Borrelia burgdorferi induces matrix metalloproteinases by neural cultures

Matrix metalloproteinases (MMPs) are associated with chronic neurologic diseases such as multiple sclerosis and senile dementia. Lyme disease is a multisystemic infection involving the nervous system, skin, joints, and heart. Neurologic manifestations of chronic Lyme disease include encephalopathy and cranial and peripheral neuropathy. Borrelia burgdorferi, the spirochaete causing Lyme disease, has been cultured from the cerebrospinal fluid (CSF), and B. burgdorferi DNA is frequently detected in the CSF of patients with Lyme neuroborreliosis. We used cerebral and cerebellar primary cultures to determine whether B. burgdorferi induces the production of MMPs by primary neural cultures. B. burgdorferi in a dose- and time-dependent manner induced the expression of MMP-9 by primary neural cultures but had no effect on the expression of MMP-2. Human and rat type I astrocytes expressed MMP-9 when incubated with B. burgdorferi in the same manner as primary neural cultures. This response may play a role in the symptomatology and the pathogenesis of Lyme neuroborreliosis.     

Lyme Neuroborreliosis: Clinical Outcomes,Controversy, Pathogenesis,and Polymicrobial Infections

Lyme borreliosis is the object of numerous misconceptions. In this review, we revisit the fundamental manifestations of neuroborreliosis (meningitis, cranial neuritis, and radiculoneuritis), as these have withstood the test of time. We also discuss other manifestations that are less frequent. Stroke, as a manifestation of Lyme neuroborreliosis, is considered in the context of other infections. The summary of the literature regarding clinical outcomes of neuroborreliosis leads to its controversies. We also include new information on pathogenesis and on the polymicrobial nature of tick‐borne diseases. In this way, we update the review that we wrote in this journal in 1995. ANN NEUROL 2019;85:21–31.     

Correlation between neurologic disease and Borrelia burgdorferi antibodies in 800 paired serum/cerebrospinal fluid samples]

Paired serum and cerebrospinal fluid (CSF) samples from 800 patients of a neurological clinic were tested for antibodies to Borrelia burgdorferi. A flagellum enzyme-linked immunosorbent assay was used for antibody screening. All serum/CSF pairs with any elevated antibody response were also tested by a Western blot, a method for confirmation. 65 patients (8.1%) had serum IgG antibodies on ELISA screening and 22 of these (2.8%) were confirmed by Western blot. 20 patients (2.5%) had elevated antibody titers in CSF by ELISA and 12 of these (1.5%) reacted to the Western blot. Clinical features of Bannwarth's syndrome (BS) were present in 12 patients (1.5%) and four patients (0.5%) showed other manifestations of Lyme borreliosis. All patients with Bannwarth's syndrome were positive in serum by both methods and 10 had elevated antibody activity in the CSF proven by the two methods. The combination of a sensitive ELISA for screening and a sensitive and specific Western blot for confirmation reduces the number of positive results but is sensitive in detecting active disease.     

Left sided sudden hemiparesis linked to a central form of Lyme disease

Lyme disease is known for its numerous neurological manifestations. Cerebral ischemic lesions are more rarely reported. We describe the case of a 27 - year old man - presenting with a left-sided hemiparesis when waking up. We first thought of a stroke, due to the presence of a light right capsulo-thalamic hypodensity on C.T. scan and the spontaneous regression of the hemiparesis within a few days. However, the lumbar puncture performed on the patient due to a fever running 38 degrees C and some drowziness showed a lymphocytic pleocytosis with a very inflammatory face of the spinal fluid. The M. R.I. revealed a right capsular and thalamic image with edema of the front part of the thalamus showing either a vascular or an inflammatory origin. The Lyme serodiagnosis in the blood and in the spinal fluid was positive, and we demonstrated an intrathecal Borrelia burgdorferi specific antibody synthesis. This case is interesting because it shows a central form of neuroborreliosis through cerebral infarct and its regressive evolution under treatment. The possible pathophysiology mechanisms have been discussed.     

