Parry-Romberg Syndrome

Etiology

The exact etiopathogenesis of Parry Romberg syndrome is still a topic of debate. The most commonly accepted theories are:

1. Theory of "trophoneurosis": The earliest understanding was a dysfunction of the trophic fibers of the trigeminal and other peripheral nerves—the complaints of chronic facial pain and trigeminal neuralgia support this theory. Confocal microscopy shows a reduction in the corneal nerve endings supplied by the ophthalmic division of the trigeminal nerve, supporting this theory.[2]
2. Immune-mediated process: The widely accepted theory is that PRS is an autoimmune disorder.[3] Overlap with linear morphea, a form of systemic sclerosis, has been commonly observed.[4] The presence of other autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, vitiligo, and thyroid disorders have been noted in rare cases.[5] The presence of anti-nuclear antibodies provides a definitive serological basis.[6][7]
3. Neuro-vasculitis theory: The histopathology of the cerebral lesions reveals a lymphocytic vasculitis similar to Rasmussen encephalitis.[8] Interstitial neurovasculitis involving the major vessels explains the aneurysms and other cerebrovascular malformations, seen occasionally in PRS cases. Similar lesions are described along the course of the trigeminal nerve.[9]  
4. Neural crest cell disorder: The presence of cerebral vascular malformations, aneurysms, and soft tissue tumors suggests a possible dysregulation of neural crest cell migration.[10]
5. Sympathetic dysfunction: The superior cervical sympathetic plexus inflammation or dysfunction causes ipsilateral facial atrophy, enophthalmos, and bone atrophy - similar to PRS. Ipsilateral sympathectomy shows a halt in the disease progression.[11][12]
6. Hereditary mechanism: Wartenberg described PRS as a heredo-degenerative disorder, with only a few familial cases noted to date. No specific inheritance pattern or gene has been isolated.[13]
7. Trauma-induced: Online surveys of PRS patients have established a debatable association between head injury in early childhood and the onset of symptoms.[14]
8. Infectious causes: Preceding infections with Varicella zoster virus, Herpes simplex virus, and Borrelia burgorferi have been described as risk factors.[15][16]

Epidemiology

The incidence of PRS varies from 0.3 to 2.5 cases per 100,000 population per year, with a male-to-female ratio of 1 to 3.[14][17] The onset of PRS is in the first 2 decades of life, with a few cases in the elderly.[18] The average age of diagnosis is 13.2 years, with an earlier diagnosis in the male population.[19] The disease shows a progressive course, followed by a "burnout" within 2 to 20 years and spontaneous remission.[3] Ophthalmic involvement occurs in up to 35% of cases.[20] Neurological symptoms manifest in 15 to 20% of cases.[14]

Pathophysiology

PRS is predominantly an autoimmune disorder with similarities to localized scleroderma or morphea. The closest mimic is linear scleroderma en coup de sabre (LSCS).[21] The major distinguishing feature is the absence of cicatricial alopecia and skin induration in PRS cases. In contrast, LSCS shows cutaneous sclerosis of the scalp, hyperpigmentation, and loss of scalp hair and eyebrows.

Histopathology

Skin biopsy shows near-complete dermal fat atrophy, minimal sclerosis, and reduced adnexal structures. The characteristic finding is a diffuse pattern of dermal infiltration with lymphocyte predominance and perivascular plasma cells.[21] Brain biopsy, though not routinely done for PRS, shows lymphocytic interstitial vasculitis.

History and Physical

The clinical criteria favoring a diagnosis of PRS over scleroderma (as proposed by Duymaz et al) are:[3]

1. Unilateral facial atrophy
2. Absent or minimal signs of prior inflammation or induration
3. Skin atrophy with thin, soft skin and no sclerosis [3]

The clinical symptoms and features to look out for during history taking and physical examination are:

Facial

• Facial atrophy: Progressive facial asymmetry due to atrophy of the subcutaneous fat, muscles, and underlying bones ( the most common clinical finding) 
• Pigmentation: Hypo- or hyperpigmented lesions over the face and ipsilateral neck
• Alopecia: Involving the eyebrow and the eyelashes

