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Show Journal of Cliniml Neuro-ophthalmology 13(2): 113-118, 1993. Cranial Neuropathy Heralding Otherwise Occult AIDS-Related Large Cell Lymphoma Joseph R. Berger, M.D., Murray Plaster, ph.D., M.D., Norman Schatz, M.D., David Droller, M.D., Pasquale Benedetto, M.D., Rita Poblete, M.D., and M. Judith Donovan Post, M.D. © 1993 Raven Press, Ltd., New York Three HIV-infected patients developed cranial neuropathy as the initial manifestation of an AIDS-related large cell lymphoma. All were homosexual men known to be HIV seropositive for 3 to 4.5 years. At the time of presentation for neurological disease, the CD4 T-lymphocyte count was <400 cells/mm3 in each. Initial manifestations were retro-orbital headache and oculomotor nerve palsy in two and an abducens nerve palsy in the other. Repeatedly negative CSF cytologies and recovery of the cranial neuropathy obscured the diagnosis. These patients illustrate that cranial neuropathy with HIV infection may herald the presence of an occult large cell lymphoma. Spontaneous or corticosteroid-associated improvement of the cranial neuropathy, absence of abnormalities on brain imaging studies, and negative CSF cytologies do not exclude this diagnosis. We suggest that a diligent and repeated search for lymphoma be considered in HIV-infected patients presenting with cranial neuropathy, including repeated CSF examinations, MRI of brain and spine (Tl and T2) with and without gadolinium enhancement, chest and abdominal CT scans, and bone marrow biopsy. Key Words: Human immunodeficiency virus, type l-AID5---Lymphoma-Cranial nerve disorders. From the Departments of Neurology a.R.B., M.F., N.S.), Internal Medicine a.R.B., R.P.), Ophthalmology a·R.B., R.P.), Oncology (P.B.), and Radiology (M.J.D.P.) of the University of Miami School of Medicine, Miami, Florida and the Broward General Medical Center (D.O.), Fort Lauderdale, Florida, U.S.A. This paper was presented in part at the 116th annual meeting of the American Neurological Association on October 1, 1991, in Seattle, Washington. This work was supported by NIH grant POI-NS-25569. Address correspondence and reprint requests to Dr. Joseph R. Berger, Department of Neurology, University of Miami School of Medicine, 1501 N.W. 9th Avenue, Miami, FL 33136, U.S.A. 113 Approximately 9% of HIV-related neurological diseases are heralded by cranial neuropathy (1). The etiologies of cranial neuropathy occurring in association with HIV infection are diverse. Among the etiologies are infectious and neoplastic meningitides and mass lesions, inflammatory disorders, and vasculitis (1-14). Additionally, isolated and recurrent idiopathic Bell's palsy has been reported to occur in association with HIV infection (Table 1) (2,13,15,16), and multiple cranial polyneuropathy has been observed at the time of HIV seroconversion (17). A review of cranial neuropathies occurring in 31 adults with the acquired immunodeficiency syndrome (AIDS) characterized 18 as multiple and 13 as single with the sixth and seventh cranial nerves most commonly affected (2). The etiologies of the cranial neuropathies were diverse and unexplained in 8 (26%) of the patients (2). Lymphoma was the etiology of the cranial neuropathy in 8 patients (26%) (2). We report three HIV-infected patients who presented with cranial nerve disease as a consequence of HIV-related large cell lymphoma. At presentation, there were no other systemic or neurological manifestations. Radiographic imaging, including computed tomography (CT) of the brain and cranial magnetic resonance imaging (MRI) without gadolinium, were unremarkable. Cerebrospinal fluid (CSF) examination initially failed to reveal neoplastic cells. Prior to the establishment of the diagnosis, the presenting cranial neuropathy substantially improved or resolved in two patients. One patient had spontaneous resolution of his presenting abducens nerve palsy and another had near-total resolution of an oculomotor palsy following empirical corticosteroid therapy. The absence of abnormalities suggestive of Iymphoma- 114 f. R. BERGER ET AL. TABLE 1. The potential etiologies of cranial nerve palsies with HIV infection (Adapted from reference 14J Infectious meningitis Fungal Cryptococcus Histoplasmosis Mucormycosis Bacterial Mycobacteria tuberculosis Listeria monocytogenes Treponema pallidum Viral Herpes zoster/varicella Cytomegalovi rus HIV meningitis Neoplastic meningitis Lymphoma Other malignancies Compression from intracranial mass lesions Neoplastic Brain lymphoma Other malignancies Infectious Toxoplasmosis Cryptococcoma Tuberculomas and tuberculous abscess Vasculitis complicating HIV infection Inflammatory Guillain Barre syndrome Chronic inflammatory polyradiculoneuropathy Miscellaneous Malignant otitis externa Idiopathic Bell's palsy Other tous meningitis and the clinical course of these patients resulted in a delay in the definitive diagnosis. CASE