Idiopathic hypereosinophilic syndrome presenting as monoplegia

Abstract

Idiopathic hypereosinophilic syndrome (IHES) is a rare disorder. It is characterised by persistent eosinophilia with eosinophil mediated tissue infiltration and organ dysfunction. Clinical features of IHES vary widely, as it may present with dermatological, pulmonary, gastrointestinal, cardiac or neurological symptoms. We hereby report a female patient who presented with sudden onset upper limb monoplegia and after thorough investigations she was diagnosed as a case of IHES. She was managed with corticosteroids and improved with same.

Background

The criteria for the diagnosis and classification of hypereosinophilia have been constantly changing. A recent consensus on terminology defined hypereosinophilia (HE) as eosinophilia more than 1.5×10⁹/L in the peripheral blood on two occasions more than 1 month apart with or without tissue hypereosinophilia.¹ Hypereosinophilic syndrome (HES) is defined as peripheral blood hypereosinophilia with organ damage and/or dysfunction attributable to tissue HE and the exclusion of other disorders or conditions as major reason for organ damage.² Box 1 ¹ lists the various causes of hypereosinophilia. HESs have also been separated into subcategories depending on their aetiology. These include primary neoplastic (HES_N), secondary or reactive (HES_R) and idiopathic HES.¹

Box 1. Causes of hypereosinophilia.

Allergic disorders

• Allergic bronchopulmonary aspergillosis

• Atopy related disorders

Drugs

• Allopurinol

• Carbamazepine

• Phenytoin

Dermatological disorders

• Allergic contact dermatitis

• Eosinophilic vasculitis

• Pemphigus

Haematological disorders

• Acute leukaemia with eosinophilia

• Myeloid and lymphoid neoplasm with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

• Myelodysplastic syndromes or myeloproliferative neoplasms with eosinophilia

• Hodgkin’s lymphoma

Immunological disorders

• Vasculitis

• Hyper IgG Syndrome

Infestations

• Ascariasis

• Filarial infections

• Giardiasis

• Hookworm infections

Specific organ limited eosinophilic syndromes

• Eosinophilic gastritis

• Eosinophilic pneumonia

Virtually any organ system may be involved in hypereosinophilic syndrome, but the heart, central nervous system (CNS), skin and respiratory tract are commonly involved. The patterns of neurological involvement in HES can be as varied as encephalopathy, peripheral neuropathy and focal central nervous system deficits from emboli or haemorrhage.³

The pathogenesis of the central and peripheral neuropathies in HES are not known; although neurotoxicity mediated by one of the eosinophil cationic granule proteins — EDN (eosinophil derived neurotoxin) is often suggested. In addition to this cationic protein, the eosinophil is capable of causing damage or dysfunction to host cells by a number of mechanisms. Specific granules contain four cationic proteins, eosinophil peroxidase, major basic protein, eosinophilic cationic protein, and EDN. Each can exert toxicities on host cells, as has been recently reviewed.⁴

Case presentation

A 60-year-old woman presented to the medicine outpatient department with sudden onset weakness of the left upper limb for 1 week and complained that she was completely unable to lift her arm or move the fingers. There was no fever, headache or blurring of vision, altered behaviour, facial asymmetry or dysarthria, seizure episode or head injury. There was no neck, arm or shoulder pain. In the past, she had not manifested any episodes of asthma or nasobronchial allergy or recurrent sinusitis. There was no history or records to suggest any deep vein thrombosis or thromboembolic events in the past.

On physical examination, she was conscious, oriented to time, place and person. Her blood pressure in supine position was 110/70 with heart rate of 82 beats/min. Urticarial lesions were present all over the body (noticed for the past 3 months). There was no pallor, icterus, cyanosis, pedel oedema or any lymphadenopathy. There was no calf tenderness or any other evidence of deep vein thrombosis. On neurological examination, the higher mental functions were normal and there were no meningeal signs. On motor system examination, the tone, power and reflexes in the bilateral lower limbs and right upper limb were normal, however left upper limb was hypertonic with power of 0/5 and exaggerated biceps and triceps reflexes. There was no discernible muscle wasting or fasciculations. The sensory system examination was within normal limits. On the abdominal examination there was no hepatosplenomegaly. A detailed respiratory and cardiovascular system examination was done. On respiratory system examination; the breath sounds were heard equally in bilateral lung fields and there was no evidence of any effusion or pleural rub. On auscultation of the precordium, first and second heart sounds were normal in character and intensity. No murmurs were heard and there were no signs of congestive heart failure.

