Vogt-Koyanagi-Harada Syndrome

What is Vogt-Koyanagi-Harada Syndrome?

Vogt-Koyanagi-Harada disease (VKH) is a rare disease that affects your nervous system, majorly impacting your sight and hearing. The first records of this disease go back to the 12th century, but it got its name from three physicians in the 20th century who described the diverse symptoms of the disease. Alfred Vogt first identified aspects of this disease, like inflammation in both eyes and loss of eyebrow color in 1906. Yoshizo Koyanagi then added to this knowledge in 1926 by describing how the disease could cause fluid buildup and separation in both eyes linked with an increase of certain cells in the spinal and brain fluid. Shortly after, Einosuke Harada recognized the skin-related symptoms. The disease occurs when the body’s immune system starts attacking certain cells in the protective coverings of the brain and spinal cord, eyes, skin, hairs, and ears.

Even though this disease shows noticeable changes in the early and later stages, understanding the exact causes behind VKH has proven difficult. Only in recent years, thanks to advancements in technology, have we started to uncover some of the genetic and immune-related aspects of the disease. Various potential eye-related complications can come from VKH, so spotting the disease early and starting treatment can decrease the severity of these issues.

Doctors typically treat VKH with medication, but in cases where complications like scarring beneath the retina, cataracts, or glaucoma arise, surgery might be necessary. The outcome of the disease heavily depends on how early treatment can be started. It can range from a dormant stage with minor symptoms to severe vision loss and pain.

What Causes Vogt-Koyanagi-Harada Syndrome?

The exact cause of VKH, a disease that affects parts of the body like the eyes and skin, is not completely known yet. However, current theories suggest that after recovering from a virus, the patient’s T-cells, which are a type of white blood cell that helps fight off diseases, attack the melanocytes, which are cells that produce skin color. Viruses like Cytomegalovirus and Epstein Barr virus have been suspected to be involved, but we don’t have definite proof for this. VKH is thought to occur when the body stops tolerating melanocytes, causing inflammation in the eye, inner ear, skin, and hair without causing cell death.

Recent genetic studies have revealed possible factors that might contribute to VKH. They’ve found that the presence of certain types of human leukocyte antigen (HLA), a molecule found on cells that helps the immune system distinguish between the body’s own proteins and proteins from harmful substances, could play a role. In particular, the presence of HLA-DRB4, HLA-DRB1-04*05, and HLA-DRB-04*01 is implicated. Other non-HLA genes related to how lymphocytes, a variety of white blood cells, produce certain proteins called IL-12 and IL17 have also been highlighted.

Changes in how the body regulates microRNA, a molecule that helps control gene activity, in the production of proteins known as interleukins and changes in non-coding RNA (RNA that doesn’t make proteins but helps in other important functions) may also contribute to this condition.

Risk Factors and Frequency for Vogt-Koyanagi-Harada Syndrome

VKH, or Vogt-Koyanagi-Harada disease, varies in how often it’s seen depending on the region. It’s the most common cause of a condition known as uveitis in India, and the second most common in Thailand. However, in the United States it’s relatively rare with only 3 to 4% of cases referred to specialist care centers being diagnosed as VKH. Each year in Japan, about 800 new cases of VKH are identified.

Interestingly, VKH is more commonly diagnosed in Hispanic and Native American populations in North America. Yet, in South American countries like Colombia with large Native and Hispanic populations, the number of VKH cases isn’t higher than the United States. Research suggests this difference might be due to certain genetic factors. In fact, twin and sibling studies have shown that genetics likely play a role in this disease.

The disease usually develops in people in their 30s and 40s, but it can affect anyone from the age of 3 to 78. Kids who get VKH typically have more aggressive forms of the disease that last a long time and can be hard to treat. People over 65 are more likely to have complications like optic disc hyperemia and choroidal detachments. Finally, VKH is seen more often in women than in men.