REPORTS Case 1 A 38-year-old bisexual man, documented to be HIV seropositive since May 1985, developed a left retro-orbital headache 1 week before hospitalization for presumed Pneumocystis carinii pneumonia in September 1988. While hospitalized, he noticed the onset of horizontal diplopia greater on leftward gaze and numbness of the right forearm, wrist, and thumb. The numbness persisted for 3 days, but shortly after its resolution he noticed right sciatic pain and severe pain in his left shoulder accompanied by a sensation of "hot grease" radiating into the fingers of the left hand. Examination revealed a left abducens nerve palsy. Chest x-ray, CT scan of the brain and orbits with and without contrast, cranial and cervical MRI, lumbar puncture with detailed microbiological studies and cytology, and gallium scan were unremarkable. The diplopia resolved within several weeks, but he no- I ellll NcunH11,htllll/lllol, Vo!. 13, No.2, 1993 ticed new difficulty raismg his right arm. Past medical history was remarkable for hepatitis B 12 years earlier. The CD4 T-lymphocyte count was 109 cells/mm3 , and the erythrocyte sedimentation rate was 88 mrnlh. Examination on November 28, 1988 revealed cervical adenopathy, left ptosis and pupillary dilation (left pupil measured 4 mm and the right 3 mm), partial left abducens and oculomotor nerve palsies, wasting and fasciculations of the left biceps and brachioradialis muscles, weakness of the opponens pollicis and abductor pollicis muscles, absent left biceps and brachioradialis muscle stretch reflexes, and decreased sensation in a left C6 dermatomal distribution. Laboratory studies were remarkable for a positive hepatitis Bsurface antibody and negative hepatitis B surface antigen. Repeat lumbar puncture showed an opening pressure of 15 ern of water, 0 WBClmm3 , protein 55 mg/dl, glucose 72 mg/dl, and nonreactive VORL. CSF microbiological studies and cytology were again negative. An electromyogram and nerve conduction study were "consistent with a left brachial plexopathy with especially severe involvement of the lateral cord." A muscle biopsy revealed evidence of "acute and chronic denervation" and a nerve biopsy showed "mildly abnormal changes favoring axonal degeneration and a single area of perivascular inflammation without true vasculitis." Oral prednisone, 20 mg three times daily, was initiated with improvement in the diplopia and numbness. Within 1 month, he developed severe left intercostal pain and numbness of the left groin followed by incontinence and difficulty walking. Examination on December 30, 1988, revealed normal mentation and cranial nerve function, weakness and atrophy of the left upper extremity, and a flaccid paraparesis with decreased sensation in the lower extremities, but no well-defined sensory level. An MRI of the lower thoracic and lumbar spine revealed multiple bony lesions involving the thoracic and lumbar spine and a large left paraspinal mass extending from T12 to L4 with involvement of the left psoas and erector spinae muscles. The cauda equina and conus medullaris were compressed by an epidural mass extending directly from the retroperitoneal lesion. An MRI-directed needle biopsy of the psoas mass revealed a large cell lymphoma. Radiation therapy (300 cGy daily for a total dose of 3,000 cGy) was initiated and dexamethasone (Decadron), 25 mg four times daily, was administered. He died on January 24, 1989. No vasculitis was observed at autopsy. There were no lymphomatous deposits in the meninges nor focal lesions of the spinal cord or cauda CRANIAL NEUROPATHY AND AIDS-RELATED LYMPHOMA 115 equina, presumably as a result of radiation and corticosteroid therapy. Case 2 A 25-year-old homosexual man, HIV seropositive for 4.5 years, but otherwise healthy, developed the sensation of a foreign body in his right eye associated with an intermittent, right temporal headache in early July 1990, followed by the onset ptosis of the right eyelid. Within 5 days, he had developed a vertical diplopia that was worsened by gaze leftward and downward and was associated with complete right ptosis. Examination revealed a complete right third nerve palsy sparing the pupil, but no stigmata of AIDS. Laboratory studies, cranial MRI, CSF examination with detailed microbiological studies and cytology, and cerebral angiography were unremarkable. Treatment with oral dexamethasone, 4 mg every 6 hours, was initiated with a gradual taper over 3 weeks. The patient experienced a prompt relief of his discomfort and marked improvement in the third nerve palsy. Two weeks after discontinuing dexamethasone, he developed right facial paresis with discomfort in the right posterior cervical and postauricular regions. Examination revealed a slight adduction deficit of the right eye and a right peripheral facial palsy. Repeat cranial MRI with gadolinium and CSF examination were again negative. The facial weakness improved with oral