Heerfordt-Waldenström syndrome (HWS) is a rare subtype of sarcoidosis. It was first reported in 1909 by Danish ophthalmologist Christian Frederik Heerfordt and formally classified as a distinct clinical picture of sarcoidosis in 1937 by Swedish physician Jan G. Waldenström.
Also called uveoparotid fever, its ICD-10 code is D86.8 (other sarcoidosis).
HWS occurs in 4.1–5.6% of sarcoidosis patients; although rare, it affects multiple organs and influences prognosis.
The overall pathology of sarcoidosis involves a Th1-type cellular immune response triggered by an etiologic antigen in susceptible individuals, leading to the formation of non-caseating granulomas composed of epithelioid cells and giant cells in various organs. Sarcoidosis frequently affects the lungs, hilar and mediastinal lymph nodes, eyes, and skin, but can involve any organ including the heart, nerves, muscles, liver, salivary glands, and bones.
An association between HWS and the HLA-DRB1*04 allele has been shown in a study of 1,000 cases.
It is not a different disease but a special clinical subtype of sarcoidosis. HWS represents the manifestation of the underlying granulomatous inflammatory reaction of sarcoidosis in a specific combination of organs (eyes, parotid glands, facial nerve, and fever).
The presentation of HWS tends to be vague, and the classic tetrad may not appear simultaneously.
Ocular involvement occurs in 11–83% of patients, with anterior uveitis being the most common. The incidence of facial nerve palsy is 25–50%, making it an important component of this syndrome. Parotid gland involvement occurs in about 6% of patients and is usually bilateral.
Ocular Findings
Anterior uveitis: Granulomatous or non-granulomatous anterior chamber inflammation. Characteristic findings include mutton-fat KP, Koeppe nodules, and Busacca nodules.
Angle nodules, tent-shaped peripheral anterior synechiae: Granulomatous lesions in the angle.
Clumped vitreous opacities: Snowball or string-of-pearls vitreous opacities1).
Posterior segment lesions: Retinal perivasculitis, multifocal chorioretinal lesions, and optic disc granulomas have been reported1).
Systemic Findings
Parotid gland swelling: Typically bilateral, soft, and painless swelling.
Facial nerve palsy: Peripheral (complete or incomplete paralysis). May be accompanied by lagophthalmos.
Fever: Most patients have a low-grade fever.
Neurological lesions: Trigeminal nerve palsy and progressive multifocal leukoencephalopathy have also been reported.
Literature reviews have reported various other complications including pericardial effusion, bilateral eyelid swelling, xerostomia, and keratoconjunctivitis sicca.
In a study of 362 sarcoidosis cases from the UK, Australia, and New Zealand, systemic complications were found in 77%, with the most common being pulmonary (56%), followed by skin (27%), arthritis (16%), and neurological (14%) 1).
The exact etiology of HWS is not fully understood, but the underlying pathology is a granulomatous inflammatory reaction.
Candidate antigens for the etiology of sarcoidosis include microorganisms such as Mycobacterium species (e.g., Mycobacterium tuberculosis) and Cutibacterium acnes, as well as inorganic substances (e.g., silicates), but definitive evidence is lacking 1). The basic structure of granulomas consists of epithelioid cells, macrophages, and lymphocytes 1).
As a genetic predisposition, an association with the HLA-DRB1*04 allele is known.
HWS is essentially a clinical diagnosis and is classified into the following two clinical types.
| Type | Diagnostic criteria |
|---|---|
| Complete type | All 4 major signs (anterior uveitis, parotid gland swelling, facial nerve palsy, fever) are present |
| Incomplete type | Two or more of anterior uveitis, parotid gland swelling, and facial nerve palsy are present |
Tests supporting the diagnosis:
Differential diagnosis:
Elevated serum ACE and bilateral hilar lymphadenopathy on chest X-ray provide strong evidence for diagnosis, but they are not definitive. Definitive diagnosis requires histological demonstration of non-caseating granulomas via tissue biopsy. If findings are inconclusive, additional tests such as chest CT, gallium scintigraphy, and bronchoalveolar lavage are performed.
Steroids are the first-line treatment, leading to resolution of facial nerve palsy, uveitis, and parotid gland swelling.
Local treatment (eye):
Systemic treatment (oral steroids):
Initial dose is 0.5 mg/kg/day (1 mg/kg/day in severe cases), tapered by 5–10 mg every 1–2 months. The final dose of 2.5–5 mg/day is continued for 1 to several months before discontinuation (total treatment duration: 3 months to over 1 year).
The following alternative drugs are selected:
If lagophthalmos due to facial nerve palsy is present, artificial tears are also used.
The basic pathology of sarcoidosis, including HWS, is the formation of non-caseating granulomas composed of epithelioid cells (cells derived from macrophages), multinucleated giant cells, and lymphocytes.
Th1-type cellular immune response (type IV allergy) plays a central role, and granulomas are thought to form as an excessive immune response to environmental antigens. Various immune cell populations are involved in the pathogenesis 1).
In ocular granulomatous inflammation:
Glaucoma in sarcoidosis occurs in approximately 11% of cases, caused by trabecular meshwork obstruction due to inflammatory debris and nodules in the angle 1).
The mechanism of facial nerve palsy is thought to be direct nerve compression and ischemia due to granuloma formation within or near the facial canal.
TNF inhibitors (infliximab, adalimumab) have shown promising results in the treatment of refractory sarcoidosis. For ocular sarcoidosis, the efficacy of infliximab has been demonstrated in case reports and retrospective studies, with expected steroid-sparing effects.
The International Workshop on Ocular Sarcoidosis (IWOS) revised the diagnostic criteria for ocular sarcoidosis in 2019, establishing three levels of diagnostic certainty (definite, presumed, possible) based on a combination of 7 intraocular clinical signs (KP, iris nodules, tent-shaped peripheral anterior synechiae, snowball vitreous opacities, chorioretinal lesions, choroidal nodules, optic nerve lesions) and 8 systemic findings. The IWOS criteria have already been implemented in approximately 50 clinical studies 1).
