Vogt-Koyanagi-Harada (VKH) syndrome

Vogt-Koyanagi-Harada (VKH) syndrome is a rare systemic disease involving various melanocyte-containing organs. Bilateral panuveitis associated with cutaneous, neurologic, and auditory abnormalities are manifestations of this inflammatory granulomatous disorder. VKH syndrome was first noted in the 10th century by a Persian ophthalmologist, Ali Ibn Isa, who described a case of poliosis associated with ocular inflammation. This association was reported again in 1873 by Schenkl, in 1892 by Hutchinson, and in 1906 by Vogt. In 1926, Haradadescribed a patient with idiopathic uveitis affecting the posterior segment, with retinal detachment and meningeal irritation. Koyanagi reported similar cases in 1929. Babel, in 1932, suggested that symptoms of the disorder described by Vogt, Koyanagi, and Harada were manifestations of the same single entity, referred to as Vogt-Koyanagi-Harada syndrome or uveoencephalitis.

Pathophysiology

The etiologic and pathogenic factors in VKH syndrome remain unclear. The clinical course of VKH syndrome with an influenzalike episode suggests a viral or postinfectious origin. Some studies invoke a possible role of Epstein-Barr virus reactivation in this disease.Although a viral cause has been proposed, no virus has been isolated or cultured from patients with VKH syndrome. Morris and Schlaegel found viruslike inclusion bodies in the subretinal fluid of a patient with VKH syndrome.
Clinical and experimental data continue to support an immunologic etiology. An autoimmune reaction seems to be directed against an antigenic component shared by uveal, dermal, and meningeal melanocytes. The exact target antigen has not been identified, but possible candidates include tyrosinase- or tyrosinase-related proteins, an unidentified 75-kd protein obtained from cultured human melanoma cells (G-361), and S-100 protein. Evidence suggests that Th1 and Th17 subsets of T cells together with cytokines interleukin (IL)–23 and IL-17 are likely involved in the initiation and maintenence of the inflammatory process.
VKH syndrome can be associated with other autoimmune disorders such as autoimmune polyglandular syndrome,hypothyroidism, Hashimoto thyroiditis, diabetes mellitus,Guillain-Barré syndrome, and IgA nephropathy.
Single reports of patients developing VKH syndrome after cutaneous injury have been noted, as well as 2 cases of this condition occurring after BCG therapy for melanoma and 1 case following surgery of metastatic malignant melanoma. Case reports indicate that even an indirect trauma in melanocyte-containing tissue may induce an inflammatory response within the eye, with Vogt-Koyanagi-Harada disease following a closed head trauma. Cases of this syndrome were reported to be linked to malignant lymphoma.
Immunologic analysis of cerebrospinal fluid (CSF) lymphocytes in VKH syndrome and studies of human uveal melanocytes show that uveal pigment can stimulate lymphocyte cultures from patients with VKH syndrome. Lymphocytes of peripheral blood and CSF from these patients may reveal in vitro cytotoxicity against allogenic melanoma cells.
Circulating antibodies against a retinal photoreceptor region have been detected in patients with this disorder.
The possibility that VKH syndrome has an autoimmune pathogenesis is supported by the statistically significant frequency of HLA-DR4, an antigen commonly associated with other autoimmune diseases. VKH syndrome has been closely associated with HLA-B54, HLA-DR4, and HLA-DR53 in Japanese patients ; with HLA-DR4, HLA-DRw53, and HLA-DQw3 in subjects of Native American ancestry; with HLA-DR1 and HLA-DR4 in Hispanic patients living in southern California; and with HLA-DR4 and HLA-DQw7 in Chinese patients.  HLA-DR4 also was found to be significantly related to VKH syndrome in white Europeans, specifically in Italian patients. These findings confirm the possibility of immunogenic predisposition and the decisive role of HLA-DR4 antigen in the development of the disease.
Data indicate that patients with VKH syndrome are sensitized to melanocyte epitopes and display a peptide-specific Th1 cytokine response. Patients bearing HLA-DRB1*0405 recognize a broader melanocyte-derived peptide repertoire, so the presence of this allele increases susceptibility to the development of VKH disease. In a group of French VKH syndrome DRB1*04-positive patients, the HLA-DRB1*0405 subtype was found in 71%^.
A recent study revealed that a decreased vitamin D-3 level has been associated with active intraocular inflammation in VKH syndrome patients.

