Unique clinical spectrum with distinguishing diagnostic features in Vogt-Koyanagi-Harada syndrome

Abstract

A 36-year-old ulcerative colitis male patient on treatment for 7 years was referred to dermatology with resistant alopecia universalis and hypopigmented patches on limbs for 5 months. During this time he also reported to ophthalmology with acute bilateral decreased vision for 5 days. His examination revealed hyperaemic discs, multifocal retinal detachments and choroidal granulomas. Taking into account the revised diagnostic criteria, atypical course of disease in the form of early cutaneous presentation followed by ophthalmic manifestations was attributed to Vogt-Koyanagi-Harada syndrome (VKHS) which was supported by relevant investigations including ophthalmic imaging, MRI and nerve conduction studies. Subclinical nerve conduction abnormalities and white matter demyelination were also seen for the first time in a patient of VKHS. Appropriate treatment was required to prevent visual complications; therefore, systemic corticosteroids with steroid sparing immunosuppressive drug therapy showed significant improvement in vision on follow-up. Cutaneous manifestations were resilient to the entire regimen.

Background

Cautious assessment of the uncommon sequence of any disease process is important to prevent life threatening morbidities. We are reporting an unfamiliar series of symptoms in a rare syndrome.

Vogt-Koyanagi-Harada syndrome (VKHS) is an uncommon multisystem autoimmune inflammatory disorder targeting melanocytes rich tissues. The organs most commonly affected are nervous system, eyes, skin and ears. The incidence of VKHS in uveitis patients is variable and estimated to constitute approximately 7% in Japan, 1%–4% in USA and 2.5% in Brazil.^1–3

Initial symptoms in VKHS are usually due to uveomenigismus while other systemic features are seen in later stage of disease.⁴ Some systemic autoimmune disorders are found to be associated with VKHS in some studies.^5–7 Multidisciplinary assessment, relevant investigations and optimum follow-up scheduling are fundamental to avoid error in diagnosis. The treatment plan is crucial to have early recovery, prevent complications and recurrence.^{8 9}

This report describes the association of VKHS and ulcerative colitis, an unexpected development of irreversible alopecia universalis and symmetrical cutaneous hypopigmentation preceding the eye symptoms, asymptomatic nerve conduction abnormalities and white matter demyelination. These findings in a VKHS patient were a new observation of awareness for our treating team of physicians and we are reporting it to familiarise clinicians with them, so as to prevent early misdiagnosis.

Case presentation

A 36-year-old male patient of ulcerative colitis had been on follow-up with gastroenterology division of medicine department for the last 7 years. During his treatment he started to develop diffuse alopecia (alopecia universalis) and symmetrical patchy cutaneous hypopigmentation on upper and lower extremities, for which he was followed up by dermatology unit and was referred to internal medicine department for systemic interpretation of his cutaneous manifestations (figure 1A–E).

Figure 1.

Alopecia totalis (A–C), bilateral symmetrical inflammatory hypopigmentation patches in legs (D), arms and forearms (E).

Five months later during his medical follow-up, patient complained of bilateral acute painless decrease in vision for 5 days. Other neurological or auditory complaints were absent

Investigations

Eye examination revealed visual acuity of 20/200 in both eyes, slit lamp examination revealed occasional cells in anterior chamber with no keratic precipitates or iris nodules. Funduscopy and optical coherence tomography showed bilateral multifocal exudative retinal detachment and hyperaemic discs (figures 2 and 3A,B). Fundus fluorescein angiography showed diffuse pin point leakage (figure 4) and late pooling at areas of exudative detachment (figure 5). Indocyanine green angiography showed the presence of multiple hypofluorescent dots consistent with choroidal granulomas. Complete blood count and biochemical profile were unremarkable.

Figure 2.

Funduscopy showing exudative retinal detachment (white arrows) with hyperaemic optic nerve head (green arrow).

Figure 3.

Optical coherence tomography of right (A) and left (B) eyes showing multifocal subretinal fluids (white arrows).

Figure 4.

Fundus fluorescein angiography of left eye showing multiple pinpoint leakage (white arrows) with inflamed optic nerve head (red arrow).

Figure 5.

Fundus fluorescein angiography of right eye shows late pooling demarcating the area of exudative retinal detachment (white arrows).

Despite patient denial of neuropathy symptoms, clinical examination revealed reduced pin prick sensation in stocking pattern and diminished reflexes in lower limbs. No other sensory or motor deficits were noted. To see further his nerve conduction study was done which showed evidence of mild or early sensory axonal polyneuropathy. The findings were prolonged distal onset latency (6.7 ms) in left tibial motor nerve, prolonged distal peak latency (4.0 ms) and reduced amplitude (7.2 µV) in left medial plantar mixed nerve and reduced amplitude (7.6 µV) in right medial plantar mixed nerve. All remaining nerves were within normal limits. This is in view of borderline low sensory nerve action potential amplitudes in the lower limbs for the age of the patient. No demyelinating features were noted (figure 6A–D). Nerve biopsy could not be done as patient refused to do so.

Figure 6.

