A Case Report of Behcet’s Syndrome in an African American Man

Clinical Case

A 32-year-old African American male with no significant medical history presented to the emergency department with a chief complaint of a four-day history of headache and neck pain, worse with flexion. He had been diagnosed with influenza at an urgent care five days before presentation and was advised to go to ER if he did not improve. Workup in the ER included the following pertinent labs: an elevated WBC of 13.1x10⁹/µL as well as elevated protein (126 mg/dL) consistent with a presumed diagnosis of viral meningitis. A CT of the head showed no abnormalities. The patient was then admitted to the hospitalist service under the care of an attending physician and clinical pharmacists for treatment of presumed viral meningitis. Upon admission the patient received empiric antimicrobial treatment with acyclovir, ceftriaxone, and vancomycin for the primary suspicion of meningitis. Based on the patient’s age and concern for infectious processes, this therapy was appropriate. On day two, the meningitis panel was negative which removed suspicion for meningitis. Bacterial cultures also showed no growth to date, so empiric antimicrobials were discontinued at that time. CSF studies for West Nile Virus to further rule out viral causation was pending. Patient continued to complain of headache, photophobia, and neck stiffness and pain. He also reported some ataxic gait with difficulty controlling his left arm. With the primary concern for meningitis eliminated, the team then evaluated the patient for diagnosis of stroke, which was also ruled out. MRI done showed diffuse leptomeningeal enhancement as seen with viral meningitis. Additionally, cortical and subcortical enhancing lesions were noted in left frontal, bilateral occipital lobe, most notable in the midbrain and posterior limb internal capsule, consistent with cerebritis. Also on day two, the patient began to complain of photophobia and white, painful ulcerations were noted on the tongue by nursing staff. On day three, symptomatic treatment was initiated with a swish-and-spit solution of diphenhydramine 2.5mg/mL, doxycycline 6.25mg/mL, hydrocortisone 50mg/mL, lidocaine 20mg/mL, and nystatin 100,000 units/mL for the patient’s aphthous ulcers.

Hospital service teams changed on day four of admission, and a new attending physician assumed care of the patient. On this day, the physician further questioned the patient about his vision, with the patient reporting the presence of “floaters”, a possible symptom of uveitis. Ophthalmology was consulted with the intention to treat the patient for Behçet’s Disease if uveitis was present. Based on exam findings, Ophthalmology suspected an acute uveo-meningeal syndrome. Suspected causes were Behçet’s, Wegener’s, Sarcoid, and Vogt-Koyanagi-Harada. A workup with guidance from Rheumatology was recommended to make a definitive diagnosis. At the end of day four, the attending physician made the decision to empirically begin treatment of ocular and neurological Behçet’s based on the diagnostic criteria including cerebritis, aphthous ulcers, photophobia, and visual floaters with uveitis. Treatment included a one-time dose of intravenous Renflexis (infliximab-abda) 400mg (5mg/kg), 50mg/day of oral azathioprine, and 125mg/day of methylprednisolone with 80mg/day of prednisone to be continued at discharge. Methylprednisolone was initiated at the end of day four, and the patient had marked resolution of photophobia and improvement in pain and muscle rigidity. On day six, patient was discharged from the hospital on azathioprine 50 mg and prednisone 60 mg daily with instructions to follow-up with Rheumatology, Ophthalmology, and the resident physicians’ clinic. At the time of discharge, Mumps, ACE level, HLA panel , Toxoplasmosis, ANA, and West Nile serologies remained pending but were found to be negative at follow-up. The PCP saw the patient10 days after discharge with improvement in ataxic gait and difficulty with left arm. The headache was improved but still present, and he continued to complain of fatigue and diffuse myalgias and arthralgias. He saw rheumatology twenty days after discharge with persistent symptoms in addition to pathergy skin findings where he had undergone lab draws. He remained on azathioprine and prednisone which was slowly tapered. He had a recurrence of headache and visual disturbance with prednisone cessation. Additionally, he was noted to have arm pain and swelling, and ultrasound revealed thrombus of left cephalic vein. He was started on anticoagulation (total of three months), and symptoms improved with prednisone resumption. At his three-month follow-up, MRI revealed resolution of lesions, and he was symptom-free. Azathioprine was discontinued and prednisone tapered slowly over one month, and he remained symptom-free at next follow-up.