The polymerase chain reaction in the diagnosis of Lyme neuroborreliosis

The polymerase chain reaction is sensitive and specific in the detection of defined DNA sequences and holds promise for diagnosing the presence of fastidious microorganisms in human infectious diseases. We developed a methodology for nested polymerase chain reaction and hybridization analysis of the cerebrospinal fluid using primers from a genomic Borrelia burgdorferi sequence and applied it to the cerebrospinal fluid (CSF) of patients suspected of having Lyme neuroborreliosis and other diseases. Polymerase chain reaction and hybridization demonstrated extremely high sensitivity for spirochetal DNA, and was highly specific, with a false-positivity rate of less than 3%. However, the results were negative or indeterminate in 54% of CSF samples from patients with definite or probable disease, indicating an absence, or extremely low level, of spirochetes or spirochetal DNA in a significant percentage of patients with Lyme neuroborreliosis. Polymerase chain reaction and hybridization of the CSF can thus be considered a useful adjunct in diagnosis, but its negativity does not rule out Lyme neuroborreliosis.     

Chronic neuroborreliosis in infancy

Lyme disease is a polymorphic and multisystemic disease caused by Borrelia burgdorferi. Neurological manifestations are found in 10%-50% of cases. We present 2 cases followed for 5 and 6 years of chronic relapsing-remitting neuroborreliosis. Diagnosis of neuroborreliosis in these cases was based on serum and cerebrospinal fluid findings. We discuss clinical, neurophysiological, laboratory and instrumental aspects regarding the difficulties of reaching a correct diagnosis. Further studies, especially in the field of immunology, should help identify the mechanisms responsible for the disease becoming chronic. With this knowledge, it may be possible to design immunological therapies for relapses, and to prevent the evolution of the disease.     

Lyme neuroborreliosis presenting as Alice in Wonderland syndrome

We describe a 7-year-old boy with Alice in Wonderland syndrome associated with Lyme disease. He presented with metamorphopsia and auditory hallucinations in the absence of previous tick bites or other signs of Lyme disease. The boy never developed clinical seizures, and electroencephalograms during these spells indicated no epileptic activity. There was no history of migraine. Cranial magnetic resonance imaging produced normal results. Lyme serology tested positive in both serum and cerebrospinal fluid. He was treated with intravenous ceftriaxone for 3 weeks, with complete resolution of signs. This case report is the first, to our knowledge, of neuroborreliosis presenting as Alice in Wonderland syndrome with complete resolution of findings after intravenous antibiotic treatment.     

聚合酶链法检测莱姆病患者尿液中伯氏疏螺旋体DNA(附17例报道)

目的:评估聚合酶链反应(PCR)检测莱姆病患者尿液中伯氏疏螺旋体DNA的诊断价值。方法:2004至2006年来自新疆莱姆病自然疫源地临床疑似莱姆病患者17例(均有蜱暴露史和莱姆病临床证据者)和6例以前确诊并治疗后完全恢复的莱姆病患者,共23例为病例组;另选择25例非疑似莱姆病患者为对照组。应用PCR方法检测尿液中伯氏疏螺旋体DNA,采用间接免疫荧光(IFA)检测血清伯氏疏螺旋体抗体。结果:①17例莱姆病患者临床表现呈多系统损害。12/17例(70.59%)为神经型(周围神经病3例,其中1例合并下肢瘀积性皮炎;游走性红斑并发莱姆脑病2例;脑膜脑炎2例;脑炎2例;脑膜炎、脑干炎和脊髓炎各1例);流感样症状2例,其中伴皮疹1例;余心脏型、精神障碍和肝病型各1例。②PCR伯氏疏螺旋体DNA检测阳性17/17例(总阳性率100%)。4例血清IFA试验伯氏疏螺旋体抗体阳性。以前确诊并治疗者6例及对照组25例尿PCR伯氏疏螺旋体DNA和血清IFA试验伯氏疏螺旋体抗体均阴性。③10例完成抗生素治疗后3个月复查,9例PCR伯氏疏螺旋体DNA检测阴性(包括3例晚期莱姆病患者),1例2年复查时仍阳性;4例血清伯氏疏螺旋体抗体阳性者复查均阴性。④早期莱姆病多采用几周的抗生素治疗方案。结论:PCR检测尿液中伯氏疏螺旋体DNA是莱姆病一个有价值的诊断工具。     

