Transient Worsening of Optic Neuropathy as a Sequela of the Jarisch-Herxheimer Reaction in the Treatment of Lyme Disease.

A 58-year-old woman developed neurologic and neuroophthalmologic manifestations of Lyme disease, including a radiculomyelitis, cranial neuritis and mild right optic neuropathy. Upon treatment with intravenous ceftriaxone a Jarisch-Herxheimer reaction occurred with encephalopathy, mild fever, worsening radiculomyelitis, and deterioration of her visual acuity. Intravenous methylprednisolone was given, and the visual acuity recovered over 72 hours. This case suggests that transient worsening of optic neuropathy can develop as a sequela of the Jarisch-Herxheimer reaction in the treatment of Lyme disease.

Journal of Neuro- Ophthalmology 14( 2): 77- 80, 1994. © 1994 Raven Press, Ltd., New York Transient Worsening of Optic Neuropathy as a Sequela of the Jarisch- Herxheimer Reaction in the Treatment of Lyme Disease Mitchell B. Strominger, M. D, Thomas L. Slamovits, M. D., Steven Herskovitz, M. D., and Richard B. Lipton, M. D. A 58- year- old woman developed neurologic and neuro-ophthalmologic manifestations of Lyme disease, includ­ing a radiculomyelitis, cranial neuritis and mild right optic neuropathy. Upon treatment with intravenous cef­triaxone a Jarisch- Herxheimer reaction occurred with en­cephalopathy, mild fever, worsening radiculomyelitis, and deterioration of her visual acuity. Intravenous methyl-prednisolone was given, and the visual acuity recovered over 72 hours. This case suggests that transient worsen­ing of optic neuropathy can develop as a sequela of the Jarisch- Herxheimer reaction in the treatment of Lyme disease. The Jarisch- Herxheimer reaction ( JHR) is a rec­ognized complication of the treatment of spiro­chetal infections. It is characterized by fever, chills, myalgia, arthralgia, exacerbation of existing le­sions, and hypotension. The symptoms usually are greatest 6 to 12 hours after initiating treatment and resolve within 72 hours ( 1- 5). In Lyme dis­ease, caused by the spirochete Borrelia burgdorferi, approximately 14% of patients have a worsening of symptoms during the first 24 hours of treatment. These exacerbations are considered to be caused by JHR ( 6). We report a case of transient deterio­ration of optic nerve function in a patient with prior optic neuropathy presumably as a sequela of JHR in the treatment of Lyme disease. From the departments of Ophthalmology ( M. B. S., T. L. S.), Neurology ( T. L. S., S. H., R. B. L.), and Neurosurgery ( T. L. S.), Montefiore Medical Center/ Albert Einstein College of Medicine, Bronx, New York, U. S. A. This work was supported in part by an unrestricted grant from the Research to Prevent Blindness, Inc., New York, New York. Address correspondence and reprint requests to Dr. Thomas L. Slamovits, Department of Ophthalmology, Montefiore Med­ical Center, 111 E. 210th Street, Bronx NY 10467, U. S. A. CASE REPORT A 58- year- old woman physician was evaluated in January 1989 with a 3- year history of hand and wrist arthralgia, frequent visits to areas endemic for Lyme disease, but no known tick bites or rash. Incidentally, there was a history of a right Adie's tonic pupil antedating her current problem by many years. Over several months she developed severe, in­termittent, right scapular pain and hand weak­ness. Examination revealed atrophy and weakness of the right shoulder girdle and hand muscles, mild difficulty with concentration, right long tract weakness, and an unsteady gait. Electromyogra­phy confirmed right cervical polyradicular dys­function. Magnetic resonance imaging ( MRI) of the head, cervical spine, and brachial plexus was un­remarkable. Cerebrospinal fluid showed 3 lym­phocytes/ mm3, 56 mg% protein, normal glucose concentration, negative cultures, and nonmalig- 77 78 M. B. STROMINGER ET Ah. nant cytology. Serum and cerebrospinal fluid Lyme serologies were negative by ELISA and Western Blot techniques, but there was a strongly positive T- cell proliferation assay against Borrelia burgdorferi ( stimulation index of 50) ( 7). VDRL, MHA- TP, and serologies for collagen vascular dis­ease were normal. In April 1989, treatment was initiated for this clinical radiculomyelitis from suspected Lyme dis­ease with intravenous ceftriaxone, 2 g BID, for 21 days. A marked JHR followed within 12 hours. This was characterized by transient encephalopa­thy, asterixis, fever to 102.6° F., widened pulse pressure, photophobia, all of which resolved within 72 hours while continuing the antibiotic. Liver function tests