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Show Journal of Neuro- Ophthalmology 17( 1): 47- 50, 1997. ( 0 1997 Lippincott- Raven Publishers, Philadelphia Fourth Nerve Palsy Caused by Ehrlichia chaffeensis Nathaniel Carter, M. D., and Neil R. Miller, M. D. Two human ehrlichioses occur in the United States: human monocytic ehrlichiosis ( HME), which is caused by Ehrlichia chaffeensis that infects mononuclear phagocytes in blood and tissue, and human granulocytic ehrlichiosis ( HGE), an infection of granulocytes that is caused by a similar but phylogenetically distinct organism. The clinical features of both forms of human ehrlichiosis are identical and include nonspecific constitutional manifestations, such as fever, headache, malaise, nausea, vomiting, myalgia, and anorexia; however, rare patients develop neurologic symptoms and signs. Few cases of human ehrlichiosis have been described in detail, and focal neurologic deficits have only rarely been reported in such cases. We describe a patient with HME who developed a trochlear nerve paresis associated with evidence of lymphocytic meningitis during the course of her illness. We believe this to be the first well- documented case of a focal neurologic complication of human ehrlichiosis. Key Words: Ehrlichiosis- Trochlear nerve palsy- Meningitis. Ehrlichieae are obligate intracellular ricketlsiae that are capable of causing systemic infection in both animals and humans ( 1,2). Human ehrlichiosis is caused by two species of Ehrlichieae that arc believed to be transmitted by the bile of several different species of ticks ( 3). The main target cell for E. chaffeensis is the monocyte ( 4- 7), and the form of human ehrlichiosis caused by this organism thus is called human monocytic ehrlichiosis ( HME) ( 7). A second species of Ehrlichieae capable of causing human disease has yet to be named, although it has been cultivated ( 8). Because this species has been detected only in granulocytes of infected persons, the disease it produces has been called human granulocytic ehrlichiosis ( HGE) ( 7- 9). Most cases of human ehrlichiosis are asymptom- Manuscript received February 6, 1996; accepted April 21, 1996. From the Neuro- Ophthalmology Unit, The Wilmer Eye Institute, The Johns Hopkins Medical Institutions, 600 N Wolfe Street, Baltimore, Maryland, U. S. A. Address correspondence and reprint requests to Dr. Neil R. Miller, Neuro- Ophthalmology Unit, The Wilmer Eye Institute, The Johns Hopkins Hospital, 600 N Wolfe Street, Baltimore, MD 21287, U. S. A. atic or associated with mild symptoms that occur 4- 10 days after a tick bite or exposure ( 9- 11) and that may not prompt medical consultation, serologic testing, or treatment ( 3,11,12); nevertheless, HME may cause severe disease that can be fatal ( 9,11). The complete clinical spectrum for HGE is not known, but reports indicate that it also varies from a mild to a severe disease ( 2,7,9,13). Severe illness or death is more likely to occur in patients 60 years of age or older and among patients in whom treatment is delayed by 8 or more days after onset of symptoms ( 2,9,11). The most common clinical features of both HME and HGE are nonspecific and include fever, headache, myalgia, nausea, anorexia, and vomiting ( 2,4,9- 11,14- 17). A macular or papular rash occurs in about 35% of patients within 1 week after the onset of constitutional symptoms ( 2,9,11,18). Both HME and HGE may have neurologic manifestations. The neurologic signs and symptoms of HME usually suggest a diffuse process and include headache, altered mental status ( confusion, hallucinations, lethargy), hyperactive reflexes, clonus, seizures, and coma ( 11,18,19). Patients with HME who have clinical evidence of neurologic dysfunction typically have laboratory evidence of aseptic meningitis, encephalitis, or both ( 11,19- 21). The most common finding, which has been described in 62- 71% of patients, is a CSF pleocytosis, usually lymphocytic, associated with an increased concentration of protein in the fluid ( 15,18,21). Some patients also have an abnormal electroencephalogram ( EEG) ( 15). Neurologic manifestations of HGE are less well characterized; however, central nervous system involvement has been reported, with the most common manifestations being headache and confusion ( 7,9,10,13). Although the results of CSF analysis have not been reported in patients with neurologic dysfunction in the setting of HGE, one would expect a pleocytosis and an increased concentration of protein similar to that reported in patients with HME. Focal neurologic deficits have only rarely been reported in human ehrlichiosis ( 18), and wc arc unaware of any report of an ocular motor nerve paresis occurring during the course of either HME or 47 48 N. CARTER AND N. R. MILLER HGE. We report the case of a patient who developed diplopia caused by a trochlear nerve paresis associated with aseptic meningitis