Pseudotumor Cerebri in Lyme Disease: A Case Report and Literature Review

Pseudotumor cerebri is an unusual presentation of Lyme disease. The case of an 8-year-old girl with pseudotumor cerebri secondary to acute neuroborreliosis is reported. She presented with acute onset of headache, papilledema, sixth nerve palsy, increased intracranial pressure, and cerebrospinal fluid pleocytosis. Serum and cerebrospinal fluid Lyme antibodies were positive. Twelve reported cases that mostly presented with systemic findings and signs of Lyme disease before development of pseudotumor cerebri were reviewed. We conclude that acute neuroborreliosis can present with pseudotumor cerebri as an initial manifestation. It is important to include Lyme disease in the differential diagnosis of pseudotumor cerebri in an area endemic for Lyme disease.     

Cells secreting antibodies to myelin basic protein in cerebrospinal fluid of patients with Lyme neuroborreliosis.

An autoimmune response to myelin basic protein (MBP) has been proposed to participate in the development of the chronic neurologic manifestations that may accompany Borrelia burgdorferi-induced Lyme disease. Using an immunospot assay, we counted cells secreting antibodies to MBP. Anti-MBP IgG antibody-secreting cells were detected in CSF from eight of 13 consecutive patients with Lyme neuroborreliosis irrespective of stage of disease. The numbers were between 1/370 and 1/5,000 CSF cells (mean, 1/1,250 in the 13 patients). The highest numbers were encountered in two patients with severe signs of CNS involvement. The numbers decreased in parallel with clinical improvement after treatment. Anti-MBP IgG antibody-secreting cells were also observed in the CSF from patients with a variety of other inflammatory diseases of the nervous system, and their role in the development of tissue damage remains unsettled. Anti-MBP IgG antibody-secreting cells were not detected in the patients' blood, reflecting accumulation of this autoantibody response to CSF.     

Meningovascular form of neuroborreliosis: similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis

Summary Recent observations have delineated the neurological manifestations of Lyme disease, but, to our knowledge, no detailed neuropathological study from autopsy cases has been reported. In this report we describe the neuropathological findings in a case of Lyme neuroborreliosis. The chronic meningitis, the occlusive meningo vascular and secondary parenchymal changes that we found are similar to those occurring in the meningovascular form of neurosyphilis. Thus, we suggest that the case described here represents the meningovascular form of tertiary Lyme neuroborreliosis.     

Cefotaxime vs penicillin G for acute neurologic manifestations in Lyme borreliosis. A prospective randomized study

We randomly assigned 21 patients with painful Lyme neuroborreliosis radiculitis (Bannwarth's syndrome) and neuroborreliosis meningitis to a 10-day treatment with either penicillin G. 4 x 5 million U/d (n = 10) or cefotaxime sodium, 3 x 2 g/d (n = 11), intravenously. We were not able to demonstrate clinical differences between groups, either during the 10-day treatment period or at follow-up examination a mean of 7.7 months after antibiotic therapy. Cerebrospinal fluid cefotaxime concentrations reached the minimum inhibitory concentration at the 90% level for Borrelia burgdorferi in all patients, while none of the patients treated with penicillin G had cerebrospinal fluid concentrations above the minimum inhibitory concentration at the 90% value. We conclude that patients with acute neurologic manifestations of Lyme borreliosis may benefit from a 10-day treatment with cefotaxime or penicillin G. Cerebrospinal fluid antibiotic concentrations above the minimum inhibitory concentration at the 90% value, as observed in all patients treated with cefotaxime, offer the most hope for long-term prognosis.     