were normal throughout her course. Clinical improvement of her radiculomy­elitis occurred over the next month. Over the ensuing 7 months she was treated for a bout of right anterior uveitis that resolved with topical corticosteroids and cycloplegia. She then developed several episodes of painless, transient visual blurring lasting seconds in the right eye. Ophthalmologic evaluation revealed normal visual acuity, but mild red desaturation in the right eye. No afferent pupillary defect was present. Visual evoked potentials demonstrated mild right monoc­ular delay. Carotid duplex scan was normal. She then developed transient glossopharyngeal neu­ralgia, tinnitus, dysgeusia, loss of taste, and left tongue atrophy. A subsequent complete neuro- ophthalmologic examination in December 1989 demonstrated a vi­sual acuity of 20/ 25 OU, a right tonic pupil with light- near dissociation, and a mild decrease in cen­tral sensitivity on static automated field testing us­ing the Octopus program 31. A repeat lumbar puncture was normal. Gadolinium enhanced MRI of the head and cervical spine was normal. A sec­ond course of intravenous ceftriaxone, 2 g/ day, for 8 weeks was initiated. Within 24 hours a marked JHR reaction occurred with encephalopathy, mild fever, and right arm weakness that resolved by 48 hours, while continuing the antibiotic. Symptoms and signs of her chronic Lyme disease improved over several weeks without further episodes of vi­sual blurring. In July 1990 she was readmitted with a history of episodic right temporal headaches, mild confu­sion, right foot weakness, and no visual com­plaints. Corrected visual acuity was 20/ 25 OD and 20/ 25 OS. She was again treated with intravenous ceftriaxone but at an increased dose of 4 g/ day. Within 24 hours she became inattentive, confused, and dysarthric, and she demonstrated a worsening right hemiparesis. She also complained of de­creased visual acuity in the right eye. The visual acuity on examination was 20/ 50 OD and 20/ 25 OS with subjective red desaturation on the right. The right pupil was poorly reactive to direct and con­sensual response consistent with her old Adie's tonic pupil. The left pupil reacted briskly to light. There was a new right afferent pupillary defect. Examination of the right disc revealed mild tem­poral pallor, and the left was normal. Given the close proximity to antibiotic therapy, the enceph­alopathy and worsening optic neuropathy were at­tributed to a JHR reaction. Intravenous methyl-prednisolone, 250 mg every 6 hours, was started, and within 72 hours the encephalopathy resolved. The visual acuity improved to 20/ 40, 20/ 30, and then 20/ 25 OD over 3 days. The subjective red de-saturation and the right afferent pupillary defect resolved. The antibiotic was continued. Oral pred­nisone starting at 100 mg daily was tapered off over the next 10 days. One week later, the visual acuity was stable at 20/ 25 OD and 20/ 25 OS, color vision testing using Ishihara plates was 15/ 15 in both eyes, and no afferent pupillary defect was detected. Static threshold perimetry by Octopus program 31 was normal. DISCUSSION Throughout our patient's course of illness, se­rum and spinal fluid was banked and ultimately tested in several laboratories. Spinal fluid was demonstrated to contain B. burgdorferi nucleic acids by polymerase chain reaction ( PCR) ( 8) and spe­cific antigens including Osp A, Osp B, and flagel­lar antigens ( 9,10). Adverse reactions during the initial treatment of spirochetal disease are well described. In 1895, Jarisch first reported the transient exacerbation of mucocutaneous lesions upon treatment of syphilis with mercury ( 2). Herxheimer subsequently asso­ciated the relapse with fever, sweating, and an­orexia that followed within 24 hours of initial treatment ( 3). In the treatment of syphilitic optic neuritis, Zimmermann described a violent inflam­matory and hemorrhagic exacerbation of optic neuritis following the first injection of arsphen-amine ( 11). In treating syphilitic iritis, Moore ( 12) reported an increase in inflammation in the af­fected eye and precipitation of iritis in an unin-volved eye with primary arsenical therapy; this he attributed to the JHR. More recently, Weinstein and colleagues ( 13) described a patient who expe­rienced decreased visual acuity after being treated with a single dose of intramuscular penicillin G / Neuro- Ophthalmol, Vol. U, No. 2, 1994 JHR IN LYME DISEASE 79 benzathine for secondary syphilis. This was asso­ciated with fever, chills, and drenching sweats, and was thought to