Polyneuropathy Associated with the Diffuse Infiltrative Lymphocytosis Syndrome

Abstract

Diffuse infiltrative lymphocytosis syndrome (DILS) arises in HIV-positive patients secondary to infiltration of lymphocytes into the peripheral tissues and produces the disease’s characteristic symptoms—parotid gland enlargement and a sicca syndrome. Many patients, however, first seek medical attention for treatment of the extraglandular manifestations of DILS, most commonly interstitial pneumonitis. In this case report, we describe an atypical presentation of DILS characterized by polyradiculoneuropathy in the absence of parotid gland enlargement or interstitial pneumonitis. Minor salivary gland biopsy of the patient’s lip confirmed a chronic inflammatory state with lymphoid aggregates within the minor salivary glands. He was started on prednisone with immediate improvement in his symptoms. This report illustrates for clinicians the diverse extraglandular manifestations of DILS and underscores the importance of considering it in the differential diagnosis of HIV-positive patients with a preserved CD4 count who present with peripheral neuropathy.

Introduction

Diffuse infiltrative lymphocytosis syndrome (DILS) is an autoimmune-like phenomenon which arises in HIV-positive patients secondary to infiltration of lymphocytes into the peripheral tissues. Patients characteristically have parotid gland enlargement and a sicca syndrome, although they may first present to physicians with the extraglandular manifestations of DILS. ¹ In this report, we describe an atypical presentation of DILS characterized by polyradiculoneuropathy in the absence of parotid gland enlargement or interstitial pneumonitis.

Case Report

A 44-year-old HIV-positive African American male with a baseline CD4 count of 1000 cells/μL and a viral load of 380 copies/mL, no longer on highly active antiretroviral therapy (HAART), presented in January 2011 to his primary care physician with 2 days of lip and bilateral periorbital swelling. Because of concern for angioedema or other allergic event, he was prescribed methylprednisolone and all other nonessential medications were discontinued including amlodipine, simvastatin, and lisinopril. While he initially experienced some improvement in his symptoms, they rapidly recurred following completion of tapering doses of steroids. The patient was restarted on HAART and referred to the allergy clinic.

In February 2011, the patient was first seen in the allergy clinic at which time he underwent an extensive workup for hereditary and acquired causes of angioedema. The workup was unremarkable, including C1-C4 esterase inhibitor, functional and nonfunctional assays, and immunoglobulin E radioallergosorbent test (RAST). The HAART was also discontinued at this time because of concern that this might be contributing to his symptoms. In March 2011, a maxillofacial computed tomography (CT) showed multilevel lymphadenopathy throughout the neck and in the supraclavicular, superior mediastinal, and axillary regions bilaterally. He was retreated with a short course of steroids and again had moderate improvement in his symptoms.

Following the discontinuation of steroids, the patient developed paresthesias in his upper back and chest and edema in his legs, in addition to the already present facial and perioral edema. In April 2011, he acutely developed bifacial weakness in a lower motor neuron pattern. Magnetic resonance imaging (MRI) of the brain on May 2 was normal. An excisional biopsy of a submental lymph node was subsequently performed and showed reactive hyperplasia without evidence of a neoplastic process. Staining for HHV-8 and Fite and GMS stains for acid fast and fungal organisms were unremarkable. In situ hybridization for Epstein-Barr virus (EBV) was mildly positive.

On May 31, the decision was made to restart HAART. Over the next 3 weeks, the patient developed a dry mouth, weakness in his right arm and leg, and numbness in his lateral right 4 fingers. At the time, his CD4 count was 627 cells/μL, CD8 count was 1639 cells/μL, and viral load was 9150 copies/mL. His symptoms subsequently progressed, and on June 14, the patient was admitted to the hospital. Pertinent neurologic findings at presentation included profound weakness of the bilateral seventh cranial nerves, asymmetric weakness largely affecting his right arm and leg in a nondermotomal pattern, hyporeflexia, and a symmetric decrease in proprioception and vibratory sensation in the distal lower extremities. He underwent an extensive workup which ultimately was negative, including a paraneoplastic panel, fungal serology, and serum polymerase chain reaction (PCR) for cytomegalovirus (CMV), toxoplasmosis, EBV, herpes simplex virus (HSV) 1 and 2, and varicella zoster virus (VZV). A high volume lumbar puncture was also performed and the cerebrospinal fluid was sent for cytology, cryptococcal antigen, and PCR for enterovirus, HSV 1/2, and CMV, all of which were negative. An electromyogram (EMG) showed moderate-to-severe sensorimotor axonal neuropathy without evidence of neuromuscular junction disease, myopathy, or demyelinating neuropathy. The degree of deinnervation noted on the EMG, however, was out of proportion to the axonal neuropathy, and a superimposed lumbosacral and cervical neurogenic process was suspected. The MRI of the cervical and lumbar spine showed a T2 hyperintense area of the brachial plexus consistent with an inflammatory process as well as infiltration of the right external obturator nerve and enlargement of the lumbosacral nerve roots. He was discharged home on June 20 with close follow-up scheduled in the infectious diseases and neurology clinics but without a diagnosis.