• VKH is a common cause of uveitis in India, less common in other regions.
• About 800 new VKH cases appear in Japan each year.
• In North America, Hispanic and Native American populations see more cases.
• The disease is more typical in people in their 30s and 40s, but can affect anyone from 3 to 78 years old.
• Children with VKH often have severe, long-lasting forms of the disease.
• Elderly patients are more prone to complications like optic disc hyperemia and choroidal detachments.
• VKH is more common in women than in men.

Signs and Symptoms of Vogt-Koyanagi-Harada Syndrome

VKH or Vogt-Koyanagi-Harada disease is an inflammatory condition that involves the eyes, skin, and central nervous system. This disease progresses over four specific phases: prodromal, acute uveitic, chronic uveitic, and recurrent chronic phase.

• The prodromal phase is usually short-lived and may go unnoticed. During this initial phase, which lasts a few hours to weeks, patients may experience symptoms like dizziness, eye pain, sensitivity to light, headaches, fever, or signs associated with inflammation of the membranes surrounding the brain and spinal cord. These symptoms are often associated with a recent viral illness.
• The acute uveitic phase is characterized by blurred vision and photophobia, which is an extreme sensitivity to light, due to inflammation of the inner parts of the eye. This inflammation can sometimes spread to the retina, optic nerve, or the ciliary body, resulting in complications like detachment of the retina, inflammation of the optic nerve, and sudden closure of the eye’s drainage angle.
• The chronic uveitic phase is when physical symptoms outside of the eye develop. These can include changes in skin color and hair, particularly loss of color in the eyebrows, eyelashes, and scalp, as well as hearing issues such as ringing in the ears, difficulty hearing, and hearing loss.
• The recurrent chronic phase includes symptoms of panuveitis, which is inflammation of all the layers of the eye, leading to severe eye problems like a “sunset glow” appearance of the back of the eye, abnormal blood vessels in the eye, glaucoma, and fibrous tissue below the retina.

The International Workshop on VKH Disease has defined three types of VKH disease: ‘complete’, ‘incomplete’ and ‘suspected’. The ‘complete’ VKH disease exhibits symptoms in the eyes, skin, and the nervous system. ‘Incomplete’ VKH disease shows either skin symptoms or nervous system symptoms. ‘Suspected’ VKH disease only presents eye symptoms. All forms of VKH must be diagnosed after ruling out other possible causes for the symptoms, such as injuries, surgery, or infections.

Testing for Vogt-Koyanagi-Harada Syndrome

Vogt Koyanagi Harada disease (VKH) is a condition that is diagnosed mainly through your symptoms, but lab testing and medical images can also help confirm it. Your doctor will ask about your past health and focus on previous similar episodes, symptoms related to your spinal cord, history of eye or orbital pain, and hearing problems. Your doctor will then perform a physical and slit lamp examination, which is a special microscope that allows them to see the front part of your eye in detail. This can show signs of past VKH episodes, such as changes in your hair or skin color.

Testing your cerebral spinal fluid, the liquid around your brain and spinal cord, during the early phase of VKH typically shows an increased number of cells, which can last for a few weeks after your symptoms have subsided. There are no specific blood tests for VKH. However, studies have found that increased levels of a specific type of serum (a component in your blood) called IgE often indicates more serious inflammation. More research is needed before we can say if there are other markers for VKH in your blood.

Indocyanine green angiography (ICGA), a medical test that uses dye and camera to visualize blood flow in the back of the eye, is the most important test for VKH. ICGA not only diagnoses VKH, but also monitors the disease process and how you respond to treatment. This procedure is useful because it checks the choroid and the retinal pigment epithelium, which are the two areas mainly affected in the early stages of VKH. The waves used in ICGA reach successfully into the choroid with less disturbance from other parts of the eye compared to a similar test called fluorescein angiography. ICGA is 90-100% effective in diagnosing VKH.

During VKH’s active phase, ICGA shows specific areas of slowed blood flow in the choroid, increased brightness around the optic nerve, multiple small leakages, and pooling in areas where the retina (the back of the eye) has detached.