Epidemiology

Frequency

United States

VKH syndrome is rare. No precise data are available regarding frequency of the disease.

International

VKH syndrome is rare but widely distributed.

Mortality/Morbidity

VKH syndrome is not associated with mortality. Acute disturbances in hearing and vision may occur, and the cutaneous changes may be permanent.

Race

VKH syndrome occurs more frequently in individuals with darker pigmentation (eg, persons of Asian, Native American, Latin American, or black heritage). VKH syndrome is one of the most common forms of uveitis among pigmented races. The manifestations of VKH syndrome in whites resemble those in the Japanese population. However, cutaneous signs are much more rarer.

Sex

Women appear to be affected with VKH syndrome more frequently than men.

Age

The onset of VKH syndrome has been reported to range from 3-89 years, with a maximum frequency in the thirties. Although often unrecognized, VKH syndrome may affect children.

History

VKH syndrome is usually preceded by a prodromal stage of nonspecific symptoms including headache, increased sensitivity to touch of the hair and skin, vertigo, nausea, nuchal rigidity, vomiting, and low-grade fever that may last a few days. Patients usually initially present to an ophthalmologist for ocular problems, including sudden loss of vision, ocular pain, and photophobia. Hearing disturbances and dizziness may be present. After weeks or months, most patients notice cutaneous signs (eg, hair loss, poliosis, vitiligo).

Physical

The American Uveitis Society developed the first diagnostic criteria for VKH Syndrome in 1978. In addition to an absence of prior ocular trauma or surgery, at least 3 of the following 4 criteria should be met to confirm the diagnosis of VKH syndrome:

• Bilateral chronic iridocyclitis
• Posterior uveitis, which may include exudative retinal detachment, optic nerve swelling, or atrophy of the retinal pigment epithelium
• Cerebrospinal fluid pleocytosis or evidence of tinnitus, dysacusis, headache or meningismus, or cranial nerve involvement
• Cutaneous findings of vitiligo, alopecia, or poliosis

Revised diagnostic criteria were established by International Committee of Experts during The First International Workshop on VKH Disease in 1999.^[33] The new criteria allowed for diagnosing VKH Syndrome in different stages of the disease, specifically addressing the early stages during which cutaneous findings are often not present.

Criteria for VKH syndrome (1-5)

1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis
2. No clinical or laboratory evidence suggestive of other ocular disease entities
3. Bilateral ocular involvement - (a) or (b) must be met, depending on the stage of disease when the patient is examined, based on early and late manifestations below.
Early manifestations of the disease
(1) There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disk hyperemia), which may manifest as one of the following: (a) focal areas of subretinal fluid or (b) bullous serous retinal detachments.
(2) With equivocal fundus findings, both of the following must be present as well: (a) focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of sequential appearance) by fluorescein angiography and and (b) diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography.
Late manifestations of the disease
(1) History suggestive of the prior presence of findings from (3)(a) and either both (2) and (3) below or multiple signs from (3)
(2) Ocular depigmentation: Either (a) sunset glow fundus or (b) Sugiura sign is sufficient.
(3) Other ocular signs may include (a) nummular chorioretinal depigmented scars, (b) retinal pigment epithelium clumping and/or migration, or (c) recurrent or chronic anterior uveitis.
4. Neurological/auditory findings (may have resolved by time of examination) - Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors; headache alone is not sufficient to meet the definition of meningismus) or Tinnitus, or CSF pleocytosis
5. Integumentary findings (not preceding the onset of CNS or ocular disease) - Alopecia, or Poliosis, or Vitiligo
Complete VKH disease is if criteria 1-5 are present.
Incomplete VKH disease is if criteria 1-3 and either 4 or 5 are present.
Probable VKH disease is isolated ocular disease; criteria 1-3 must be present.
The classic course of VKH syndrome consists of the following 3 phases:

1. In the meningoencephalitis phase, the degree of neurologic symptoms may vary. Generalized muscle weakness, hemiparesis, hemiplegia, dysarthria, and aphasia have been reported. Most of the neurologic symptoms have been directly attributed to changes in CSF (eg, pleocytosis, increased pressure, protein levels), inflammatory arachnoiditis, or resulting subarachnoidal adhesions. Mental changes ranging from mild confusion to psychosis may occur.
2. The ophthalmic-auditory phase is characterized by common features such as decreased visual acuity, eye pain, eye irritation, and loss of vision. Dysacusis (usually bilateral) and tinnitus develop in 50% of patients.
3. The convalescent phase is characterized by cutaneous signs developing after uveitis begins to subside, usually within 3 months from the onset of disease. Although cutaneous signs typically occur several weeks to months after the onset of ocular inflammation, skin changes have sometimes been observed many years before uveitis appeared. Pigmentary changes tend to be permanent. Poliosis, which occurs in 90% of patients, involves the eyebrows and eyelashes and, occasionally, the scalp and body hair. Poliosis affects 50% of patients and usually appears after the onset of alopecia, which may be patchy or diffuse. Vitiligo manifests in 63% of patients and is often symmetric. Most patients have perilimbal vitiligo (Sugiura sign). Atypical variants of vitiligo with inflammatory raised borders and plaque-type inflammatory erythema have also been reported. Halo nevi may be present.

Causes

The cause of VKH syndrome is unknown, but a viral factor has been suggested in the pathogenesis. An autoimmune reaction to melanocytes with the involvement of T-cell–mediated cytotoxicity and apoptosis is postulated. Although almost all instances of VKH syndrome are sporadic, and familial cases are rare, some authors suggest that the condition may be inherited, probably as an autosomal recessive trait. Numerous data demonstrate the association of HLA-DR4 antigen and VKH syndrome in different racial groups. According to some studies, the major factor contributing to susceptibility for the disease is presence of the DRB*0405 allele.

Differentials

• Alezzandrini Syndrome
• Alopecia Areata
• Piebaldism
• Vitiligo

Laboratory Studies

• For quick diagnosis and early treatment, Vogt-Koyanagi-Harada (VKH) syndrome requires a multidisciplinary management strategy involving dermatologists and ophthalmologists.
• Perform neurologic examination with lumbar puncture to detect associated abnormalities.
• Detailed CSF cell analysis is necessary. Changes in the CSF include pleocytosis with the presence of melanin-laden macrophages (specific for the syndrome and helpful in confirming the diagnosis), increased protein levels, and increased pressure.

Imaging Studies

• Standardized A-scan and contact B-scan echography, performed by ophthalmologist
• Orbital MRI
• Brain MRI

Procedures

• Perform fluorescein angiography, which shows multiple hypofluorescent areas in the retina at the level of the retinal pigment epithelium.
• Perform indocyanine green choroidal angiography.
• Audiometry may reveal sensorineural hearing loss.

Histologic Findings

A skin biopsy specimen taken a month after the onset of VKH syndrome ocular symptoms will likely reveal a mononuclear infiltrate concentrated in the area of hair follicles and sweat glands, consisting mostly of T lymphocytes with a small number of B cells. In depigmented skin, the absence of melanin, as anticipated in vitiligo, can be noted. Vasodilatation in the dermis, pigment-laden macrophages, and a lymphocytic infiltrate have also been described.