Following discharge, the patient developed progressive numbness and weakness which spread to include both upper extremities and right lower leg, as well as pain in his toes and posterior legs. He was readmitted to the hospital on July 5 with progressive weakness and sensory abnormalities. A large volume lumbar puncture was repeated and was again unremarkable, including cytology and PCR for HSV 1/2, VZV, CMV, and EBV. Repeat maxillofacial CT showed homogeneous nonenhancing lymph nodes throughout the head and neck regions bilaterally but with normal parotid glands. The patient underwent a minor salivary gland biopsy of his lip which showed chronic inflammation involving the squamous epithelium with lymphoid aggregates within minor salivary glands, consistent with a focus score of 5 according to the modified Chisholm and Mason criteria for sialadenitis of minor salivary glands (Figure 1). There was no evidence of a neoplastic process. These histologic findings in conjunction with the clinical findings of facial swelling, polyradiculopathy, bilateral cranial nerve VII palsies, and xerostomia were felt to be consistent with DILS with involvement of multiple peripheral nerves. The patient was continued on HAART, started on 40 mg prednisone daily, and discharged to a subacute rehabilitation facility on July 12. Two weeks after discharge, he had improved strength. The prednisone was increased to 60 mg daily to accelerate this improvement.

Figure 1.

Minor salivary gland biopsy from patient with diffuse infiltrative lymphocytosis syndrome (DILS). Histology showed a grade 4 (focus score 5) lymphocytic infiltrate according to the modified Chisholm and Mason criteria (1) for saliadenitis of the minor salivary glands.

Discussion

Diffuse infiltrative lymphocytosis syndrome is a common, though underrecognized, condition affecting 3% ² to 8% ³ of HIV-positive patients. It was described in case reports ⁴ as early as 1984 but was not recognized as a discrete clinical entity until 1989. ⁵ In 1992, Itescu proposed criteria for the diagnosis of DILS. ¹ These criteria require that patients (1) are HIV positive as determined by both ELISA and Western blot; (2) have bilateral salivary gland enlargement or xerostomia for greater than 6 months; and (3) have histologic confirmation of salivary or lacrimal gland lymphocytic infiltration in the absence of either a granulomatous or neoplastic process. While not part of the presumptive diagnostic criteria, patients with DILS characteristically have marked reversal of circulating CD4/CD8 T cells in the setting of normal or increased total lymphocyte count. ¹ Biopsies show a CD8 lymphocytic infiltrate with 2 or more foci of at least 50 lymphocytes per 4 mm ² or grade 4 according to the Chisholm and Mason criteria for the diagnosis of Sjogren syndrome. ^1,6,7

Patients with DILS develop a major histocompatibility complex–restricted, antigen-driven oligoclonal proliferation of CD8 CD29 lymphocytes expressing selective homing receptors. ^7,8 These lymphocytes infiltrate the tissues and produce a constellation of symptoms similar to those seen in Sjogren syndrome. Patients commonly present with bilateral parotid gland enlargement and xerostomia, although submandibular gland enlargement may occur in the absence of parotid gland pathology. Eye findings including xerophthalmia and keratoconjunctivitis sicca are observed in 40% of patients with DILS. ¹ Most patients, however, first seek medical attention for treatment of the extraglandular manifestations of DILS. Lymphoid interstitial pneumonitis, the most common extraglandular manifestation, is thought to be present in 25% to 50% of these patients. Additional manifestations include lymphocytic hepatitis, renal tubular acidosis, polymyositis, generalized lymphadenopathy, and neurologic complications.^9,10 The neurologic manifestations of DILS can occur either centrally or peripherally and include lymphocytic aseptic meningitis, unilateral or bilateral seventh cranial nerve palsy, anterior uveitis, and peripheral sensorimotor polyneuropathy. ¹¹

