Neuroborreliosis in adults NEUROBORRELIOSIS IN ADULTS E. Schmutzhard ABSTRACT Neuroborreliosis is an infection of the central and peripheral nervous system caused by spirochetes of the genus Borrelža, possibly by certain genospecies, e.g. B. burgdorferi, genospecies garinii. The nervous system is first afflicted during the early stage of Lyme Borreliosis with dissemination; the main features include meningitis, radiculoneuritis and polyneuritis cranialis. Late Lyme Borreliosis presents as sensory polyneuropathy in association with acrodermatitis chronica atrophicans or as progressive Borrelia encephalomyelitis. The diagnosis is confirmed by the presence of intrathecally produced specific antibodies and positive culture or PCR respectively. The accepted treatment of neuroborreliosis is either by ceftriaxone, possibly also by penicillin or doxycycline. KEYWORDS neuroborreliosis, diagnosis, therapy INTRODUCTION Several species of the genus Borrelia are capable of infecting the central and/or peripheral nervous system, hence causing the clinical entity of neur- oborreliosis (NB). This review of NB in adults does not deal with diseases caused by trapica! Borrelia species ( e.g. B. recurrentis or B. duttoni), but only with the neurologic manifestations of B. burgdorferi (Bb) infection. In 1922 C. H. Garin and C. H. Bujadoux described a patient with meningoradiculitis following a tick bite and associated with erythema migrans (EM) (1). In a very extensive review A. Bannwarth tried acta dermatovenerologica A.P.A. Vol 5, 96, No 3-4 to categorize this disease entity, assuming it to be a rheumatological disorder (2). It was only after the discovery of the causative agent (3) of Lyme arthritis ( 4) that the etiology of this nervous system disease was recognized as being spirochetal (5-7). This disease, now known as Lyme Borreliosis (LB) is present in nearly every part of the world, showing focal clustering. CLINICAL PRESENTATIONS The course of adult NB is highly variable: In about 30% to 40% of patients the disease starts with a characteristic skin lesion, the so-called erythema 131 Neuroborreliosis in adults (chronicum) migrans, which appears days to weeks after a tick bite in an endemic area. Neurologic, cardiac, articular and chronic skin involvement develops later. A chronological approach, indicating a stage- like course of disease was emphasized in the early years after the discovery of the causative agent, Bb. Today LB is divided into following clinical entities: (i) early LB without dissemination (EM), (ii) early LB with dissemination, cardiac and neurologic manifestations, (iii) late LB, (iv) asymptomatic LB, (v) late Lyme encephalopathy. Neurologic signs and symptoms can appear at any tirne within the early LB with dissemination and the late LB stages. Late Lyme encephalopathy still is a matter of discussion. Only recently have different genospecies of Bb been delineated which are associated with distinct clinical manifestations of LB: B. burgdorferi sensu stricto, B. afzelii, B. pacifica and B. garinii (8-11); the latter being most frequently associated with neurologic disease. EARL Y L YME BORRELIOSIS WITH DISSEMINATION The typical triad of this stage consists of lymphocytic meningitis, cranial neuropathy and radiculoneuritis (7), occurring either in combination or oligosympto- matic (12,13). A presentation resembling aseptic meningitis is more frequently seen in children and young adults and may take an acute, chronic or relapsing course (14). Cerebrospinal fluid (CSF) analysis indicates mono- nuclear pleocytosis, predominantly lymphocytes and plasma cells (15). Within 4 weeks after the onset of the neurologic disease, intrathecal synthesis of specific antibodies (lgG, IgM and IgA (16,17)) as well as oligoclonal bands (17) may be seen. Myalgia, arthralgia and fatigue frequently precede or concur with this disease. Radiculoneuritis, the hallmark of Garin- Bujadoux-Bannwarth-Syndrome, usually starts with extremely severe radicular pains, characteristically accentuated during the night hours and almost unresponsive to analgesic drugs including morphine derivatives (14). Facial palsy frequently appears within days after the radicular signs and symptoms have started. However, the disease may present as pure polyneuritis cranialis (18). Neurophysiological exami- nation reveals widespread peripheral axonal injury (19). A sural nerve biopsy shows an infiltration of the vasa nervorum by mononuclear elements (lymphocytes and plasma cells) without necrosis of the vessel walls (20). 