Medical Care

• For pigmentary changes with Vogt-Koyanagi-Harada (VKH) syndrome, treatment options mirror those for vitiligo.
• For eye inflammatory changes, treatment includes systemic corticosteroids, with an average initial dose of 80-100 mg of oral prednisone per day. Early, aggressive use of systemic corticosteroids and a gradual tapering of drug dosage for 6 months after presentation are recommended to prevent progression and development of complications. Some authors recommend pulse corticosteroid therapy.
• In patients whose conditions fail to respond to high-dose corticosteroid (oral or intravenous) therapy or who develop significant adverse effects, immunosuppression with cyclosporine or other antimetabolites (eg, azathioprine, cyclophosphamide, methotrexate [MTX]) may be required.
• Case reports suggest that intravenous immunoglobulins (IVIGs) and infliximab may be of interest in the treatment for VKH syndrome. Further trials are needed to assess the efficacy of these agents.
• Topical and periocular corticosteroids are used. If systemic medications are not effective,subtenon injections may be considered before intraocular treatment modalities.
• Cycloplegic-mydriatic eye drops are used symptomatically.

Surgical Care

• Surgical therapy for glaucoma is necessary in some patients. Surgical intervention includes laser iridotomy, surgical iridectomy, and trabeculectomy. 
   
   

  Consultations

  Ophthalmologists and neurologists must be consulted.
  
  
  

  Medication Summary

  The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
  
  

  Corticosteroids

  Class Summary

  Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.
  
  

  Prednisone (Deltasone, Orasone)

   

  Synthetic adrenocortical steroid with predominantly glucocorticoid properties. Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
  
  
  
  

  Immunosuppressive agents

  Class Summary

  Have antiproliferative and immunosuppressive effects.
  
  
  

  Pediatric Dosing & Uses

  Dosing Forms & Strengths

  tablet

  • 50mg

  powder for injection

  • 100mg/vial

  oral suspension

  • 50mg/mL

  Safety and efficacy not established; however used as adults (off label)
  
  
  

  Pregnancy & Lactation

  Pregnancy Category: D
  Lactation: excreted at low levels in breast milk/not recommended
  
  
  

  Pharmacology

  Absorption: good (PO)
  Half-Life: 5 hr
  Duration: variable
  Plasma Concentration: <1 mcg/mL
  Protein Bound: 30%
  Metabolism: liver
  Metabolites: mercaptopurine, 6-thiouric acid
  Dialyzable: partially
  

  Pharmacogenomics

  Azathioprine is a prodrug and extensively metabolized to the active metabolite 6-mercaptopurine
  6-mercaptopurine is activated further by guanine phosphoribosyltransferase (HGPRT) to form thioinosine monophosphate (TIMP) and by kinase enzymatic pathways to form active 6-thioguanine nucleotides
  Thiopurine S-methyltransferase (TPMT) inactivates 6-mercaptopurine
  Although complete TPMT deficiency is rare in the general population (0.3%), TPMT screening should be performed prior to administration in all patients prescribed azathioprine or 6-mercaptopurine
  With TPMT deficiency, a larger proportion of 6-mercaptopurine is converted to the cytotoxic 6-thioguanine nucleotide analogues, which can lead to bone marrow toxicity and myelosuppression
  Alleles associated with decreased TPMT enzymatic activity are TPMT*2, TPMT*3A, and TPMT*3C
  
  
  

  IV & IM Information

  IV Incompatibilities

  Stable in neutral or acid solutions, but in alkaline solns is hydrolyzed to mercaptopurine
  

  IV Administration

  Can be administered IVP over 5 min at a concentration not exceeding 10 mg/mL
  Can be further diluted with NS or D5W & administered by intermittent infusion over 30-60 min (usual) but infusions ranging from 5 min to 8 hr have been done
  

  Storage

  Store powder at room temp protected from light
  Reconstituted soln is stable for 2 wk at room temp (25°C); may be less stable under refrigeration
  Use within 24 hr since no preservatives
  

  
  
  
  
  
  

   

Sarcoidosis

Sarcoidosis is a disease in which inflammation occurs in the lymph nodes, lungs, liver, eyes, skin, or other tissues.


