Neuro-Sweet syndrome with late cutaneous findings: A rare disease entity

Introduction

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an inflammatory disease characterized by fever, leukocytosis, and tender, erythematous papules comprised of neutrophilic dermal infiltrate.¹ When neutrophilic aseptic inflammation involves the central nervous system (CNS), the extremely rare neuro-Sweet syndrome (NSS) may occur.¹ A range of non-specific neurologic manifestations may ensue, including meningitis, encephalitis, hemiparesis, and visual disturbances, which ultimately poses a diagnostic challenge.2, 3, 4 We present the case of a 26-year-old female who developed acute neurologic symptoms followed by late onset cutaneous lesions consistent with NSS that improved only with treatment of her neutrophilic dermatosis.

Case description

A 26-year-old female with a history of ulcerative colitis (UC), seronegative ankylosing spondylitis, and psoriasis presented to the emergency department (ED) with a 3-day history of non-specific and worsening neurologic symptoms, including bifrontal headaches, nausea, vomiting, photophobia, mild neck stiffness, and 1 episode of a self-resolving low-grade fever. Two months prior to her presentation, she had transitioned from adalimumab to upadacitinib for management of her UC and spondylarthritis, and she had completed a 2-week course of ciprofloxacin for suspected pouchitis. Two weeks after her initial presentation, she presented to hospital again for sudden blurry vision and ongoing headaches. Computed tomography angiography (CTA) of the head was normal, and she was discharged. One week later, she presented to hospital a third time for worsening headaches, blurry vision, new dizziness, right-sided weakness, right-sided sensory deficits, and diplopia. Ciprofloxacin was discontinued due to emesis. Bloodwork was unremarkable. Cerebrospinal fluid (CSF) analysis demonstrated high total nucleated cells, high total protein, and normal glucose. CSF serum, infectious workup (including HSV, CMV, and cryptococcal antigen), and cultures were negative. Her recent transition to upadacitinib prompted suspicion for an infectious etiology; thus, the patient was admitted to hospital and started on broad spectrum antibiotics (meropenem, vancomycin, ampicillin) and acyclovir. Brain magnetic resonance imaging (MRI) showed multiple patchy areas of T2/FLAIR hyper signal involving the brainstem and left thalamus, as well as in the right frontal and parietal lobes, with associated patchy areas of enhancement and diffusion restriction, as well as focal leptomeningeal enhancement, suggestive of meningoencephalitis/rhombencephalitis. Upadacitinib was discontinued.

While in hospital, the patient developed a non-tender, non-pruritic rash. On exam, the arms demonstrated well-demarcated, pink edematous dermal papules (Fig 1, A and B). Erythematous macules coalescing into patches with no overlying scale were present on the lower legs (Fig 1, C) and non-specific erythematous papules on the cheek and nose were noted (Fig 1, D). There was no mucosal involvement.

Fig 1.

Well-demarcated, erythematous edematous papules and plaques on the right (A) and left (B) arms. Erythematous, blanchable, macules coalescing into patches on the lower legs (C). Erythematous papules and plaques on the face (D).

The patient continued to clinically deteriorate with worsening neurological symptoms, including decreased facial sensation, diplopia, and migraines, as well as ongoing fevers, fatigue, and new arthritis. On re-assessment, she developed new papules with central pustules on the arms, and facial lesions evolved into discrete pustules (Figs 2 and 3, A-C). Tacrolimus 0.1% ointment twice daily to the face was prescribed.

Fig 2.

Discrete juicy red papules with a central pustule on the right arm.

Fig 3.

Erythematous thin papules and plaques on the face (A and B). Edematous juicy pink papules on the dorsal right hand and wrist (C).

Skin biopsy of the arm revealed nodular infiltrates of neutrophils in the full thickness dermis and extending to the subcutis. Perivascular and peri-adnexal lymphocytes were also present. Subtle basal vacuolar changes were present without significant dyskeratosis. Gram and Grocott stains were negative for microorganisms (Fig 4). Tissue culture demonstrated no organisms. Given her worsening neurologic status with no clear neurological driver and no response to treatment for infection, a diagnosis of NSS was made. High dose methylprednisolone (1g IV daily) for 5 days was initiated.

Fig 4.

A, Nodular aggregates of neutrophils in the upper dermis along with a mild, perivascular lymphocytic infiltrate and mild epidermal acanthosis (10×). B, Nodular aggregates of neutrophils in the subcutis (10×). C, Dense, neutrophilic infiltrates with leukocytoclastic debris (20×). D, Nodular infiltrates of mixed inflammation extending from the superficial dermis to the subcutis (2×).

Following steroid initiation, her rash rapidly improved. Her fever, arthritis, and headaches subsequently resolved with significant improvement of her vision. The patient was transitioned to 60 mg of prednisone with taper by 5 mg every 5 days for 60 days. She continued to demonstrate cutaneous and neurological improvement and was thus discharged. She was seen by Rheumatology as an outpatient and was restarted on upadacitinib. She was also seen by Dermatology approximately 2 weeks after discharge with sustained neurological improvement and complete clinical resolution of her rash.

Discussion

While idiopathic SS comprises the majority of cases, SS may also be associated with inflammatory bowel disease, malignancy, pregnancy, and upper respiratory or gastrointestinal infections.^5,6 Drug induced SS has been associated granulocyte-colony stimulating factor, antibiotics, and nonsteroidal anti-inflammatories.^6,7 In the present case, possible contributors to the development of SS included a history of UC, pouchitis, and cephalexin use.

Encephalitis or meningitis is the most common neurological association with SS.¹ Postmortem neuropathological findings of NSS were shown to have opaque, thickened, and fibrotic leptomeninges adherent to the brain surface, particularly in the basal portion, while coronal sections showed congested veins associated with small hemorrhages in cerebral white matter, basal ganglia, thalamus, pons, medulla, cerebellar white matter and dentate nucleus.⁴ MRI showed abnormal high signals in the midbrain, pons, thalamus, basal ganglia, temporal lobe, internal capsule and cerebral white matter.⁴

In NSS, dermal involvement may not always precede neurologic symptoms.^2,3 Kokubo et al and Hisanaga et al reported the onset of skin involvement compatible with SS after initial neurologic episodes.^4,8 In the present case, the patient developed cutaneous lesions compatible with NSS 3-wk after initial onset of neurologic findings. The lack of infectious foci and response to broad spectrum antibiotics, in conjunction with evidence of a primary neurologic disease, biopsy findings, and subsequent rapid improvement following corticosteroids initiation further supported the diagnosis of NSS. A paradoxical reaction temporally associated with the switch from adalimumab to upadacitinib should also be considered. The delayed appearance of cutaneous manifestations precludes the possibility of a skin biopsy, hindering the distinction of NSS from neurologic mimickers, including neuro-Behçhet disease.¹

SS has an immediate response to systemic glucocorticoids, and in NSS, CT, MRI, and CSF findings improve alongside neurologic symptoms.^2,6 Steroid pulse therapy (ie intravenous methylprednisolone 1 g/d for 3 days) is often followed by oral prednisolone (40-60 mg/d), which is gradually tapered.⁹ When it is preferable to avoid systemic corticosteroids, colchicine, dapsone, and potassium iodide have been used.⁶ JAK inhibitors may also be beneficial in refractory cases.⁶

While rare, NSS should be considered in at-risk patients presenting with non-specific and unexplained neurologic symptoms, especially prior to the development of cutaneous findings consistent with neutrophilic dermatoses.