during the course of well- documented HME. CASE REPORT A 44- year- old woman with an unremarkable past medical history except for mild asthma, experienced a tick bite to her neck in February 1995, while jogging in a wooded area near her home. She subsequently developed erythema around the bite but was otherwise well until 3- 4 weeks later, when she developed fever, frontal headaches, nausea, and pain in the chest, back, and right leg. She was seen by her primary care physician on 2 March 1995, at which time she was treated with cefuroxime and ibuprofen for a presumed viral illness. The next evening, she went to the emergency room of a local hospital because the headaches and back pain had not improved. On examination, the patient's vital signs included blood pressure of 135/ 82, respirations 20/ min, pulse 90/ min, and temperature of 38° C. She had mild neck stiffness, clear nasal discharge, a nonproductive cough, mild dyspnea, and wheezing. She was alert and oriented, without any gross motor or sensory deficits. There was no pain to bilateral straight leg raising. A diagnosis of possible sepsis was made, and the patient was admitted to the hospital for treatment with parenteral antibiotics. After admission to the hospital, the patient was treated with intravenous cefotaxime and, subsequently, ceftriaxone. In the meantime, laboratory examination revealed a normal complete blood count and differential, normal concentrations of AST and ALT in the serum, normal erythrocyte sedimentation rate, and a negative serologic test for infectious mononucleosis. Cultures of urine and sputum showed no evidence of bacterial growth. Plain radiographs of the chest, paranasal sinuses, and thoracic and lumboscaral spine showed no abnormalities. A radionuclide scan of the body and an unenhanccd computed tomographic ( CT) scan of the brain were normal. An assay of Lyme titers in the serum was negative. An immunofluorescent test of the patient's serum for immunoglobulin G ( IgG) and immunoglobulin M ( IgM) antibodies to E. chaf-j'eensis was positive for IgG antibodies at a titer of 1/ 160, with an IgM titer of less than 1/ 40, and a diagnosis of human ehrlichiosis of the monocytic type ( HME) was made. A lumbar puncture was not performed at this time. The patient received a 1- week course of intravenous antibiotics and was then treated with oral doxycycline 100 mg po b. i. d. She was discharged from the hospital on 10 March 1995, 7 days after admission. Shortly after discharge, the patient began to experience binocular oblique diplopia that was worse in down and left gaze. On 20 March 1995, 18 days after the onset of symptoms and 10 days after being discharged from the hospital, she was referred to a local neurologist because of persistent diplopia. The neurologic examination was normal except for vertical strabismus. Magnetic resonance ( MR) imaging gave normal results. A lumbar puncture revealed a normal intracranial pressure. The CSF contained 240 white blood cells/ mm3, with 83% lymphocytes and 15% monocytes/ histiocytes. The concentration of protein in the CSF was slightly increased ( 58 mg/ dl), whereas the glucose concentration was normal ( 55 mg/ dl). A diagnosis of aseptic meningitis caused by E. chaffeensis was made. The patient's diplopia persisted, and on 5 April 1995, 2 months after the onset of symptoms, she underwent repeat laboratory studies. A complete blood count and differential revealed a borderline normal white blood count of 4.19 million/ u, l ( normal 4.20- 5.40 million/| JL1), with 48% lymphocytes and 4% atypical lymphocytes. Platelet count was normal. Repeat assessment of AST and ALT revealed normal concentrations of these enzymes in the serum. On 10 April 1995, a repeat lumbar puncture was performed. The CSF contained 61 white blood cells/ mm3, 94% of which were lymphocytes and 5% of which were monocytes/ histiocytes. The concentrations of both protein and glucose in the CSF were normal. In addition, the CSF showed a negative reaction for syphilis using the Venereal Disease Reaction Laboratory ( VDRL) test, and no antibodies to Borrelia burgdorferi by western blot test, did not contain oligoclonal bands, and had a normal IgG index. Smears and cultures for bacteria, ova, and parasites gave negative results. Assays for antibodies to E. chaffeensis in both serum and CSF were now less than 1/ 40 for both IgG and IgM. The patient was referred to the N e u r ophthalmology Unit of the Wilmer Eye Institute on 19 June 1995, about 3 months after the onset of diplopia. Her only nonvisual complaints at this time were fatigue and occasional difficulties with word finding. On examination, visual acuity without correction was 20/ 20 + 1 OD and 20/ 20 - 1 OS. Near vision with a + 1.75 sphere was Jl + OU. Color vision was a brisk 10/ 10 bilaterally using Hardy- Rand- Rittler pseudoisochromatic plates. Kinetic perimetry demonstrated full visual fields in