Nerve conduction study in tibial and medial plantar mixed nerves (A–D). Prolonged distal onset latency (6.7 ms) in left tibial motor nerve (A), prolonged distal peak latency (4.0 ms) and reduced amplitude (7.2 µV) in left medial plantar mixed nerve (C). The right medial plantar mixed nerve showing reduced amplitude, that is 7.6 µV (D).

As peripheral neuropathy was found, so we did his contrast enhanced MRI to rule out central neurological changes also, which surprisingly showed small hyperintensity foci on fluid attenuation inversion recovery (FLAIR)/T2-weighted images in subcortical white matter of the both frontal lobes, left temporal lobe and along the periventricular region of body of left lateral ventricle (figure 7A–F). The lesions were non-enhancing on postcontrast study (figure 8). Diffusion weighted images showed no restriction favouring them as likely demyelination foci. No changes were found in the MRI orbits bilaterally (figure 9).

Figure 7.

Plain MRI brain FLAIR sequence (A–F) showing hyperintense foci on axial (A–D) images: (A) left lateral periventricular region, (B) bilateral frontal lobes periventricular regions, (C) right occipital, (D) left temporal lobe; and sagittal (E, F) images: (E) periventricular and frontal regions, (F) left temporal lobe.

Figure 8.

MRI axial T1 postcontrast MRI showing non-enhancing left periventricular lesion (yellow arrow).

Figure 9.

MRI axial T1 postcontrast MRI showing normal orbits bilaterally.

Clinical signs, symptoms and diagnostic findings were fulfilling the revised diagnostic criteria of the incomplete variety of VKHS (eyes along with either neurological or skin involvement).

Differential diagnosis

Sympathetic ophthalmia could be considered a possible differential after eye examination but this entity is solely for patients with history of penetrating trauma or surgery which was not in our patient.

Treatment

Patient was taking steroids, mesalazine and immunomodulator (adalimumab) for ulcerative colitis for the last 7 years.

For his dermatological manifestations patient was on steroids. After diagnosing alopecia universalis and inflammatory hypopigmentation as a consequence of Vogt-Koyanagi-Harada, a discussion was made with ophthalmology team and patient started taking intravenous methylprednisolone 1 g daily for 3 days followed by oral prednisolone 1 mg/kg with immunomodulator mycophenolate mofetil 1 g two times per day.

Outcome and follow-up

On follow-up after a week of treatment, his vision improved dramatically to 20/20 in both eyes with resolution of exudative retinal detachments (figure 10A,B).

Figure 10.

Optical coherence tomography of right (A) and left (B) eyes showing flat macula with resolved subretinal fluids.

But during his follow-up in previous 9 months his alopecia universalis and hypopigmented patches are refractory to the treatment.

Discussion

VKHS is a rare multisystem autoimmune granulomatous inflammatory disorder. It has global variation in incidence. In

USA it is approximately 1.5–6 per 1 million patients, but in Japan it is found to be in approximately 800 new patients per year.¹⁰ It is found more in races with dark pigmented skin including Asians, Middle Easterners, Hispanics and Native Americans. The age of onset is second to fifth decade of life and is more common in females.^{10 11}

The etiopathogenesis is been described as T cell mediated autoimmunity against melanocytes, melanin and retinal pigmented epithelium in individuals with genetic susceptibility to HLA-DRB1 *0405 and HLA-DR4.^12–14 The autoimmunity targets are ocular, auditory, integumentary and nervous systems. First presentation of the disease is commonly meningismus or blurring of vision due to uveomeningitis or uveitis, respectively. Other symptoms may include tinnitus or hypoacusis due to ear involvement. Alopecia, poliosis, inflammatory cutaneous hypopigmentation and vitiligo may be seen as a consequence of cutaneous involvement. Neurological features could be meningismus, malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, myelitis, hemiparesis, cranial nerve palsies or combination of these.^{4 14} To best of our search peripheral neuropathy in VKHS has not been mentioned in the literature so far but we found in our patient necessitating further studies.

Out of four stages of VKHS that is prodromal, acute uveitic, convalescent and chronic, skin changes of the disease process are manifested few months later which is the third convalescent stage.¹⁴ Ocular symptom is an early presentation and hair fall is usually seen as reversible alopecia areata.^{15 16} But hair loss in the form of alopecia universalis is reported only once in 50-year-old woman.¹⁷ In the revised diagnostic criteria of VKHS incomplete category is the most common. Either neurological/auditory or skin changes should be present to label the disease as an incomplete category of VKHS.^{4 18}

VKHS has been mentioned to be associated with other autoimmune disorders and malignancies like Hashimoto’s thyroiditis, connective tissue disorders, type 1 diabetes mellitus, coeliac disease, malignant melanoma, lymphoma and chondrofibromyxoma.^{5 6} Its association with ulcerative colitis is very rare and might be related to their common human leucocyte antigen (HLA) in the pathogenesis.⁷ There are only three cases reported to date demonstrating concurrent ulcerative colitis and VKHS, our patient being the fourth one.^{7 19 20}