Lyme neuroborreliosis

Neuroborreliosis, an infection of the nervous system caused by spirochetes of the genus Borrelia, has achieved worldwide attention in the last decade as part of the clinical spectrum of Lyme disease. This disorder, caused by Borrelia burgdorferi, has increased in incidence to become the most frequent arthropod-borne infection in North America and Europe. As a result of this rapid rise in incidence and of its protean neurological manifestations, this disease has created an important challenge to modern neurology. The diverse manifestations of neuroborreliosis require that it be included in the differential diagnosis of many neurological disorders. This review takes a chronological approach to clinical neuroborreliosis to summarize its most important aspects. The limitations as well as the benefits of laboratory diagnosis are also considered, with the aim of providing assistance in this area. Recent advances in neuroimmunology regarding the pathogenesis of neuroborreliosis that may elucidate its protean clinical spectrum are summarized.     

Spirochetal infection of the nervous system.

Neurologic infection is a characteristic feature of spirochetes. The neurologic manifestations of spirochetal infection are a source of continuing public concern: Lyme neuroborreliosis in endemic areas, neurosyphilis in HIV infected patients, and neuroborreliosis during outbreaks of relapsing fever. These are reviewed in this article. The techniques for diagnosis and recommendations in the management of these infections are also discussed.     

Central and peripheral nervous system infection, immunity, and inflammation in the NHP model of Lyme borreliosis

The relationship between chronic infection, antispirochetal immunity, and inflammation is unknown in Lyme neuroborreliosis. In the nonhuman primate model of Lyme neuroborreliosis, we measured spirochetal density in the nervous system and other tissues by polymerase chain reaction and correlated these values to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid, and to inflammation in tissues. Despite substantial presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, in the central nervous system, only minor inflammation was present there, though skeletal and cardiac muscle, which contained similar levels of spirochete, were highly inflamed. Anti-Borrelia burgdoferi antibody was present in the cerebrospinal fluid but was not selectively concentrated. All infected animals developed anti-Borrelia burgdorferi antibody in the serum, but increased amplitude of antibody was not predictive of higher levels of infection. These data demonstrate that Lyme neuroborreliosis is a persistent infection, that spirochetal presence is a necessary but not sufficient condition for inflammation, and that antibody measured in serum may not predict the severity of infection.     

Lyme borreliosis

Lyme disease is a multisystemic disease caused by a spirochete, Borrelia Burgdorferi that is transmitted by ticks. A clinical diagnosis is easy when a tick bite is followed 3 weeks later by erythema migrans, than by involvement of nervous system, joints or heart. In case of neuroborreliosis, serological tests, performed in blood and cerebro-spinal fluid, support the diagnosis and patients recover rapidly with antibacterial treatments. However an accurate diagnosis remains sometimes problematic, especially distinction between a coincidental positive serologic test and a nervous system Lyme borreliosis which require antibiotics. Furthermore, the role of autoimmunity in the pathophysiology of late Lyme disease, antibiotic choice in early disease, duration of treatment, and utility of vaccination are discussed.     

Autoantibodies to human manganese superoxide dismutase (MnSOD) in children with facial palsy due to neuroborreliosis

AIM: Acute peripheral facial palsy due to neuroborreliosis is associated with a distal neuritis. In patients with Lyme disease the activity of antioxidant enzymes is decreased. With respect to the pathogenesis of neuroborreliosis, sera of children with acute peripheral facial palsy were investigated for autoantibodies against human manganese superoxide dismutase (MnSOD), which were suspected of raising the oxidative injury of infected tissues. METHODS: Sera of 20 children with acute peripheral palsy with neuroborreliosis, sera of 20 children with facial palsy without reference to Lyme disease and sera of 14 blood donors were tested for antibodies against human MnSOD using an ELISA. RESULTS: The concentrations of IgM autoantibodies to MnSOD of the children with neuroborreliosis were significantly increased, compared with the two control groups. CONCLUSIONS: We propose that the antibodies detected block the protective effects of MnSOD resulting in an increased oxidative inflammation.     