132 Less frequently acute myelitis, encephalitis, focal nodular myositis and vasculitis are prominent features of disseminated NB (21-23). LATE LYME BORRELIOSIS In the late stage of the disease the peripheral and central nervous system may be involved. (i) Peripheral nerve involvement: peripheral neuropathy has been associated with the chronic dermatological stage of the disease, acrodermatitis chronica atrophicans (ACA) (24,25). More than half of ACA patients develop this predominantly sensory neuropathy. Motor impairment is usually not present. Electrophysiological findings are consistent with a mild to moderate predominantly axonal neuropathy (25). (ii) In very rare instances central nervous system involvement has been described by a chronic course of the disease; Ackermann et al. coined the term of progressive BoJTelia encephalomyelitis (26). These patients present with a wide range of neurologic disorders including spastic paraparesis, ataxia, brainstem dysfunction, cognitive impairment, neurogenic bladder dysfunction, etc. The evolution is gradual, progressing over months and years. The CSF shows a typical mononuclear pleocytosis, increased protein content and intrathecal synthesis of IgG, IgM and IgA. This constellation definitely allows to distinguish this disease entity from multiple sclerosis (27). The latter should never be confused with progressive BoJTelia encepha- lomyelitis. In Northern America CNS involvement has been reported rather frequently (28-30), observing a meningovascular form of NB resembling tertiary neurosyphilis (31). ASYMPTOMATIC NEUROBORRELIOSIS Pfister et al. reported on the detection of Bb in the CSF of an otherwise healthy individual (32). It is not known whether this is a frequent or infrequent finding. Moreover, its clinical implications have not yet been fully elucidated. LATE LYME ENCEPHALOPATHY A mild chronic encephalopathy with memory disturbances and sleep disorders has been found in patients with LB in North America (28,29,33). Usually the CSF shows a normal cell count and only a mild increase in protein content. In most cases, intrathecal synthesis of antibodies to Bb can be seen. A controlled trial, subjecting 20 patients (a mean of 57 months acta dennatovenerologica A.P.A. Vol 5, 96, No 3-4 Neuroborreliosis in adults after acute NB) and 20 matched control persons to a wide range of neuropsychological testings, revealed statistically significant memory and learning deficits in the group of patients having suffered from acute NB with dissemination almost 5 years earlier (34). Similar findings were reported earlier by Krupp et al. and Kaplan et al. (35,36) in noncontrolled series. LABORATORY DIAGNOSIS OF NEUROBORRELIOSIS A patient presenting with a typical history of a tick bite and EM as well as the classical clinical presentation and inflammatory CSF changes is beyond doubt in terms of diagnosis. Unfortunately a tick bite is frequently not remembered, EM by far not always present and the clincial presentation - in a rather high percentage - either oligosymptomatic or atypical. CSF changes are unspecific, however the presence of intrathecal IgG, IgM and IgA certainly raise the level of suspicion. Isolation of the spirochetes from the CSF has been accomplished, but this diagnostic golden standard is difficult and untimely. Improvements in the detection of antibodies to Bb have resulted in a reliable laboratory diagnosis (37). J. C. Garcia-Monco and J. L. Benach constructed an algorithm to evaluate serologic information to diagnose NB and consider clinical and treatment parameters (38). The demonstration of intrathecal specific antibody production has now become the golden standard procedure for the laboratory diagnosis of NB (39-41). An additional important finding in the CSF is a markedly increased IgM index; oligoclonal IgG bands in the CSF can be seen during the course of disease (39,40). Polymerase chain reaction (PCR) is a reliable adjunct to other laboratory tests, as it is more sensitive than bacterial cultures (38). Positive PCR findings have been obtained from the CSF of patients with a disease duration of less than 2 weeks (42) and 4 to 8 months (43). THERAPY