A 16-year-old male with limb weakness, reduced muscle tone and absent reflexes was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) secondary to idiopathic hypereosinophilic syndrome (IHES). Oral corticosteroids decreased the eosinophil count but disease relapse and elevation of the eosinophil count occurred after the dose was tapered. However, organ dysfunction was responsive to intravenous immunoglobulin. The use of intravenous immunoglobulin for CIDP secondary to IHES has not been reported.
A Idiopathic hypereosinophilic syndrome (IHES) is a rare disorder characterized by a sustained peripheral blood eosinophil count over 1.5 × 109 /L (duration ≥ 6 months) associated with signs and/or symptoms of end-organ dysfunction in the absence of other known causes of eosinophilia. Peripheral neuropathy is not uncommon but chronic inflammatory demyelinating polyneuropathy (CIDP) secondary to IHES has been seldom reported. Here, we report a case of a young man with IHES who presented with CIDP.
A 16-year-old male presented to our hospital in May 2012 with a second episode of weakness of all four limbs and finger numbness after an upper respiratory tract infection. He experienced a similar episode in December 2010 and symptoms resolved after a pulse of intravenous immunoglobulin (IVIG). None similar history was found in his family. Physical examination showed muscle weakness in all four limbs, both proximal and distal, decreased muscle tone and absent tendon reflexes, but without muscle atrophy. Routine blood examination of the first episode revealed an eosinophil count of 4.36 × 109 /L and a leukocyte count of 10.32 × 109 /L. Cerebrospinal fluid (CSF) analysis showed elevated protein of 78mg/dl without other abnormalities. Nerve conduction studies showed prolonged distal latency and reduced compound motor action potentials (CMAPs) in median, ulnar, tibial and peroneal nerves. The CMAPs of right ulnar and left peroneal were 0.9mV and 1.0mV respectively. Motor conduction velocities were slow, ranging from 20 to 25 m/s. F-waves were markedly prolonged or even not found. Sensory nerve action potentials were absent in the left arm. No fibrillation potentials and positive sharp waves were found in needle electromyography. The patient responded well to IVIG again.
The patient suffered from relapses at 2, 4, 8, 10 and 12 months after the second episode but remissions were successfully induced by IVIG despite the persistent eosinophilia. The eosinophil count was consistently in the range of 4.0~4.5 × 109 /L except during the several months under corticosteroid therapy. A comprehensive investigation was conducted. The autoimmune disease panel, allergy testing and tests for the presence of parasites were all negative. Liver and kidney function tests, cardiac enzymes, C-reactive protein, erythrocyte sedimentation, coagulation function, complement components, lactic acid, tumor markers, thyroid function and antibodies were common. Chest CT scan, electrocardiogram, pulmonary function and bronchoprovocation test, spinal MRI, electroencephalogram, and abdominal ultrasound were also normal. The bone marrow aspirate and biopsy revealed an active proliferation with predominantly elevated granulocytic eosinophils, a myeloid to erythroid precursor ratio (M: E ratio) of 2.36:1, and an increased proportion of eosinophils (14%) with normal morphology.
Figure 1. Histology of a lymph node biopsy showing chronic inflammation accompanied by a reactive proliferation of histiocytes.
The peripheral blood smear showed 48% mature eosinophils. Bone marrow karyotyping was normal. FIP1L1-PDGFRA chromosomal fusion was not detected by fluorescence in situ hybridization (FISH). Abnormal subgroups including CD3− CD4+ and CD3−CD4+CD8− cells were absent on examination of T cells subgroups. Ultrasound showed multiple superficial lymph nodes enlargement. Histopathological examination of a lymph nodes biopsy that had been taken after administration of IVIG revealed lymphoidocytes and histiocytes in the fibrous and adipose tissues with hyperplastic vessels containing a few sporadic eosinophilic granulocytes and cells containing pigment granules, occasional mitoses, and chronic inflammation accompanied by a reactive proliferation of histiocytes (Figure 1). The patient was diagnosed with CIDP secondary to IHES and had been on oral methylprednisolone since September 2012, starting at 32 mg/day. Although the eosinophilia resolved quickly after taking corticosteroids, it recurred as dose reduced to 16 mg/day and muscle weakness reappeared in January 2013. The patient subsequently ceased corticosteroid therapy because of the multiple recurrences despite therapy. He was encouraged to restart corticosteroid therapy after the last replase in July 2013 but he later consulted another hospital. Given to the potential side effects of steroid, doctors there chose interferon alfa to successfully reduce the eosinophil count. To date, the patient has been fortunately in remission for the past one year.
IHES belongs to the group of disorders known as hypereosinophilic syndromes (HES), which mainly affect individuals between the ages of 20 and 60 years but may occur at any age. The differential diagnosis for HES includes parasitic infection, allergy, autoimmune diseases like Churg-Strauss syndrome, adverse drug reaction, malignancy, organ-specific eosinophilic disorder, and immunodeficiency disorder-all of which were excluded in the present case. We also excluded HES variants including chronic eosinophilic leukemia and myeloproliferative HES based on the absence of FIP1L1- PDGFRA fusion and other chromosomal abnormalities. The absence of T cells with phenotypes of CD3−CD4+ or CD3− CD4+CD8− led to the exclusion of lymphocytic HES . Familial HES was also ruled out. IHES commonly involves the heart, lung, skin, nerves, blood system including coagulation, and the digestive tract. Both the central nervous system and the sensory and motor nerves of the peripheral nervous system may be affected, as demonstrated in the present case.
The mechanism of hypereosinophilia-induced peripheral neuropathy remains unclear. The findings of the muscle biopsy in the case reported by Scola et al  and the lymph node biopsy in the present case demonstrated that tissue damage was due to inflammation. Inflammatory chemokines and cytokines including proinflammatory, Th1 and Th2 cytokines modulate the eosinophil number and function in immune reactions . The most probable mechanism of tissue injury is the release of cytotoxic substances such as major basic protein, eosinophil cationic protein, neurotoxins, and other oxidizing molecules and enzymes by eosinophils, which may led to peripheral nerve injury . In the present case, we suspect that the immunoglobulins combined with the abovementioned proteins, thereby neutralizing their toxic effects.
For patients without symptoms or signs of organ involvement, close-follow-up without treatment may be undertaken. However, as organ damage occurs, glucocorticoid is the firstline treatment for IHES . If symptoms recur after tapering the dose to > 10 mg/day of prednisone, therapy consisting of hydroxyurea, interferon alfa could be used in conjunction with corticosteroids or as monotherapy. Responses to vincristine, cyclophosphamide, etoposide, imatinib mesylate, 2-chlorodeoxyadenosine, cytarabine and cyclosporine-A have also been reported, as well as antibodies including mepolizumab and alemtuzumab in selected cases [1,5,6]. In our case, it was noteworthy that the CIDP as a complication of IHES responded rapidly to IVIG, which has not been previously reported. Given the therapeutic aim of preventing organ involvements, IVIG may be reserved for cases whose organ damage fail to respond to corticosteroid therapy rapidly in IHES.
1.Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol. 2010, 126: 39-44.