be a JHR. In addition to exac­erbating local lesions and a rise in body tempera­ture, other forms of autonomic dysfunction have been described. Characteristically there is an early hypertensive phase associated with vasoconstric­tion, chills, and increased heart rate, followed by a precipitous fall in blood pressure with low periph­eral vascular resistance ( 1,5). The etiology of the JHR has not been fully delineated ( 4). Three theo­ries are proposed. According to the first, the mas­sive release of endotoxin upon spirochetal death mediates the reaction ( 1,5,14). Second, a release of leukocyte pyrogen with massive phagocytosis of the dying spirochetes may occur ( 1,15). The third possibility is that treatment results in the forma­tion of immune complexes associated with the re­lease of an unknown antigen ( 1,16,17). Indepen­dent of the specific mechanism, a fall in hemolytic complement and plasma kininogen with a rise in plasma histamine is found in patients exhibiting the JHR ( 18). Our patient presents with a number of previ­ously well- described manifestations of Lyme dis­ease, including arthralgias, myeloradiculopathy, and cranial polyneuropathy ( 19). Although her Lyme serology was negative by ELISA and West­ern Blot techniques a number of experimental tests were positive. She had a positive lymphoprolifer-otive response to B. burgdorferi at a level that is 95% specific for this diagnosis ( 7,20). B. burgdorferi nu­cleic acids were shown to be present in spinal fluid by PCR and specific antigens were also demon­strated in cerebrospinal fluid ( 8- 10). Her illness was responsive to antibiotics. In addition, despite extensive investigations and long- term follow- up of over 4 years, there is no evidence for alternative diagnoses, including multiple sclerosis, sarcoid­osis, collagen vascular disorders, or cancer. During the first course of treatment with intra­venous ceftriaxone the patient developed a classic JHR with fever, orthostasis, exacerbation of her presenting neurologic symptoms, and resolution while the antibiotic was continued. These findings are in contrast to a drug reaction that is present until discontinuation of the drug, has a more de­layed onset, and would not have exacerbated her focal neurologic deficits. ( 21) She later developed evidence of Lyme optic neuropathy manifest as transient visual loss with acuity of 20/ 25, subnor­mal visual evoked responses, and threshold visual field abnormalities. A previously undescribed complication of the JHR reaction in the treatment of Lyme disease is the worsening of optic nerve function. This presented as decreased visual acuity to 20/ 50, red desaturation, and an afferent pupil­lary defect in the right eye all starting within 24 hours of her third antibiotic treatment. The method for treating the JHR in spirochetal disease is controversial. In louse- borne relapsing fever ( Borrelia recurrentis), where the JHR has a mortality rate as high as 12%, attempts to reduce the severity of the reaction have included the use of antipyretics, hydrocortisone, and slow- release penicillin ( 22). Hydrocortisone in doses of 20 mg/ kg/ h for 4 hours- starting an hour before tetracy­cline injection- decreases rectal temperature ini­tially, but does not prevent the full reaction follow­ing treatment ( 23). Hydrocortisone in a dose of 500 mg intravenously 2 hours before and after eryth­romycin therapy decreases the time until deferves­cence and the magnitude of the hypotensive phase but does not prevent the rigors nor febrile re­sponse ( 24). More recently, meptazinol, an opioid antagonist, has been shown to reduce peak tem­perature and to shorten the chill phase of the JHR in louse- borne relapsing fever ( 25). In comparison, the JHR in the treatment of syphilis tends to be less severe and its incidence dependent on the stage of the disease ( 4,26). However, as with louse- borne relapsing fever, the administration of 20 to 60 mg of prednisone suppresses the febrile response and in some cases prevents the exacerbation of focal symptoms, but does not specifically hinder the de­velopment of the reaction ( 27). Because of the ex­tent of optic neuropathy along with encephalopa­thy during the JHR in our patient, intravenous cor­ticosteroids were begun in hopes of preventing further deterioration in visual function. Whether her optic neuropathy would have returned to base­line without treatment is speculative. In treating patients with Lyme disease, the pos­sibility of JHR should be recognized. 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