both eyes. The pupils were equal in diameter and normally reactive to both light and near stimuli. There was no relative afferent pupillary defect. The extraocular movements were full. There was a small right hyperphoria of 2 prism diopters at distance and near, increasing to 3 prism diopters in left gaze, 5 prism diopters on downgaze, and 7 prism diopters on gaze down and to the left. The patient had no vertical shift on right gaze, upgaze, or downgaze to the right. She had a positive head tilt test, developing a right hy-pertropia of 2 prism diopters on head tilt to the right but showing no vertical strabismus on head tilt to J Neitro- Ophlhalmol, Vol. 17. No. /, 1997 FOURTH NERVE PALSY FROM EHRLICHIOSIS 49 the left. The patient had no torsion when tested with double Maddox rods or using the Lancaster red-green test. She was able to stereo 9 of 10 circles on the Titmus test and could fuse the Worth 4- Dot test at distance and near. Slit lamp biomicroscopy revealed no abnormalities. Intraocular pressures were normal. Ophthalmoscopy revealed no abnormalities in the ocular fundi. Corneal and facial sensation were symmetric and normal bilaterally. The patient was thought to have a resolving right trochlear nerve paresis associated with aseptic meningitis caused by E. chaffeensis in the setting of human monocytic ehrlichiosis. No treatment was recommended, and she was referred back to her local physicians for continued follow- up. Four months later, she was contacted by telephone, at which time she stated that she no longer had any diplopia and was feeling well. DISCUSSION Since the first case of human ehrlichiosis was described in the United States in 1987, over 400 cases of HME and less than 100 cases of HGE have been reported in 30 states ( 13). Only a few of these cases have been described in detail, but none has been characterized by an ocular motor nerve paresis, and in only one case has a focal neurologic deficit been described. Everett et al. ( 18) reported a series of 30 patients with human ehrlichiosis diagnosed by serologic testing, identification of a specific nucleic acid profile using the polymerase chain reaction ( PCR), or both. Eight of these patients ( 26.7%) had CSF examinations because of mental status changes, photophobia, or intense headache. Of these eight patients, five ( 62.5%) had results consistent with meningeal inflammation, including an increased concentration of protein ( 78- 206 mg/ dl) and a pleo-cytosis that was lymphocytic in four of the five patients. One of the five patients with neurologic symptoms and evidence of meningitis was a woman who was said to have developed a left central facial nerve palsy during the course of her illness. Assays of serum and CSF for antibodies to B. burgdorferi were said to be " nondiagnostic." Repeat lumbar puncture at this time disclosed persistent pleocyto-sis and increased protein in the CSF. The patient had previously been treated with doxycycline. She was now treated with ceftriaxone, and the facial nerve paresis resolved completely over several weeks. There are several features of the case described by Everett et al. ( 18) that are unclear. First, an isolated left central facial nerve paresis without other neurologic deficits would be most unusual in the setting of an aseptic meningitis and would localize the lesion to the right precentral gyrus. We believe it more likely that the facial nerve weakness in this case was peripheral, rather than central. Second, it is unclear whether the diagnosis of ehrlichiosis in this patient was made by antibody assay, PCR, or both. Finally, if an antibody assay was performed in this patient, it is unclear if the test used antigen from E. canis ( the species that causes infection in dogs and other members of the Canidae family) or antigen from E. chaffeensis, both of which were used to test patients described in this study. Trochlear nerve palsies caused by infection are rare but usually occur in the setting of acute, subacute, and chronic meningitis. In most cases, the trochlear nerve paresis is caused by inflammatory or vascular damage to the cranial nerve roots and is associated with other cranial neuropathies ( 23); however, isolated pareses have been reported in bacterial, viral, fungal, helminthic, and spirochetal diseases ( 24). Trochlear nerve paresis has been reported in other cases of rickettsial disease, including epidemic typhus ( 25) and acute febrile cere-brovasculitis ( 26), but to our knowledge, this is the first case of isolated trochlear nerve paresis associated with meningitis in the setting of human ehrlichiosis. There are too few well- documented cases of human ehrlichiosis to make any generalizations regarding either the neurologic or ocular complications of these diseases; however, it seems clear that meningitis can occur during the course of both HME and HGE. 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