Lower cranial nerve involvement as the initial manifestation of Lyme borreliosis

Lyme disease or Lyme borreliosis is an infectious disease transmitted by ticks and caused by Borrelia burgdorferi. Being clinically different from Relapsing Fever it may cause an array of symptoms, specially cutaneous and neurological but also musculoskeletal and cardiac ones. Within the neurologic manifestations of Lyme disease the affectation of low cranial nerves is, to our knowledge, extremely infrequent. We present the clinical case of a 35 years old male whose initial symptoms were low cranial nerve dysfunction with a cerebrospinal fluid compatible with meningitis. Serology against Borrelia burgdorferi both in serum and cerebrospinal fluid was positive.     

Intrathecal immune response in patients with neuroborreliosis: specificity of antibodies for neuronal proteins

Cerebrospinal fluid (CSF) and serum samples of 47 patients with serologically proven neuroborreliosis were examined by Western blotting for antibodies to a crude extract of human cortex (CNS) comprising a multitude (> 40) of protein bands. Intrathecal synthesis of total immunoglobulins was determined by the Reiber formula and of autoantibodies to CNS proteins by enzyme-linked immunoassay (ELISA) and by Western blotting. Employing ELISA, intrathecal synthesis of autoantibodies (IgG, IgM and/or IgA) was demonstrated in 40 of 47 patients with neuroborreliosis (85%), in 5 of 40 with multiple sclerosis (12%), and in 22 of 40 with viral meningoencephalitis (55%). Of 40, 35 and 15 patients with neuroborreliosis and an intrathecal synthesis of total IgG, IgM or IgA, 20 revealed an intrathecal production of IgG antibodies (50%), 24 of IgM antibodies (68%) and 6 of IgA autoantibodies (40%) in the CSF. The specificity of autoantibodies differed greatly between most patients. Of 24 different CNS proteins which elicited an immune response in various patients, identities could be determined only for the myelin basic protein (5 of 40) and for the three neurofilament proteins (NF-68, NF-150, NF-200) (13 of 40 patients). In this limited number of patients no significant correlation between individual clinical symptoms and certain autoantibodies could be detected. The higher frequency of intrathecally produced autoantibodies in patients with neuroborreliosis is assumed to result from mitogenic rather than specific activation of autoreactive B-cell clones byBorrelia burgdorferi. The pathogenic relevance of these autoantibodies remains to be determined.     

Cerebrospinal fluid interleukins, immunoglobulins, and fibronectin in neuroborreliosis

Intrathecal synthesis of IgM and IgG, oligoclonal immunoglobulin bands, and the levels of fibronectin, soluble interleukin 2 receptor, interleukin 6, and tumor necrosis factor alpha were investigated with the use of enzyme-linked immunosorbent assay in 46 paired cerebrospinal fluid and serum samples from 32 patients with meningopolyradiculoneuritis due to Borrelia burgdorferi (Lyme borreliosis stage 2). Cerebrospinal fluid and serum interleukin 6, although not specific for neuroborreliosis, were good indicators of disease activity, while the serum soluble interleukin 2 receptor level was only mildly elevated. Tumor necrosis factor alpha was never detected in cerebrospinal fluid or serum specimens, and cerebrospinal fluid IgM, IgM index, and cerebrospinal fluid IgM/cerebrospinal fluid IgG ratios were significantly higher than in all other neuroimmunologic disorders evaluated and may be valuable diagnostic indicators for neuroborreliosis. The estimation of intrathecally synthesized IgG and IgM fractions for the differential diagnosis of neuroimmunologic disorders did not add to IgG and IgM index calculations.