Idiopathic hypereosinophilic syndrome presenting as mononeuritis multiplex. Lessons learned after 18-months of follow-up

Dear Editor:

Hypereosinophilic syndrome (HS) is a rare systemic disease included in the group of myeloproliferative disorders. It is diagnosed in patients presenting elevated eosinophil counts below 1500 cells/µL for over 6 consecutive months and eosinophilic infiltration of tissues and organs after excluding such secondary causes of eosinophilia as drug reactions, infections, immune disorders, or allergies.¹

Several subtypes have been described, including a myeloproliferative and a lymphoproliferative form; diagnosis of these subtypes is based on the detection of genetic mutations (in BCR-ABL and FIP1L1/PDGFRA fusion genes) and expression of eosinophil membrane proteins. However, idiopathic HS does not meet these diagnostic criteria.²

From a neurological viewpoint, idiopathic HS is characterised by involvement of both the central nervous system (venous thrombosis and encephalopathy) and the peripheral nervous system (peripheral neuropathy).^3,4 The pathogenic mechanism of peripheral neuropathy is unclear. Although nearly all affected tissues present eosinophil infiltration, histopathology studies of the damaged nerves do not reveal direct infiltration, inflammation, or vasculitis. The role of eosinophils as secretory cells and mediators of the cytotoxic response seems to explain the pathophysiology of peripheral neuropathy, particularly major basic protein and eosinophil-derived neurotoxin, which are responsible for neuropathic axonal damage through disruption of vasa vasorum permeability and perineuronal oedema, respectively.^5,6

We present the case of a 49-year-old woman with no relevant medical history who presented mononeuritis multiplex as the initial manifestation of idiopathic HS. She consulted due to one month’s history of acute pain beginning in the left forearm, and subsequently affecting the right elbow and the anterior aspect of the right thigh. Pain progressed to persistent paraesthesia and weakness in the areas previously mentioned. The examination confirmed mild motor weakness in the left arm (flexor digitorum profundus muscle of the fourth and fifth digits, adductor minimi digiti, first dorsal interosseous, and adductor pollicis) and right leg (posterior tibialis, triceps surae, flexor digitorum longus, and flexor digitorum brevis); absent right Achilles reflex; and hypoaesthesia and hypalgesia in the territories of the left ulnar and saphenous nerves and the posterior aspect of the right leg.

A complete blood count revealed an elevated eosinophil count (2100 cells/µL), mild thrombocytopaenia (99 000 platelets/µL), and a white blood cell differential with 26% eosinophils. A possible adverse drug reaction was ruled out; serology studies for Epstein Barr virus, cytomegalovirus, hepatitis C virus, HIV, Borrelia, and syphilis yielded negative results, and stool examination detected no parasites. Antibody testing detected a low titre of antinuclear antibodies with a homogeneous pattern, and normal immunoglobulin levels (IgE: 2.45 kU/L; normal range, < 100 kU/L); the patient tested negative for the remaining parameters (complement, anti-dsDNA, anti-RNP, anti-Scl-70, anti-SN, anti-Ro, anti-La, ANCA, anti-CCP, cryoglobulins, antineuronal antibodies). Cytochemical analysis and a monoclonal antibody study of the CSF yielded normal results. Electromyography revealed multiple mononeuropathy, with mild involvement of the left ulnar nerve and extremely severe involvement of the right peroneal and posterior tibial nerves. Bone marrow biopsy yielded normal results. Cytogenetic testing of the BCR-ABL and PDFGRA genes revealed no pathological alterations. Peripheral nerve biopsy was not performed.

Suspecting idiopathic HS as the cause of mononeuritis multiplex, we started treatment with high-dose corticosteroids (methylprednisolone dosed at 1 g/day) for 5 days, which improved our patient’s symptoms and laboratory parameters within weeks. We subsequently started treatment with prednisone, tapering the dose to 15 mg/day. A follow-up examination at 6 months revealed no motor or sensory impairment, with the patient presenting a normal blood eosinophil count. At 18 months, a decrease in the dose of prednisone to 5 mg/48 hours resulted in an elevated blood eosinophil count (> 3000 cells/µL) and acute limb ischaemia in the right leg. We increased the dose to 30 mg/day and started treatment with hydroxycarbamide.

Hypereosinophilia may cause bilateral, symmetrical sensory and motor symptoms affecting the distal part of the limbs; asymmetrical involvement in the form of mononeuritis multiplex is extremely rare.⁶ Our patient presented idiopathic HS manifesting as mononeuritis multiplex, with an initially complete response to corticosteroid therapy. Following tapering of the corticosteroid, she presented severe systemic symptoms and required immunosuppresive therapy; this underscores the need for strict monitoring of eosinophil levels and early onset of corticosteroid-sparing immunosuppressive therapy due to the risk of relapse.

Idiopathic HS should be included in the differential diagnosis of mononeuritis multiplex: although the condition is a rare cause of multiple mononeuropathy, it responds well to specific treatment.

Funding

No funding was received for this study.

Conflicts of interest

The authors have no conflicts of interest to declare.