Causes, incidence, and risk factors



The cause of the disease is unknown. In sarcoidosis, tiny clumps of abnormal tissue (granulomas) form in certain organs of the body. Granulomas are clusters of immune cells.



The disease can affect almost any organ of the body, but it most commonly affects the lungs.



Possible causes of sarcoidosis include:



*



Extreme immune response to infection

*



High sensitivity to environmental factors

*



Genetic factors



The condition is more common in African Americans than Caucasians, especially in Caucasians of Scandinavian heritage. Females are usually affected more often than males.



The disease typically begins between ages 20 and 40. Sarcoidosis is very rare in young children.



A person with a close blood relative who has sarcoidosis is nearly five times as likely to develop the condition.

Symptoms



There may be no symptoms. When symptoms occur, they can involve almost any body part or organ system in your body.



Almost all patients have lung or chest symptoms:



*



Chest pain (most often behind your breast bone)

*



Dry cough

*



Shortness of breath



Symptoms of general discomfort or uneasiness often occur:



*



Fatigue (one of the most common symptoms in children)

*



Fever

*



Joint achiness or pain (arthralgia)

*



Overall feeling of discomfort, illness, or lack of well-being

*



Weight loss (one of the most common symptoms in children)



Skin symptoms:



*



Hair loss

*



Raised, red, firm skin sores (erythema nodosum), almost always on the front part of the lower legs

*



Rash

*



Scars that become raised or inflamed



Nervous system symptoms may include:



*



Headache

*



Seizures

*



Weakness on one side of the face



Eye symptoms include:



*



Burning

*



Discharge from the eye

*



Dry eyes

*



Itching

*



Pain

*



Vision loss



Other symptoms of this disease:



*



Dry mouth

*



Fainting spells if the heart is involved

*



Nosebleed

*



Swelling in the upper part of the abdomen



Signs and tests



A physical exam may show the following:



*



Abnormal breath sounds (such as rales)

*



Enlarged liver

*



Enlarged lymph glands

*



Enlarged spleen

*



Rash



Often the disease is found in patients with visible physical signs who have an abnormal chest x-ray.



Different imaging tests may help diagnose sarcoidosis:



*



Chest x-ray to see if the lungs are involved or lymph nodes are enlarged

*



CT scan of the chest

*



Lung gallium scan



To diagnose this condition, a biopsy is needed. Biopsy of the lung using bronchoscopy is usually done. Biopsies of other body tissues may also be done.



This disease may affect the results of the following lab tests:



*



Calcium levels (urine, ionized, serum)

*



CBC

*



Immunoelectrophoresis - serum

*



Liver function tests

*



Quantitative immunoglobulins (nephelometry)

*



Serum phosphorus



Treatment



Sarcoidosis symptoms will often get better on their own slowly without treatment.



Patients whose eyes, heart, nervous system, or lungs are involved may need to be treated with corticosteroids (prednisone or methylprednisolone). Therapy may continue for 1 or 2 years. The most severely affected patients may need lifelong therapy.



Drugs that suppress the immune system (immunosuppressive medicines) are sometimes also needed:



*



The drug used most often is methotrexate, but azathioprine and cyclophosphamide are also sometimes recommended.

*



Hydroxychloroquine is useful for skin sarcoidosis.



Rarely, some people with end-stage heart or lung damage may need an organ transplant.

Expectations (prognosis)



Many people with sarcoidosis are not seriously ill, and the disease may get better without treatment. About 30 - 50% of cases get better without treatment in 3 years. About 20% of people whose lungs are involved will develop lung damage.



The overall death rate from sarcoidosis is less than 5%. Causes of death include:



*



Bleeding from the lung tissue

*



Heart damage, leading to heart failure and abnormal heart rhythms

*



Lung scarring (pulmonary fibrosis)



Complications



*



Fungal lung infections (aspergilloma)

*



Glaucoma and blindness from uveitis (rare)

*



Kidney stones from high calcium levels in blood or urine

*



Osteoporosis and other complications of taking corticosteroids for long periods of time.

*



Pulmonary hypertension