PCR in lyme neuroborreliosis: a prospective study

OBJECTIVES: DNA proof is the only widely available direct diagnostic tool in Lyme borreliosis. Sensitive PCR detecting of spirochetal DNA was prepared and a prospective study in neuroborreliosis was performed. MATERIALS AND METHODS: 57 hospitalised patients with active neuroborreliosis and proved CSF antibodies synthesis were examined. Nested-PCR (utilizing three targets) was used for the detection of specific DNA in plasma, CSF and urine. RESULTS: Before treatment 36 positive patients (63.1%) were found in all tested specimens in parallel, 28 patients (49.1%) were positive in urine, 20 in CSF (35.0%) and 16 in plasma 28.0%). Later only urine was tested and the following results were obtained: 17 positive patients (30.0%) immediately after treatment, 8 (14.0%) after 3 months and one patient persisted positivity after 6 months. CONCLUSIONS: The highest sensitivity of PCR was achieved in the acute period of neuroborreliosis - 63.1% in three body fluids comparing with CSF antibody synthesis.     

Acute and chronic neuroborreliosis with and without CNS involvement: a clinical,MRI, and HLA study of 27 cases

Summary Of the 96 serologically confirmed neuroborreliosis cases seen in our clinic between 1983 and 1988, 11 patients had mild to moderate and 4 patients had serious cerebral and/or spinal cord symptoms. Nine of these 15 patients with CNS involvement exhibited a primary chronic course of the illness. After high-dose intravenous therapy with penicillin, doxycycline or cefotaxime, given mostly in combination with cortisone, gradual recovery occurred with normalization of CSF findings characteristic of neuroborreliosis, and normalization of significantly elevated Borrelia burgdorferi IgG antibody titres in CSF and serum. Brain MRI and CT showed evidence of or were suggestive of vascular involvement which correlated with clinical symptoms in 11 of the 15 patients with CNS involvement. Brain MRI changes that were similar but much slighter in number and intensity were seen in 5 of 12 neuroborreliosis patients without clinical signs of CNS involvement (lymphocytic meningoradiculitis; Bannwarth's syndrome). The frequencies of the HLA-DR7 (75%), HLA-B44 (50%) and HLA-A29 (33%) antigens in 12 neuroborreliosis patients with clinical symptoms of CNS involvement were significantly different from the frequencies in 12 neuroborreliosis patients without CNS involvement and in 100 control subjects. Diagnostic criteria of active neuroborreliosis are proposed.     

Infectious myelopathies: clinical, serological, and prognostic patterns

INTRODUCTION: Serological confirmation of an infectious acute myelitis injury is difficult to confirm as it is sometimes due to a post-infectious etiology. OBJECTIVES: The aim of this study was to define the clinical, biological and prognostic patterns of infectious myelitis. PATIENTS AND METHODS: This retrospective study included 153 subjects hospitalized in the department of neurology between 1993 and 2002 for treatment of a noncompressive acute myelopathy. Biological confirmation of recent infection was obtained in 12 patients (8 p. 100). RESULTS: An infectious syndrome, beginning prior to the neurological symptoms, was found in 67 percent of patients. The clinical symptoms were severe with loss of sensoromotor and sphincter functions and ascending spinal cord dysfunction (acute transverse myelopathy). Spinal cord MRI showed extended centromedullar high intensity signals with rapid and complete regression. CSF analysis cell count was above 30/mm3 with hyperproteinorachia, in 75 percent and 58 percent of patients respectively. CSF electrophoresis did not detect oligoclonal bands. Clinical outcome was good in all patients except one, however sphincter disorders recovered slowly. DISCUSSION: Our study illustrates a stereotypical clinical, biological and prognostic pattern for infectious acute myelitis. These findings contribute significantly to therapeutic decision making and establishing prognosis at the initial phase of acute myelopathy.     

Upregulation of matrix metalloproteinase-9 in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis

It was investigated (1) whether metalloproteinase-9 (MMP-9), MMP-3, and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1, the natural tissue inhibitor of MMP-9) are increased in the CSF of patients with Lyme neuroborreliosis and (2) whether macrophages can express MMP-9 when stimulated with Borrelia burgdorferi. Zymography showed MMP-9 activity in 26 of 31 (84%) CSF samples from patients with acute stage 2 Lyme neuroborreliosis, but not in 20 controls with non-inflammatory neurological disorders. Activity of MMP-2 was detected in all CSF samples in both patients with neuroborreliosis and controls, suggesting a constitutive release of MMP-2. Using enzyme linked immunosorbent assay (ELISA) MMP-3 (which can activate MMP-9) was detected in low concentrations in the CSF of 13 of 29 patients with neuroborreliosis, but not in controls. TIMP-1 was increased twofold in CSF samples from patients with neuroborreliosis in comparison with the controls. MMP-9 activity was induced in vitro in a mouse macrophage cell line (RAW 264.7) when stimulated with two different genospecies of B burgdorferi (B garinii, B afzelii ). This MMP-9 activity was reduced in a dose dependent manner when macrophages stimulated with B burgdorferi were coincubated with NF-kappaB SN50, a cell permeable peptide which inhibits the translocation of NF-kappaB into the nucleus of stimulated cells. The data show that (1) MMP-9 activity is present in the CSF of patients with neuroborreliosis, (2) macrophages stimulated with B burgdorferi are a possible source of MMP-9 increase, and (3) activation of NF-kappaB may play a part in the upregulation of MMP-9 by B burgdorferi.     