Optical coherence tomography (OCT) is another non-invasive test used to study VKH and help diagnose it. OCT provides more detailed images of the retina. It can also display changes in choroidal volume and thickness. Though ICGA takes the lead when it comes to tracking the progress of VKH, OCT plays a crucial role in diagnosing VKH when used in conjunction with other imaging techniques. It shows changes in patients with recurrent VKH, even when there are no other signs of inflammation upon clinical examination.

Recently, new technologies like OCT-angiography (OCTA) are being considered for their ability to diagnose and manage VKH. These tests show decreased blood flow in the smallest blood vessels in the choroid and align with the findings from ICGA. Also, studies show a reduction in the flow after treatment begins. However, more research is needed to understand how OCTA can aid in managing VKH.

Treatment Options for Vogt-Koyanagi-Harada Syndrome

Vogt-Koyanagi-Harada disease (VKH) was traditionally treated using intensive corticosteroid therapy, administered directly into the bloodstream. While successful, there was a correlation between the length of this therapy and the risk of the disease recurring or causing other complications from repeated inflammation. In older studies, the condition often happened again within six months of finishing treatment.

In recent studies, however, patient outcomes improved significantly when this treatment was complemented with targeted local therapies and something called immunomodulatory therapy (IMT), which is a type of treatment that helps to adjust the immune system’s response.

One particular local treatment, a Su-Tenon injection of a drug called triamcinolone, was shown to be very effective at resolving eye symptoms linked to VKH – in some studies, up to 78% of patients had no recurring eye symptoms for up to three years. Another option, a fluocinolone intravitreal implant (a tiny device implanted in the eye that releases a drug called fluocinolone), was linked with significantly lower rates of eye inflammation recurrence compared to eyes that did not receive the implant. However, these treatments did increase certain side effects connected to glucocorticoid therapy, which is a type of drug used to treat a variety of diseases. It notably increased the risks of a type of cataract that often requires surgical removal and increased intraocular pressure (pressure inside the eye), which may also require surgery to control.

Additionally, since VKH affects multiple systems in the body, local treatments only address the eye-related part of the disease and not the symptoms affecting the skin or ears. This makes a combined treatment approach, using steroids together with IMT, particularly desirable, especially for patients already taking systemic IMT or those with only minor systemic symptoms.

In terms of IMT, several drugs have shown effectiveness, including alkylating agents, antimetabolites, and TNF-alpha inhibitors. While no single drug has been universally effective for all VKH patients, cyclosporine has shown improved results in chronic cases of the disease, and methotrexate has been effective when combined with the fluocinolone intraocular implants. A drug called infliximab has been promising in treating children with VKH, while another drug, adalimumab, has been effective in handling challenging cases of VKH, especially those linked to corticosteroid-related complications. It has shown success in controlling disease symptoms even up to six months in small case studies.

VKH is typically managed with medication, with surgery playing a limited role in treatment. Surgical procedures are generally used to address complications brought about by VKH, such as cataract removal, procedures to reduce intraocular pressure, or addressing subsequent issues like macular holes, which are small holes in the part of the eye responsible for detailed, central vision.

What else can Vogt-Koyanagi-Harada Syndrome be?

There are several conditions with symptoms that might be confused with VKH (Vogt-Koyanagi-Harada) disease. Thorough examination and detailed medical history are key in distinguishing between these conditions.

• Sympathetic Ophthalmia: This autoimmune condition usually follows an eye injury or surgery, and leads to an immune response causing inflammation in the uvea, a layer in the eye.
• VKH-like Drug Toxicity (checkpoint inhibitors): Certain drugs known as checkpoint inhibitors can cause health issues similar to VKH. If these medications are the cause, symptoms should stop when the medication is discontinued.
• Choroidal Melanoma: This eye cancer can cause issues like retinal detachments, and may appear similar to VKH in some cases.
• Infectious Posterior Uveitis: Conditions like syphilis, tuberculosis, and endogenous endophthalmitis could lead to symptoms like subretinal nodules and retinal detachment, which are also seen in VKH. These infectious diseases should be ruled out before beginning treatment for VKH.
• Alport and Cogan Syndromes: These syndromes exhibit hearing loss and retinal issues, but have specific characteristics that separate them from VKH. Alport syndrome involves significant inner retinal changes, while Cogan syndrome is characterized by inflammation in the blood vessels of the retina.
• Sarcoidosis: This can cause posterior uveitis similar to VKH. However, its unique presentations and specific findings on fluorescent angiogram can help differentiate it from VKH.
• Systemic Lupus Erythematosus Chorioretinopathy: While this lupus-related condition can cause retinal detachments similar to those seen in VKH, it does not usually cause thickening of the choroid, a layer just beneath the retina.