Only few cases have been found to show brain parenchymal changes in VKHS patients.^21–24 MRI has found to be a helpful tool in assessing extent of disease and thus early neurological morbidity management. On T2/FLAIR sequences scattered periventricular focal white matter, brain stem and peduncles lesions with pachymeningeal and/or leptomeningeal enhancement have been described, while spinal cord involvement is the rarest.^24–26

We are presenting a young male patient who had been diagnosed with ulcerative colitis 7 years ago and diagnosed with VKHS recently. His initial symptoms of disease were in skin, which are irreversible alopecia universalis and hypopigmented skin patches in both limbs and appeared 5 months before acute uveitis. To best of our literature review this spectrum of peculiar findings of ulcerative colitis associated with VKHS having skin changes at the forefront, subclinical peripheral neuropathy and MRI changes of multiple focal brain parenchymal demyelinations, has never been reported before.

Eye investigations play an important role in diagnosis of VKHS. The uveitis associated with VKHS has acute and chronic stages. In acute the features are of granulomatous choroiditis associated with exudative retinal detachment, optic disc hyperaemia and swelling, with relatively quiet anterior chamber. The chronic stage shows granulomatous panuveitis with subsequent sunset glow fundus appearance and chorioretinal scarring.^{8 12 27} The advantage of peripheral nerve conduction studies is yet to be seen as it has never done before but in our patient.

Early and aggressive intervention with corticosteroids promises good outcome in VKHS and visual acuity can be preserved by reducing inflammation. Corticosteroids refractory cases are started on immunosuppressants while resistant cases are considered to be shifted on immunomodulators.^{8 12}

The aim of treatment for VKHS in acute phase is to prevent visual threatening complications by reducing ocular inflammation for which early and aggressive treatment with corticosteroids promises good outcome. Non-steroidal immunosuppressants are becoming part of initial treatment along with corticosteroids and some studies suggested this regimen to be more beneficial in preventing long term visual morbidity and recurrence of disease.^{8 9} Few biological response modifiers (immunomodulators) have also shown required clinical outcome.^10–12

There are many immunosuppressant drug options but our hospital protocol is to start the patient with mycophenolate mofetil with high dose pulsed therapy of methylprednisolone and in refractory cases we use immunomodulator, that is, rituximab. Prognosis of the disease is related to many factors. Early diagnosis, adequate treatment and less severe presentation symptoms may be helpful in recovery, reducing morbidity and avoiding recurrence.^{10 28}

Patient’s perspective.

I was diagnosed to have ulcerative colitis 7 years ago and was doing fine with my cortisone, Asacol and Humira. But suddenly I noticed that my hair started falling and I had pale small multiple patches on my skin. My gastroenterologist referred me to a dermatologist, and he advised me certain creams for applying on my skin. Though my condition was not debilitating but I was little frustrated that my hair fall was not improving and not only was I bald, but I had NO EYEBROWS! The loss of eyebrows may cause problem with my identity. I had hair loss on my arms, legs and chest also. My small skin patches were gradually spreading, and I had them on my arms as well. All of them were affecting my self-esteem and body image. My dermatologist referred me to an internal medicine doctor to see if there is any underlying pathology related to internal medicine. I was being investigated for any medical disorder when I noticed visual loss and contacted the eye department of the hospital.

In the eye department I went through a series of tests and finally I was diagnosed of a disease named Vogt-Koyanagi-Harada syndrome. The name itself was so difficult but I had some news from eye and internal medicine doctors who were in liaison with each other.

My internal medicine doctor told me good news that though the name is a bit complicated due to the fact that my immune system is misdirected, and multiple systems of my body can be involved but the further damage can be prevented through early intervention. At the same time, I was told that generalised hair loss is called alopecia universalis and patches on my skin are also attributed to this disease and seem to be permanent as I was not responding to immunity enhancing medicines.

I was told by my eye doctor that the outcome of treatment is good, and I will have good recovery from eye symptoms which was a big relief for me. My eyesight responded really well to the treatment. Though I felt bad about my permanent alopecia universalis and skin patches, but I was happy to have my eyesight back.

As a part of my routine workup I was advised to go for certain more investigations to see the electrical activities of nerves and MRI brain and the results were surprising for my doctors even!

My doctors told me that I had a very unusual finding in the electrical activity of my nerves and my MRI showed that coating of the nerve fibres was damaged. I felt depressed and at the same time special to know that I was an individual with multiple new manifestations of Vogt-Koyanagi-Harada syndrome which were not seen in any patient before.

I felt extremely grateful to my doctors who discovered the pathologies in my nerves despite the fact I didn’t notice them. I am quite hopeful that anything disastrous can be prevented as my doctors are following me up very well.

Learning points.

• Patients with Vogt-Koyanagi-Harada syndrome (VKHS) may have peripheral neuropathies and central demyelination, which was observed in our case.

• VKHS early presentation may not necessarily be uveomeningitis, patient can also present with cutaneous symptoms as first ever seen in our patient.

• Despite being asymptomatic we can expect focal brain parenchymal demyelination on MRI in VKHS patients which could be helpful in preventing early neurological morbidity.

• Alopecia and hypopigmentation can be permanent sequelae in VKHS.