Treatment is based on the administration of antibiotics, penicillin G (20-30 mill. U t.i.d.) or ceftriaxone (2g once daily) ( 44-46). However, complex pathogenetic mechanisms, not yet fully understood, may require future alternative therapies. The duration of treatment is at least 2 weeks or even longer depending on the response. Oral tetracyclines, e.g. doxycycline 200 mg daily for 2 weeks, can be administered to patients allergic to penicillin or cephalosporins and may prove as effective as an IV penicillin in patients with the classical triad of NB ( 47). At present corticosteroids are not recommended (38,48). This paper was presented in part at the Intemational Symposium: Lyme Bo1Teliosis - update 1996, 19-21 April, Graz, Austria REFERENCES l. Garin CH, Bujadoux CH. Paralysie par les tiques. J Med Lyon 1922; 71: 765-67. 2. Bannwarth A. Chronische lymhocytare Meningitis, entziindliche Polyneuritis und Rheumatismus. Arch Psychiatr Nervenkr 1941; 113: 284-376. 3. Burgdorfer W, Barbour AG, Hayes SF et al. Lyme disease - a tick-borne spirochetosis? Science 1982; 216: 1317-19. 4. Steere AC, Malawista SE, Snydman DR et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut commu- nities. Arthritis Rheum 1977; 20: 7-17. 5. Reik L, Steere AC, Bartenhagen NH et al. Neurologic abnormalities of Lyme disease. Medicine (Baltimore) 1979; 58: 281-94. 6. Pfister HW, Einhaupl K, Preac-Mursic V et al. The spirochetal etiology of lymphocytic meningo- acta dennatovenerologica A.P.A. Vol 5, 96, No 3-4 radiculitis of Bannwarth (Bannwarth's syndrome ). J Neurol 1984; 231: 141-44. 7. Pachner AR, Steere AC. The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology 1985; 35: 47-53. 8. Baranton G, Postic D, Saint Girons I et al. Delineation of Bo1Telia burgdorferi sensu stricto, Bo1Telia garinii sp. nov. and group VS461 associated with Lyme Borreliosis. Int J Syst Bacteriol 1992; 42: 378-83. 9. van Dam AP, Kuiper H, Vos K et al. Different genospecies of Bo1Telia burgdorferi are associated with distinct clinical manifestations of Lyme Borreliosis. Clin Infect Dis 1993; 17: 708-17. 10. Belfaiza J, Postic D, Bellenger E et al. Geno- mic fingerprinting of Borrelia burgdorferi sensu lato by pulsed field gel electrophoresis: correlation 133 Neuroborreliosis in adults with the defined four species. In: Cevenini R, Sambri V, La Placa M (eds.). Advances in Lyme Borreliosis Research. Soc Edit Esculapio, Bologna 1994; 61 -64. 11. Johnson RC. Lyme disease: past, present and future. In: Cevenini R, Sambri V, La Placa M ( eds. ). Advances in Lyme Borreliosis Research. Soc Edit Esculapio, Bologna 1994; 1-6. 12. Halperin JJ, Golightly MG, Andriola M et al. Lyme Borreliosis in Bell's palsy. Neurology 1992; 42: 1268-70. 13. Schmutzhard E, Pohl P, Stanek G. Involvement of BoJTe!ia burgdo,feri in cranial nerve affection. Zbl Bakt Hyg 1986; 263 A: 328-33. 14. Kristoferitsch W. Neurological manifestations of Lyme Borreliosis: clinical definition and differential diagnosis. Scand J Infect Dis Suppl 1991; 77: 64-73. 15. Pohl P, Schmutzhard E, Stanek G. Cerebrospinal fluid findings in neurological manifestations of Lyme disease. Zbl Bakt Hyg 1986; 263 A: 314-20. 16. Henriksson A, Link H, Cruz M, Stiernstedt G. Immunoglobulin abnormalities in cerebrospinal fluid and blood over the course of lymphocytic meningo- radiculitis (Bannwarth's syndrome). Ann Neurol 1986; 20: 337-45. 17. Martin R, Martens U , Sticht-Groh V et al. Persistent intrathecal secretion of oligoclonal, BoJTelia burgdoferi-specific IgG in chronic meningoradi- culomyelitis. J Neurol 1988; 235: 229-33. 18. Schmutzhard E, Pohl P, Stanek G. Polyneuritis cranialis associated with BoJTelia burgdo,feri infection. J Neurol Neurosurg Psych 1985; 48: 1182-84. 19. Vallat JM, Hugon J, Lubeau M et al. Tick-bite meningoradiculoneuritis: clinical, electrophysiologic and histologic findings in 10 cases. Neurology 1987; 37: 749-53. 20. Meier C, Grahmann F, Engelhardt A, Dumas M. Peripheral nerve disorders in Lyme Borreliosis. Nerve biopsy studies from eight cases. Acta Neuro- pathol (Berl) 1989; 79: 271-78. 21. Schmutzhard E, Willeit J, Gerstenbrand F. Meningopolyneuritis Bannwarth with focal nodular myositis, a new aspect in Lyme Borreliosis. A case report. Klin Wochenschr 1986; 64: 1204-8. 22. Schmutzhard E, Stockhammer G, Kleedorfer B, et al.: Unusual neurological manifestations of second stage Lyme Borreliosis. Ann NY Acad Sci 1988; 539: 274-82. 