Ophthalmic

• Enophthalmos: Progressive enophthalmos secondary to atrophy of retrobulbar fat and the alterations in orbital anatomy due to bone atrophy
• Eye-lid alterations: Pseudoptosis secondary to enophthalmos, lid retraction, lagophthalmos, eyelid atrophy, and late-onset eyelid pseudo-coloboma.[22] 
• Orbital tumors: Orbital neurinoma - an incidental finding on magnetic resonance imaging (MRI)[23]
• Extraocular muscle (EOM) changes: Thinning or fibrosis of EOM, sudden onset horizontal or vertical strabismus, nystagmus, and diplopia.
• Conjunctival pigmentation: Abnormal pigmentation of the palpebral conjunctiva
• Scleral finding: Spontaneous scleral melt [24]
• Corneal manifestations: Reduced corneal sensations, reduced stromal nerve fibers on confocal microscopy, exposure to keratopathy with secondary infective keratitis, keratitc precipitates, primary endothelial failure, stromal edema, band-shaped keratopathy, and flour-like deposits in the corneal stroma.[25] 
• Uveal changes: Acute uveitis with iritis, iridocyclitis, vitritis, panuveitis, iris atrophy, iris crystalline deposits, and Fuchs heterochromic iridocyclitis.[26]
• Lens findings: Cataract and lenticular dislocation
• Intra-ocular pressure (IOP) alterations: Rise of IOP with acute trabeculitis or end-stage neovascular glaucoma, and ocular hypotony with iridocyclitis, ciliary body hypotrophy, or atrophy
• Retinal findings: Retinal vasculitis, neuroretinitis, telangiectasia, pigment epithelial changes, retinal folds, exudative retinal detachment (RD), Coats disease, central retinal artery occlusion, chorioretinal atrophy, and retinitis pigmentosa like changes 
• Involutional stage: Multiple vitreoretinal or glaucoma filtration surgeries predispose the globe to involutional changes

Neuro-ophthalmological

• Optic nerve involvement: Optic neuropathy and papillitis 
• Cranial nerve palsy: Oculomotor and trochlear nerve palsy, with restrictive strabismus
• Anisocoria: Horner syndrome and tonic pupil due to autonomic disturbances

Neurologic

• Epilepsy: Focal, generalized seizures or status epilepticus
• Pain: Headche, trigeminal neuralgia, and facial pain
• Cerebro-vascular accidents: Ischemic stroke, cerebral hemorrhage, microinfarcts, microhemorrhages, and subsequent cerebral atrophy
• Vascular malformations: Aneurysms, cavernoma, hypoplastic or stenotic vessels
• Movement disorders: Muscle spasms, synkinesia, pyramidal symptoms, dystonia, torticollis, and gait disturbances
• Speech abnormalities: Aphasia and dysarthria  
• Limb abnormalities: Limb weakness, pain, or atrophy in rare cases[14] 
• Neuropsychiatric manifestations: Cognitive disturbances, hallucinations, and psychiatric disorders

Maxillofacial

• Bony changes: Hypoplasia of the maxilla, zygomatic bone, mandible, temporal, and rarely frontal bones
• Oral manifestations: Unilateral tongue atrophy, gingival atrophy, atrophy of hard palate, and abnormal development of the teeth

Cardiac

• Hypertrophic cardiomyopathy and rheumatologic heart disease

Endocrine

• Hashimoto thyroiditis and metabolic disorder

Evaluation

PRS is primarily a clinical diagnosis. Various investigation modalities can be employed to rule out any overlap with similarly presenting syndromes. 

Ocular Evaluation

• Best-corrected visual acuity, refraction, and pupillary reaction assessment
• General examination for symmetry of the face, head posture, extra-ocular muscle movements, and strabismus workup
• Orbit examination, evaluation of lid abnormalities, and ptosis workup
• Meticulous slit-lamp examination
• IOP measurement by Goldmann applanation tonometry
• Detailed fundus examination
• Orbital ultrasound: In cases with media opacity due to vitritis, cataract, or corneal opacity, this modality helps diagnose the associated posterior segment pathology. Ultrasound biomicroscopy is used to look for ciliary body changes.[15]
• Orbital imaging: Orbital computed tomography (CT) scan is used to evaluate the changes in bony orbit