Polyneuropathy was recognized as a complication of this “Sjogren-like syndrome” years before DILS was first named in the literature. ^11,12 A 1987 case report by Guillon describes a patient, later found to be HIV positive, who presented with exertional dyspnea and lower extremity paresthesias. ¹¹ Physical examination was notable for decreased deep tendon reflexes and reduced position and vibration sense. Electrophyioslogic studies confirmed a sensorimotor axonal neuropathy, and a subsequent peroneal nerve biopsy showed focal loss of large myelinated fibers with diffuse lymphocytic infiltration into the neuronal tissue. The patient was followed for 2½ years and, even in the absence of treatment, had marked clinical improvement in his neuropathy.

A decade later, 2 case–control studies confirmed Guillon findings and better characterized the polyneuropathy associated with DILS. The first study by Moulignier described 12 patients with DILS who had both clinical and electrophysiological signs of peripheral neuropathy. ¹³ All patients presented either acutely or subacutely with a painful, sensorimotor neuropathy. The neuropathy was symmetric in 8 patients and asymmetric in 4 patients, in 2 of which it evolved to become confluent. Of the 12 patients, 10 had an axonal neuropathy by EMG, while 2 presented with a demyelinating neuropathy. Almost all patients (10 of 12) showed either partial or complete remission with antiretroviral therapy or corticosteroids. These findings were confirmed in a 1998 study by Gherardi which characterized the peripheral and histological findings of DILS neuropathy and compared it with 4 other HIV-associated peripheral neuropathies. ¹⁴ In all 6 patients with DILS, the neuropathy was shown by EMG to be a sensorimotor, axonal neuropathy. It was multifocal in 4 patients and symmetric in 2. Furthermore, the histology of DILS differed from the other HIV-associated neuropathies (mononeuritis multiplex, inflammatory demyelinating polyneuropathy, distal sensory polyneuropathy, and toxic distal sensory polyneuropathy). Patients with DILS had more than 100 000-fold the HIV-1 proviral load in whole nerve extracts than that observed in other HIV-associated neuropathies. Furthermore, none of the patients with DILS had p24 antigenemia. This supported previous studies demonstrating that DILS is a systemic response to HIV infection and that the virus itself gives rise to specific oligoclonal CD8CD29 T cells which infiltrate the tissues and suppress viral replication in the periphery. ^7,8,15

In this case report, we describe a patient who presented with facial swelling in the setting of a CD4 count of 627 cells/μL, CD8 count of 1639 cells/μL, and viral load of 9150 copies/mL. Over a period of months, his symptoms progressed with development of a debilitating sensorimotor, axonal polyradiculoneuropathy involving both the lumbosacral and cervical nerves. A minor salivary gland biopsy confirmed a predominantly lymphocytic infiltrate without granulomatous or neoplastic processes. While a number of case studies have described patients with DILS polyneuropathy,^15,16,17 this is only the second that we are aware of in which the patient presented primarily with neurologic complaints. The first, published in 2010 by Chahin, describes a HIV-positive male with a CD4 count of 298 cells/μL and a viral load of 42 066 copies/mL, with 8 months of progressive pain and weakness in his lower extremities but who lacked lymphadenopathy or parotid gland involvement. ¹⁸ His physical examination was remarkable for profound distal sensory and motor weakness, later shown by EMG to be predominantly axonal. A sural nerve biopsy showed infiltration of CD8 lymphocytes into epineural and perineural sites. The patient was treated with a combination of antiretroviral agents and experienced marked improvement in his neurologic symptoms. A repeat sural nerve biopsy 4 months after beginning therapy confirmed resolution of the inflammatory infiltrates.

Diffuse infiltrative lymphocytosis syndrome is a relatively common problem in individuals infected with HIV. While patients with DILS frequently present with parotid enlargement or a sicca syndrome, these symptoms may be mild or even absent. Our case demonstrates the importance of appreciating the diverse extraglandular manifestations of DILS and recognizing that peripheral neuropathy may be the predominant manifestation of this multifaceted disease. Clinicians should consider DILS in the differential diagnosis of HIV-positive patients with a preserved CD4 count who present with polyneuropathy. Those patients with a CD8 lymphocytosis may warrant a further workup for DILS including electrophysiological studies and possibly submandibular and/or sural nerve biopsies. This will allow for prompt initiation of appropriate therapy and, hopefully, for disease remission.