Investigations

On investigations, haemogram revealed haemoglobin of 12.7 g/L, total leucocyte count of 23.1×10⁹ cells/L with 70% eosinophils (eosinophil count of 13.8×10⁹ cells/L) and a normal platelet count. A review of her previous haemogram records confirmed that hypereosinophilia had been persistent for more than 2 months. The peripheral blood smear did not exhibit any microfilaria and stool routine microscopy for ova/cyst had no evidence of parasitic infestation. Serology for microfilaria antigen was negative. Quantitative D-dimer and fibrin degradation products were 0.28 micrograms/ml and 4 micrograms/ml, respectively, both of which were within the normal range. Rest of the parameters including urinary analysis, liver function tests and renal function tests were normal.

The paranasal and chest radiograph and abdominal ultrasound were essentially normal. A high-resolution CT chest was done to rule out tropical pulmonary eosinophilia and any features of pulmonary thromboembolism like any pulmonary infarcts or any focal lesions like pleural effusion. Venous Doppler ultrasound of both lower limbs showed no evidence of deep vein thrombosis. Nerve conduction study of upper and lower limbs revealed a normal pattern.

On MRI brain (figure 1), multiple areas of hyperintensity were seen on fluid attenuated inversion recovery image in the subcortical white matter of bilateral right frontal and parietal and occipital regions showing true diffusion restriction on diffusion weighted image and apparent diffusion coefficient images. Magnetic resonance venography was normal. A possibility of vasculitic infarct was entertained so immunological workup with ANA, p-ANCA and c-ANCA was done which came out to be negative. An ECG was done which showed normal sinus rhythm. A transthoracic two-dimensional echocardiography was performed to locate any cardiac cause of emboli, however it was normal. The ejection fraction was within 55% to 60%. There was no right ventricular dilatation or hypokinesia and no systolic or diastolic dysfunction of the ventricles. There was no regional motion abnormality at rest. No pulmonary hypertension or any evidence of infective endocarditis.

Figure 1.

(A) Apparent diffusion coefficient image, (B) diffusion weighted image showing correspoding areas of diffusion restriction, (C) fluid attenuated inversion recovery image showing scattered areas of hyperintensity along cortical and subcortical regions in bilateral fronto-parietal regions.

Since myeloproliferative neoplasms are an important consideration in such a case, a bone marrow examination (both aspiration and trephine biopsy) was carried out (figure 2), which revealed hypercellularity (52%) with preponderance of eosinophilic series suggesting hypereosinophilic syndrome. The molecular study for relevant mutations (BCR-ABL, PDGFRA, PDGFRB, FGFRI) was performed and it was negative. Patient also had urticarial skin lesions all over the body which could not be biopsied as the patient refused consent for the same.

Figure 2.

Bone marrow aspiration showing eosinophils including eosinophil precursors.

Differential diagnosis

The diagnosis of HES requires that eosinophilia of identifiable aetiologies be eliminated by appropriate investigations. For patients living in tropical areas; parasitic infections with helminthic parasites (ascariasis, trichinosis, strongyloidiasis) and filarial infections should be excluded. A detailed drug history ought to be elicited as regularly prescribed drugs such as allopurinol, phenytoin or carbamazepine can result in peripheral eosinophilia. For those with cutaneous involvement and eosinophilia, the lesions can be distinguished by biopsy and histopathology. The major vasculitis that is associated with eosinophilia is the Churg-Strauss syndrome. A history of asthma, paranasal sinus abnormalities, pulmonary infiltrates, mononeuropathy or polyneuropathy, blood eosinophilia greater than 10% and a biopsied blood vessel demonstrating extravascular eosinophils characterise this syndrome. Features common to myeloproliferative disorders include elevated B12 levels, splenomegaly, cytogenetic abnormalities, myelofibrosis, anaemia, erythrocyte abnormalities including teardrop cells, myeloid dysplasia and basophilia.