What to expect with Vogt-Koyanagi-Harada Syndrome

VKH or Vogt-Koyanagi-Harada disease often has a fairly positive outcome if it’s treated early and effectively. The health of the patient may progressively decline with repeated bouts of the disease. The prognosis or the potential outcome can be worse depending on the age of onset and number of recurring episodes. A significant symptom of VKH in its worst stage is called ‘sunset glow fundus’, which indicates poor eyesight. Sadly, this symptom has been known to occur even if the obvious signs of the earlier stages of the disease are successfully managed.

Studies have found that combining treatment with steroids and supplementary Immune Modulating Therapy (IMT) is vital. This combination treatment can reduce the rate of ‘sunset glow fundus’ from 60% to 16% in VKH patients. Furthermore, rates of a serious complication called subretinal fibrosis, which can cause permanent vision loss and can’t be treated, were reduced from 34% to 16% in acute early patients that were given combination steroid and IMT treatment from the outset.

Possible Complications When Diagnosed with Vogt-Koyanagi-Harada Syndrome

VKH, also known as Vogt-Koyanagi-Harada disease, can cause multiple complications in different parts of the body. Some of these include trouble hearing or ringing noise in the ears, patches of skin that lose their color (vitiligo), feeling of fullness in the ear, and problems related to eye health. Of these, hearing loss can affect almost 68% of VKH patients. Thankfully, the right therapy with corticosteroids often aids recovery. But, if corticosteroids aren’t well-tolerated, patients might not see much improvement, even with immune-modifying therapy. In some situations, cochlear implants might be required to help hearing. Some patients who can’t take corticosteroids have seen improvement with a procedure that involves injecting corticosteroids directly into the eardrum.

Common Skin Symptoms Include:

• White patches on the skin (Vitiligo)
• Loss of hair color (Poliosis)

Such conditions can often improve with antidepressant treatment, and topical application of certain creams may help restore the skin’s normal color.

During the early phases of VKH, inflammation in the eye can lead to a severe form of glaucoma, a condition that damages the optic nerve. Treatment options for this condition are often ineffective and must be examined on a case-by-case basis.

Eye Complications Include:

• Cataracts, or cloudiness in the eye lens, which can occur in up to 45% of patients.
• Glaucoma and nerve damage in the eye as a result of high eye pressure, affecting around 33% of patients.
• Macular holes, which are small breaks in the center of the eye’s retina.
• Chronic retinal detachments, or lifting of the retina from its normal position.
• Subretinal fibrosis, or scar tissue beneath the retina. In certain populations, this condition can occur earlier and more frequently.
• Choroidal neovascularization, where new blood vessels grow beneath the retina and can leak, affecting 14 to 17% of patients.

In most cases, following the prescribed treatment protocols can lead to significant improvement in the overall eye health. However, surgical intervention may occasionally be required, and in some severe cases, vision loss may occur.

Preventing Vogt-Koyanagi-Harada Syndrome

It’s crucial for patients to understand that Vogt-Koyanagi-Harada disease is an illness that affects the whole body and that this disease can come back or get worse after treatment. If you don’t get treated each time the disease comes back, it may cause even more serious health problems over time. Many patients with this disease need to take medicine to lower the body’s immune response for the rest of their lives. It’s important for patients to learn about different signs and symptoms so they can tell if their condition is getting worse.