prednisone, 40 mg daily. One month later, he noted the onset of dysphonia and dysphagia. Examination revealed bilateral facial paresis, leftward deviation of the uvula, diminished gag reflex, flaccid dysphonia, weakness and atrophy of the left trapezius muscle, and a depressed right knee jerk. The absolute CD4 T-lymphocyte count was 485 cells/mm3 . Chest x-ray was normal. A lumbar puncture showed an opening pressure of 18 cm of water, 160 white blood cells (86% mononuclear; 14% polymorphonuclear), protein 146 mg/dl, and glucose 32 mg/dl with a concomitant serum glucose of 137 mg/dl, IgG 11.0 mg/dl, and normal IgG index. The CSF microbiological studies, including stains, culture, VORL, and cryptococcal antigen, were negative. CSF cytology was reported as "questionably abnormal." Five additional lumbar punctures, including a cisternal tap, during the ensuing 2 weeks were virtually identical, but failed to reveal abnormal cytology. Repeat cranial MR with gadolinium and CT scan of the chest, abdomen, and pelvis were normal. Therapy for lymphomatous meningitis was initiated empirically, consisting of methotrexate, 10 mg intrathecally biweekly, and prednisone, 150 mg daily with gradual taper. Facial strength returned to normal and dysphonia and dysphagia improved. In October, the dysphagia and diplopia recurred with concomitant numbness of the left side of his face, left fingertips, and both feet. Examination showed right abducens and left trochlear nerve palsies, bilateral peripheral facial paresis, diminished gag reflex, flattening of the left side of the soft palate, increased weakness of the left trapezius muscle, weakness and wasting of the left deltoid, and sensory loss of the left face and fingertips. A bone marrow obtained in December 1990 showed infiltration by lymphoblasts and the chest x-ray a mass in the posterior sulcus. An Ommaya reservoir was placed for intrathecal methotrexate therapy and M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) was initiated. CSF showed 6 WBClmm3 , protein 29 mg/dl, glucose 73 mg/dl, and negative cytology. A repeat cranial MR in January 1991, performed because of altered mental status revealed periventricular enhancement. He tolerated the chemotherapy well with partial remission of his cranial neuropathies over the next 5 months. He died on June 5, 1991. No autopsy was performed. Case 3 A 37-year-old homosexual man, HIV seropositive for 4 years, presented on August 25, 1990, with severe right orbital pain and diplopia of 3 days duration. Examination showed right ptosis, anisocoria with the right pupil sluggishly reactive at 5.5 mm and the left briskly reactive at 3 mm, absent right eye adduction and elevation with limited depression, but preserved abduction and mild gait unsteadiness. Laboratory studies were remarkable for a hemoglobin of 10 g/dl and lactic dehydrogenase (LDH) of 1,689 V/ml. The chest x-ray was normal. A CT of the brain with double dose delayed contrast revealed only mild atrophy. MR angiography revealed no aneurysms. Lumbar puncture revealed clear colorless CSF with an opening pressure of 20 cm water, 0 RBClmm3 , 7 WBClmm3 (100% mononuclear), protein 67 mg/dl, glucose 59 mg/dl, nonreactive VORL, and negative microbiological studies and cytology. During the course of the hospitalization, he developed a right abducens nerve palsy and right hip pain with radiation into his thigh, and, subsequently, dyesthesias in a left L3--4 dermatomal distribution. Repeat J eli" Neuro-ophthalmol, Vol. 13, No.2, 1993 116 J. R. BERGER ET AL. lumbar puncture revealed 3 RBClmm3 , 58 WBCI mm3 (100% mononuclear), protein 289 mg/dl, glucose 24 mg/dl. Microbiological studies and cytology were again negative. Cranial MRI on September 18, 1990, revealed gadolinium enhancement of the tentorium (Fig. 1). Repeat lumbar puncture at that time showed 1,490 RBClmm3 , 24 WBClmm3 , protein 144 mg/dl, and glucose 40 mg/dl. All special studies including cytology were negative. The LDH remained elevated at 4,383 U/ml. One day later, he developed fever to 38.9°C. with jugular venous distension and a gallop rhythm. Chest x-ray revealed enlargement of the cardiac silhouette and echocardiogram confirmed a massive pericardiaI effusion with cardiac tamponade. Pericardiocentesis revealed an exudative fluid with 1,485 RBClmm3 , 3,114 WBClmm3 (95% polymorphonuclear cells), protein 2,800 mg/ dl, LDH > 12,000 U/ml and specific gravity of 1.014. Cytology of the pericardial fluid showed cells consistent with a large cell lymphoma (Fig. 2). With systemic chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisone) and radiation therapy directed to the base of his skull, his right oculomotor nerve and left abducens nerve palsies improved substantially. However, a stormy FIG. 1. Cranial magnetic resonance image of Case 3. Contrast-enhanced T1-weighted coronal image (repetition time: 750 ms; echo time: 20 ms) showing subtle enhancement along the tentorium (arrowhead). hospital course ensued, complicated by chylous fistula at the site of a central venous line, sepsis, and disseminated intravascular coagulation, and he died of cardiorespiratory arrest 7 weeks after his hospital admission. Permission for an autopsy was denied. DISCUSSION Cranial neuropathy heralded the presence of AIDS-associated systemic large cell lymphoma in these three patients. The remission of the cranial neuropathies (spontaneous in one and steroidinduced in another), the initial negative CSF cytologies, the normal radiographic imaging and the absence of systemic evidence of lymphoma obscured the diagnosis initially. One patient (Case 1) who presented with an abducens palsy and numbness of his right forearm and thumb that remitted spontaneously was at first considered to have a mononeuritis multiplex secondary to vasculitis. The correct diagnosis was not established until 3 months later, when an MRI showed thoracic and lumbar bone lesions and a paraspinal mass that proved to be lymphomatous. Mononeuritis multiplex secondary to vasculitis was also considered in another patient (Case 2) until repeat CSF examination revealed "questionably abnormal" cells. Despite a high index of suspicion, multiple subsequent CSF cytologies failed to demonstrate abnormal cytology. The diagnosis was not firmly established until a bone marrow biopsy was performed. The correct diagnosis was suspected in the third patient (Case 3) in light of his clinical presentation and increased serum LDH, but was not firmly established until he developed a lymphomatous pericardial effusion 1 month after presentation. Approximately 5% of patients with AIDS develop lymphoma (18). Non-Hodgkin's lymphoma is estimated to be 60 times more common in AIDS patients than in the general United States population (19). Lymphomas associated with AIDS may be systemic or arise within the central nervous system. The typical presenting manifestations of systemic lymphomas include the appearance of a rapidly growing mass lesion or the development of "type B" systemic symptoms, including unexplained fever, drenching night sweats, and weight loss (20). AIDS-related systemic lymphoma, however, is characterized by a high frequency of extranodal disease at the time of presentation. The incidence of the latter is reported at 56% to 86%, rates substantially higher than that seen with systemic lymphoma occurring in the general popula- CRANIAL NEUROPATHY AND AIDS-RELATED LYMPHOMA 117 FIG. 2. Cytopathology of pericardial fluid of Case 3. Pericardial fluid showing cells consistent with large cell lymphoma (Pap stain). tion (18). A central nervous system presentation occurs in approximately one-third of AIDS-related lymphomas (18). The most common form of presentation is lymphomatous leptomeningitis, which may be either asymptomatic or symptomatic. In an AIDS Clinical Trials Group study of AIDS-related lymphoma in which lumbar puncture was mandated by protocol, 17% of patients had unsuspected neoplastic cells in the CSF (18). In 67 HIVinfected patients with systemic, non-Hodgkins lymphoma, 14 had involvement of the meninges, 5 had either cranial or peripheral nerve involvement, and 5 had paraspinal masses (21). Clinical features of symptomatic lymphomatous leptomeningitis include headache, altered mental status, seizures, cranial neuropathies, and radiculopathies. Cranial neuropathy may be the presenting manifestation of malignant lymphoma (22). In one study of 24 patients with cranial neuropathy due to lymphomatous leptomeningitis unassociated with AIDS, the most commonly involved cranial nerves were the facial, oculomotor, and abducens (23). Complete resolution of cranial neuropathy due to meningeal lymphoma following therapy (24) as well as spontaneous remission have been reported (25). The direct spread of lymphoma cells into the central nervous system (CNS) from contiguous extraneural sites has been suggested as the most common mode of entry (26). The high frequency of lymphomatous bone marrow infiltration that occurs in association with lymphomatous leptomeningitis (26-29) suggests that the malignant cells enter from the medullary cavity through the dura and into the subarachnoid space (26). Because cranial neuropathy in an HIV-infected patient may herald an otherwise occult systemic lymphoma, we strongly recommend that a diligent and repeated search for lymphoma be considered in patients with otherwise unexplained cranial neuropathies, particularly when associated with an elevated serum lactic dehydrogenase (30). Repeated CSF examinations with immunocytochemical studies (31) are mandated due to the difficulty in distinguishing reactive lymphocytes from lymphoma cells. Plain and gadolinium-enhanced MRI of brain and spine (Tl and T2) need to be obtained and chest and abdominal CT scans should be considered in order to detect the presence of extraCNS disease. 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