Neurology Evaluation

• Electroencephalogram: For workup of epilepsy cases, to localize the cerebral lesions
• Cerebrospinal fluid (CSF) analysis: CSF examination is usually found normal. The oligoclonal bands and raised IgG index are associated with T2 hyperintense lesions on MRI.[19]
• Neuro-imaging: CT scan delineates the cranial bony deformity, thinning of diploe, and intracranial calcifications. MRI T1 sequence localizes the patches of cerebral atrophy. MRI T2 sequence pinpoints the hyperintense foci in the subcortical region. MR angiogram demonstrates the extent and location of vascular malformations. Brain spectral photoemission CT (SPECT) scan can detect subclinical CNS lesions in PRS cases.[27]

Rheumatology Evaluation

• Anti-nuclear antibody (ANA): The most commonly associated serology finding in 25 to 52% of cases.[28]
• Rheumatoid factor: Elevated titers in localized scleroderma and LSCS cases.[29]
• Other serology tests: C-reactive protein, HLA-B27 typing, extractable nuclear antigen, Anti-Scl-70, Anti-cardiolipin, and Anti-dsDNA antibodies are of limited value

Dental Evaluation

• To monitor progressive deformity of the jaw bones and teeth abnormalities by serial orthopantomograms and photographs.

Dermatology Evaluation

• Skin biopsy is not performed routinely. However, the histopathological findings help differentiate PRS from LSCS.

Treatment / Management

The goals of management are:

• To halt the active disease progression and induce remission
• Treatment of acute exacerbations like seizures and uveitis
• Cosmetic rehabilitation after complete remission

Medical Management

The standard management is systemic immunosuppression. 

• Methotrexate (MTX): The preferred agent; the dose is 0.3 to 1 milligram/kilogram/week (mg/kg/wk). MTX is administered in oral or parenteral form. Therapy is continued for 12 to 24 months to prevent relapses.
• Corticosteroids: MTX is combined with oral prednisolone or intravenous methylprednisolone (IVMP).[30] For 2 months, oral prednisolone is given at a 1 mg/kg/day dose, followed by tapering doses in the third month. IVMP is administered as pulse therapy at 1000 mg/day for 3 days every month for 6 months. 
• Other agents: Mycophenolate mofetil, cyclophosphamide, hydroxychloroquine, and cyclosporine are employed for resistant cases. 
• Psoralen and ultraviolet A (PUVA): Variable efficacy in halting the disease activity.[31]
(B3)

Ophthalmic Management

• Acute uveitis: Topical cycloplegics, topical and systemic steroids are the mainstay treatments. Acute trabeculitis is treated with topical antiglaucoma medications. Relapses are common, and aggressive management is the norm.
• Keratitis: Lid tapping and profuse topical lubrication are advised for exposure keratopathy. Early diagnosis and treatment of super-added infective keratitis is a must.
• Corneal opacity: An optical penetrating keratoplasty offers a good visual outcome for severely opacified corneas due to exposure keratopathy, infective keratitis, and primary endothelial failure.
• Scleral melt: Scleral patch graft is the preferred management option. 
• Glaucoma: Antiglaucoma medications can control the IOP in early cases. The severe cases with inadequate control of topical medications require trabeculectomy surgery.
• Restrictive strabismus: The small-angle deviations are corrected by the prism glasses. The large-angle strabismus cases need definitive surgical correction.
• Retinal vasculitis: The active disease shows vascular lesions in the mid-peripheral retina and mild vitritis. Topical and systemic immunosuppression is the primary treatment. The advanced disease shows neovascularization, vitreous hemorrhage (VH), or tractional retinal detachment (TRD). The visible nonperfused retina is lasered in cases with posterior segment neovascularization. Vitreoretinal surgery with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is needed for cases of nonresolving VH and TRD.

Neurological Management

• Seizures: The anti-epileptic drugs are titrated as per response for long-term management.
• Neuropsychiatric disorders: An expert psychiatrist consultation is essential.

