the arteries for signs of narrowing, blockage, or swelling are often required to establish the diagnosis and to monitor disease activity over time.  Polyarteritis nodosa

The onset of this rare disease can occur at any age but most often appears between the ages of 40 and 60 years.  Men are affected more often than women.  Symptoms can mimic those of many other diseases, but the most common initial complaints are fever, abdominal pain, numbness or pain in the legs and limbs, muscle aches, weakness, abnormal sensations, and unexplained weight loss. As the disease progresses, the kidneys may fail and high blood pressure may develop rapidly. Damage to the PNS with neuropathy is more common than damage to the CNS, but if the disease does involve the CNS, damage to the brain and spinal cord tissue can occur.   In some instances, the disease can recur after a few years.  If untreated, the disorder is often fatal, ending in the failure of vital organs.

Deficiency of adenosine deaminase 2 (DADA2)

DADA2 is a rare, genetic form of vasculitis caused by a mutation in the CECR1 gene.  Although most forms of vasculitis typically do not run in a family, DADA2 can occur in more than one family member.  Symptoms of DADA2 overlap with symptoms of polyarteritis nodosa, including fever, skin nodules, a lace-like rash of the trunk and limbs (livedo reticularis), and joint pain.  Most individuals with DADA2 experience strokes in infancy or early childhood.  DADA2 was discovered by researchers at the NIH and first reported in the medical literature in 2014.

In addition, other forms of vasculitis can cause neurological complications.  Among these disorders is Kawasaki disease, a rare form of vasculitis that can cause stroke or brain damage in children.  It primarily affects children age 5 or younger.  Inflammation of the walls of blood vessels in the coronary arteries may cause aneurysms.  Symptoms include high fever lasting at least five days, swollen hands and feet, red eyes and lips, and swollen lymph nodes. Most children can fully recover if treated early.  Among other systemic vasculitis syndromes that can affect the nervous system are Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, cryoglobulinemia, system lupus erythematosus, Behcet disease, Sjogren’s disease, and rheumatoid arthritis.  Inflammation of blood vessels that supply the nervous system can occur due to infections such as endocarditis (infection of heart valves), herpes zoster or upper face chickenpox, mycoplasma, and tuberculosis.

References

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