23. Midgard R, Hofstad H. Unusual manifestations 134 of nervous system BoJTelia burgdo,feri infection. Arch Neurol 1987; 44: 781-83. 24. Kristoferitsch W, Sluga E, Graf M et al. Neuro- pathy associated with acrodermatitis chronica atro- phicans. Clinical and morphological features. Ann NY Acad Sci 1988; 539: 35-45. 25. Logigian EL, Steere AC. Clinical and electro- physiologic findings in chronic neuropathy of Lyme disease. Neurology 1992; 42: 303-11. 26. Ackermann R, Rehse-Kiipper B, Gollmer E, Schmidt R. Chronic neurologic manifestations of erythema migrans borreliosis. Ann NY Acad Sci 1988; 539: 16-23. 27. Schmutzhard E, Pohl P, Stanek G. Bomlia burgdo,feri antibodies in patients with relapsing/remitting form and chronic form of multiple sclerosis. J Neurol Neurosurg Psychiatr 1988; 51: 1215-18. 28. Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalities in Lyme neuroborreliosis. Neurology 1991; 41: 1571-82. 29. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990; 323: 1438-44. 30 .. Pachner AR, Duray PH, Steere AC. Central nervous system manifestations of Lyme disease. Arch Neurol 1989; 46: 790-95. 31. Miklossy J, Kuntzer T, Bogousslavsky et al. Meningovascular form of neuroborreliosis: simila- rities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis. Acta Neuropathol (Berl) 1990; 80: 568-72. 32. Pfister HW, Preac-Mursic V, Wilske B et al. Latent Lyme neuroborreliosis: presence of BoJTelia burgdo,feri in cerebrospinal fluid without concurrent inflammatory signs. Neurology 1989; 39: 1118-20. 33. Halperin JJ, Krupp LB, Golightly MG, Volkman DJ. Lyme Borreliosis-associated encephalopathy. Neurology 1990; 40: 1340-43. 34. Benke T, Gasse T, Hittmair-Delazer M, Schmutz- hard E. Lyme encephalopathy: Neuropsychological and clinical variables. Acta Neurol Scand 1995; 91: 353-57. 35. Krupp LB, Masur D, Schwartz J. Cognitive functioning in late Lyme Borreliosis. Arch Neurol 1991; 48: 1125-29. 36. Kaplan RF, Meadows ME, Vincent LC et al. Memory impairment and depression in patients with Lyme encephalopathy. Comparison with fibromyalgia acta dennatovenerologica A .P.A. Vol 5, 96, No 3-4 Neuroborreliosis in adults and nonpsychotically depressed patients. Neurology 1992; 42: 1263-67. 37. Turnani H, Volker V, Reiber HO. Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis. Neurology 1995; 45: 1663-70. 38. Garcia Monco JC, Benach JL. Lyme neuro- borreliosis. Ann Neurol 1995; 37: 691-702. 39. Rehse-Kiipper B, Ackermann R. Demonstration of locally synthesized Borrelia antibodies in cerebrospinal fluid. Zbl Bakt Hyg 1986; 263A: 407- 11. 40. Hansen K, Cruz M, Link H. Oligoclonal Borrelia burgd01feri-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis. J Infect Dis 1990; 161: 1194-1202. 41. Murray N, Kristoferitsch W, Stanek G, Steck AJ. Specificity of CSF antibodies against components of Borrelia burgd01feri in patients with meningo- polyneuritis Garin-Bujadoux-Bannwarth. J Neurol 1986; 233: 224-27. 42. Luft BJ, Steinman CR, Neimark HC. Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA 1992; 267: 1364-67. 43. Lebech AM, Hansen K. Detection of Borrelia burgdorferi DNA in urine samples and cerebrospinal fluid samples from patients with early and late Lyme neuroborreliosis by polymerase chain reaction. J Clin Microbiol 1992; 30: 1646-53. 44. Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. Ann Intern Med 1983; 99: 767-72. 45. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late Lyme Borreliosis - randomized comparison of ceftriaxone and penicillin. Lancet 1988; 2: 1191-94. 46. Schmutzhard E, Wilske B, Baurnhackl U et al.: Ceftriaxone in the treatment of early and disseminated Lyme Borreliosis with meningitis. In: Cevenini R, Sambri V, La Placa M (eds.). Advances in Lyme Borreliosis Research. Soc Edit Esculapio, Bologna 1994; 163-66. 47. Karlsson M, Hammers-Berggren S, Lindquist L et al. Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborre- liosis. Neurology 1994; 44: 1203-7. 48. Kri.iger H, Kohlhepp W, Konig S. Follow-up of antibiotically treated and untreated neuroborreliosis. Acta Neurol Scand 1990; 82: 59-67. AUTHOR'S ADDRESS Erich Schmutzhard, MD, professor of neurology, Department of Neurology, University Hospital, AnichstraBe 35, A-6020 Innsbruck, Austria acta dennatovenerologica A.P A. Vol 5, 96, No 3-4 135