Rehabilitation Strategies

Cosmetic rehabilitation is attempted after at least one to 2 years of halt in the progression of the disease.[32] The commonly employed management options are:

Oculoplastic Management

• Enophthalmos: Intra-orbital injection of fillers like silicone gel, hyaluronate derivates, or autologous fat graft with adipose-derived stem cells has good cosmetic results.  
• Ptosis: Primary correction of the enophthalmos often provides satisfactory cosmesis. Frontalis sling surgery is reserved for severe cases.   
• Eyelid retraction: Surgically treated with levator recession or levator lengthening with relaxing myotomy technique.
• Lagophthalmos: Persistent lagophthalmos requires surgical correction with permanent lateral tarsorrhaphy.
• Drooping of eyebrow: Browpexy or Z-plasty are good treatment options
• Atrophic/Phthisis bulbi: A painless involutional globe with adequately formed conjunctival fornices requires a primary trial of the prosthetic shell. The painful phthisical eye may require enucleation surgery with a silicone implant. 
• Contracted socket: The mucous membrane and fat grafting are needed for total surgical socket reconstruction in severe cases with forniceal shelving. A healthy socket is then given a trial of the prosthetic shell. 

Plastic Surgery Management

• Synthetic tissue fillers: Minimally invasive modality to correct facial asymmetry. The commonly employed fillers are silicone gel, polyethylene, hydroxyapatite, and poly L-lactate.[33] These have excellent results in mild to moderate disease. 
• Autologous fat grafting: The Coleman technique has acceptable cosmetic outcomes for most cases.[34]
• Skeletal reconstruction: Bone paste cranioplasty, bone implants, bone/cartilage grafts, and orthognathic surgery have variable success rates. 
• Free soft tissue transplantation: Extensively used for large-volume reconstruction. Commonly used flap sites are greater omentum, lateral thigh, parascapular muscles, latissimus dorsi muscle, and dorsal thoracic adipofascial flap. This procedure provides satisfactory cosmetic outcomes. 

Differential Diagnosis

The closest differential diagnosis for PRS includes the following:

1. Rassmussen encephalitis (RE): It presents with unilateral cerebral involvement and intractable seizures. Focal neurological deficits and subsequent atrophy mimic the presentation of PRS. The histopathological findings of lymphocytic vasculitis in both RE and PRS may complicate the diagnosis. PRS may be associated with cases of RE, developing progressive hemifacial atrophy.[35]
2. Barraquer-Simons syndrome: It is an acquired progressive lipodystrophy disorder affecting the face, neck, thorax, abdomen, and rarely the extremities. Central nervous system involvement is suggested by epilepsy and bilateral cerebral atrophy. A gradual symmetric bilateral loss of subcutaneous fat tissue with renal involvement helps differentiate this syndrome from PRS.[36]
3. Hemifacial hypertrophy: This condition shows an asymmetric enlargement of half of the face and head instead of hemiatrophy.[37] It is an important clinical differential for asymmetric facial deformity.
4. Hemifacial fat necrosis: The causes range from bulbar poliomyelitis, connective tissue diseases to trauma. The absence of muscular or osseous involvement helps differentiate these causes from PRS.[38]
5. Congenital deformities: Conditions like congenital hemiatrophy or torticollis may mimic facial asymmetry caused by PRS. A careful history of onset helps differentiate these entities.

Staging

The currently used classification system for PRS cases is as follows: 

• Mild: Skin and/or subcutaneous fat atrophy over a single division of the trigeminal nerve
• Moderate: Skin and/or fat atrophy involving 2 branches of the trigeminal territory
• Severe: Atrophy spread over all 3 divisions of the trigeminal nerve or any bony atrophy [39]

Prognosis

The disease reaches the burn-out phase within 2 to 20 years of active disease activity. Facial asymmetry is often significant, with gross disfigurement. Ocular manifestations ranging from uveitis to keratitis to retinal pathologies require active management. Repeated attacks of uveitis or retinal vasculitis can lead to secondary glaucoma with variable visual prognosis. The neurological manifestations are often well-controlled and cause minimal disability.

Complications

The complications that can manifest with PRS are as follows:

Ophthalmic Complications

• Corneal opacity
• Glaucoma
• Restrictive strabismus
• Retinal detachment
• Loss of vision
• Phthisis bulbi or atrophic bulbi
• Contracted socket

Neurological Complications

• Recurrent seizure attacks and status epilepticus
• Subarachnoid hemorrhage from rupture of the cerebral aneurysms [9]
• Spontaneous carotid-jugular fistula and carotid dissection due to cerebral vascular malformations
• Cerebral infarction from focal stenosis of the cerebral vasculature