Discussion

Also referred to as the “Silk Road Disease”, Behçet’s is a rare, chronic, relapsing auto-inflammatory systemic vasculitis characterized by recurrent oral and genital ulcerations, uveitis, neurological and GI manifestations, as well as systemic vasculitis involving arteries and veins of all sizes. Symptoms, especially aphthous ulcers, are generally recurrent throughout patient’s life. Although exact recurrence and triggers are unknown, severity of initial presentation may define life-long reoccurrence risk.¹ The name of the disease originates from its first discovery in 1937 by Hulusi Behçet who described three patients with oral and genital ulcerations, uveitis, and erythema nodosum.² While Behçet’s is credited with the disease’s discovery, it is believed that it may have first been described by Hippocrates.³ The disease is most common along the area known as the “Silk Route” that spans across Asia into the Mediterranean.⁴ Carriers of the human leukocyte antigen B51 (HLA-B51) have been most frequently associated with the disease, with HLA-B51 being a common genetic factor found in Japanese, Turkish, and middle eastern populations.² Prevalence of the disease in the United States is 5.2 people per 100,000 population.² Although previously documented, these details underscore the rarity of the disease, especially in patients of African American lineage.⁵

Exact pathophysiology and etiology are not well understood in Behçet’s’s disease, but it is generally accepted that these patients have abnormal T cell responses causing increased cell mediated cytotoxicity and cross reactivity to external and internal antigens as well as increased neutrophil activity including overproduction of reactive oxygen species leading to oxidative tissue damage. Additional theories implicate endocrine dysfunction in this immune dysregulation.⁶

Uveitis and recurrent aphthous ulcers are mainstays of diagnosis, and most clinicians are familiar with these findings, but neurological findings are harder to characterize and, yet, can have more severe outcomes if untreated. CNS findings in Behçet’s’s disease are classified as parenchymal (as in our patient) or non-parynchymal. Non-parenchymal disease includes cerebral venous sinus thrombosis and arterial involvement. Parenchymal involvement is more prevalent and involves the brainstem, hemispheres, spine, and meninges. In parenchymal disease, CSF findings tend to show normal glucose and increased protein whereas non-parenchymal disease tends to have normal CSF findings. Symptoms respond quickly to treatment.⁷

Treatment can be systemic or target-based therapy depending on manifestation of disease. Systemic treatment is typically with glucocorticoids or with glucocorticoids with azathioprine. Severe course or courses refractory to first line treatment are treated with mycophenolate, cyclophosphamide, TNF-α inhibitors, cyclosporine, or rituximab.^7,8 No definite data is present regarding the benefit of prophylactic treatment with anticoagulation.⁹

In a study involving 817 patients conducted by Saadoun et al., the overall mortality of patients with Behçet’s disease was 5% after a median follow-up of 7.7 years.¹⁰ Mortality and morbidity in Behçet’s disease appear to be related to the neurological, ocular, and vascular manifestations of the disease. Disease burden related to ocular, GI, and mucocutaneous manifestations seems to be the greatest early in the disease course and typically burn out. CNS and vascular disease may present late in the disease course. Parenchymal involvement has more likelihood of relapses compared to nonparenchymal involvement.¹¹ Male sex, HLA-B51 genotype, parenchymal (specifically brainstem) involvement, elevated WBC and protein in the CSF, and relapse with steroid taper were associated with poor prognosis.¹²

There is accumulating evidence that HLA-B∗51 positivity differs among the clinical subtypes of Behçet’s syndrome, and the pathogenic role of HLA-B51 is still not entirely understood.⁷ Our patient’s HLA B 51 testing was negative, and he is not of middle eastern or far eastern descent as is typical of Behçet’s disease. This background led to a delay in the diagnosis of Behçet’s Disease by 2 physicians and delayed appropriate care by 2-3 days. Once the differential diagnosis of meningitis vs. Behçet’s was pursued, further history taking led to the discovery of urogenital lesions which increased specificity for Behçet’s.³ Additionally, the patient had presented to the emergency room twice over the past 7 years with complaints of cysts across his body, blurry vision, and oral lesions. These details, coupled with Behçet’s being most common among patients between 20 to 40 years of age, suggests the patient had potential manifestations of the disease several years prior to his diagnosis.³ Diagnosis is based on scoring greater than or equal to 4 on the International Criteria for Behçet’s’s disease: 2 points for genital aphthous lesions, 2 points for oral aphthous lesions, 2 points for ocular lesions (anterior/ posterior uveitis or retinal vasculitis), 1 point for skin lesions, 1 point for vascular lesions, 1 point for neurologic manifestations, and 1 point for pathergy.¹³ Per these criteria our patient scores a minimum of 7 points. He also had brainstem lesions on MRI, as is characteristic of parenchymal neurological manifestations of Behçet’s’s disease in addition to pleocytosis and elevated protein on CSF studies. Finally, he had a significant symptom improvement to treatment with glucocorticoids and azathioprine.

Diagnostic criteria and typical presentations are taught to medical providers in order to treat typical and common cases. In more ambiguous presentations such as our patients’, it is important to lean on thorough history and comprehensive physical exam and expand on the differential accordingly. Failure to do so leads to delay in care and worsening outcomes for the patient.