Treatment

Before visiting our hospital, patient had already received albendazole and trial of diethylcarbamazine (DEC) for 21 days considering parasitosis as the cause for hypereosinophilia. At our centre, after confirmation of the diagnosis, patient was administered intravenous pulse therapy with injection methylprednisolone, 1 g intravenous for 5 days.⁵ A dramatic fall in eosinophil count was seen on day 3 of treatment and the eosinophil count was reduced to 2.3×10⁹ cells/L. Patient was later discharged on oral prednisolone only, 70 mg per day in two divided doses according to her weight and was followed up regularly weekly on outpatient department basis.

Outcome and follow-up

Patient was continued on prednisolone at a dose of 70 mg for 1 week and then it was tapered at the rate of 10 mg per week up to a maintenance dose of 20 mg per day over 6 weeks. She was followed up monthly on the maintenance dose of corticosteroid. There was marked improvement in her eosinophil count (0.31×10⁹ cells/L) and her functionality of the limb improved up to 80% of her baseline after 3 months on corticosteroids. The patient was lost to follow-up after 3 months of treatment and succumbed later at her residence due to an unknown cause.

Discussion

In a tropical country like India, reactive causes like allergic and parasitic infestations are the most common causes for hypereosinophilia and a trial of anti-helminthics like albendazole and microfilaricidal drug (DEC) is generally rewarding. In patients who do not respond, further evaluation should be directed to identify any organ or tissues affected by hypereosinophilia.

If no reactive causes are identified, it is recommended to proceed with a bone marrow examination to look for any neoplastic causes for hypereosinophilia.¹ Further molecular studies like fluorescent in-situ hybridization or PCR for BCR/ABL, JAK2^V617F transcripts, FIP1L1-PDGFRA, PDGFRB and FGFR1 genetic rearrangements should be undertaken. Patients with these features are less likely to respond to prednisone and more likely to require cytotoxic therapy. The diagnosis of idiopathic hypereosinophilic syndrome is one of exclusion and must be considered only after thoroughly evaluating for all other causes as listed in box 1.

The most common manifestations of hypereosinophilic syndrome are pulmonary, skin, gastrointestinal, cardiac and neurological lesions. Numerous neurological lesions have been described, in particular of the central and peripheral nervous system. The following have been recorded in literature so far: hemiplegia, paraplegia, quadriplegia, mononeuritis multiplex, neuropathy, sensory polyneuropathy, radiculopathy, seizures, meningitis, stroke and encephalopathy.⁶

Monoplegia generally presents due to acute ischaemic stroke, neuropathy, brachial plexopathy, epilepsy, head or spinal trauma. Cardiac evaluation like echocardiography should be done to rule out any cardioembolic phenomenon. Vasculitic workup including ANA, p-ANCA and c-ANCA should be done considering possibility of vasculitic infarct. A rare possibility is of the isolated vasculitis or primary angiitis of the central nervous system which mainly affects younger stroke patients lacking cerebrovascular risk factors and diagnostic criteria needs presence of classic angiographic or histopathological features of angiitis within the CNS.

In our patient, the MRI brain was suggestive of multiple small infarcts in cortical and subcortical regions in bilateral fronto-parietal regions and diagnostic workup as outlined above did not demonstrate the usual causes. Impaired anticoagulation by eosinophilic cationic proteins could be an alternative mechanism. The preferential indirect involvement of CNS by eosinophils (‘CNS-tropism‘) may underlie the neurological manifestations of HES.

The management of HES depends on the aetiology. Often the management of the underlying cause controls the hypereosinophilia. In case of neoplastic cause, tyrosine kinase inhibitors can be used. The management of HES without imatinib sensitive mutations (FIP1L1-PDGFRA, PDGFRB rearrangement, BCR-ABL) is focused on reduction in eosinophil counts and limitations of end organ damage. Corticosteroids are the first-line agents for this. Initially a high dose of steroids followed by a tapering dose, usually prednisolone 1 mg/kg is started in the beginning.⁵ If no response is seen with steroids then hydroxyurea and interferon can be tried.⁷ Therapy with cyclosporine has been shown to be effective in patients with the lymphoproliferative variant of HES.⁸

Learning points.

• Idiopathic hypereosinophilia syndrome can present with diverse neurological manifestations and very rarely as monoplegia as in our case.

• Idiopathic hypereosinophilia syndrome should be considered as a differential once through investigations have been carried out to exclude parasitic, neoplastic and vascultic causes of eosinophilia.

• Early administration of corticosteroid is beneficial in idiopathic hypereosinophilia syndrome with neurological involvement.