Devic's neuromyelitis optica. Presentation of 2 new cases and review of the bibliography

Devic's neuromyelitis optica is a clinical entity characterized by severe transverse myelitis, acute unilateral or bilateral optic neuropathy, no clinical involvement beyond the spinal cord or optic nerves and a monophasic or recurrent evolution. We report two cases, both female, affected by spinal cord and visual symptoms suggesting Devic's neuromyelitis. First patient, a 30 y.o. woman, was admitted due to acute flaccid tetraparesis preceded by left optic neuropathy five months before. CSF showed normal IgG level and no synthesis of oligoclonal bands. Brain and spinal cord MRI showed left optic neuropathy, signal hyperintensities at cervical and thoracic levels on the T2 weighted sequence, and diffuse enhancement after e.v. gadolinium DPTA. Second patient presented optical neuropathy at 19 years of age, transverse myelitis at 47 years of age, and a new cervical myelopathy two years later, at 49 y.o. Brain and spinal cord MRI showed bilateral optic atrophy and multiple hyperintensities among C1/C2 and C6/C7 levels, some of them cavitated. Pleocytosis, protein count of 511 mg/dl, presence of IgGs but negative oligoclonal bands was observed on CSF. In general, Devic's optic neuromyelitis has poor functional prognoses, recurrences may follow onset affecting spinal cord and optic nerves. In our two cases, we did not identify a specific cause despite all the diagnostic work-up.     

Pathogenetic role of myelitis for syringomyelia

BACKGROUND: CSF-flow obstruction is regarded as a mandatory factor for the development of syringomyelia. However, there are conditions in which syringomyelia is not associated with evident persistent CSF-flow obstruction, as in the case of inflammatory spinal cord lesions. In these instances we hypothesize that the accumulation of vasogenic edema may play a role in the development of the syrinx. Recently proposed theories underline, even in the event of CSF-flow obstructions, a major role for the accumulation and final coalescence of interstitial spinal fluid, rather than CSF penetration through the spinal cord. AIM: To clarify the relationship between syrinx development and spinal cord inflammation, through the analysis of the role of intrinsic medullary factors versus CSF-flow block. METHODS: A prospective case series including patients with transient syringomyelia associated with different examples of non-infectious myelitis: sarcoidosis, post-infectious transverse myelitis, Devic's disease and multiple sclerosis. Cavitations resulting from cystic myelomalacia were excluded. CSF-flow block was assessed by structural MRI. RESULTS: Syringes associated with myelitis shared some common features: they developed during the acute phase of myelitis and disappeared after steroids, were all non-communicating cavitations involving the central canal, and occurred in the same spinal segment affected by myelitis. CSF-flow obstruction was detected in one patient (Chiari I malformation), while in the other three patients we could not detect anatomical predispositions. CONCLUSION: Only one patient had structural abnormalities, though without evidence of a pathogenetic role in itself: however, CSF space obstruction and reduced CSF compliance could have accelerated the development of syringomyelia triggered by intramedullary inflammation. The clinical and radiological features in this patient are consistent with the label "presyringomyelia". The absence of any anatomical predisposition in the other patients suggests a major pathophysiological role for intrinsic medullary mechanisms, including blood-spinal cord barrier breakdown, impairment of extracellular fluid drainage, and leakage of subarachnoidal CSF into the nervous tissue.     

Non-compressive myelopathy: clinical and radiological study

Fifty seven patients (42 males and 15 females) with non-compressive myelopathy were studied from 1997 to 1999. Acute transverse myelitis (ATM) was the commonest (31) followed by Vit B12 deficiency myelopathy (8), primary progressive multiple sclerosis (5), hereditary spastic paraplegia (3), tropical spastic paraplegia (2), subacute necrotising myelitis (1), radiation myelitis (1), syphilitic myelitis (1) and herpes zoster myelitis (1). 4 cases remained unclassified. In the ATM group, mean age was 30.35 years, antecedent event was observed in 41.9% case, 25 cases had symmetrical involvement and most of the cases had severe deficit at onset. CSF study carried out in 23 patients of ATM revealed rise in proteins (mean 147.95mg%, range 20-1200 mg/dL) and pleocytosis (mean 20.78/cumm, range 0-200 mm3). Oligoclonal band (OCB) was present in 28% of cases of ATM. The most common abnormality detected was a multisegment hyperintense lesion on T2W images, that occupied the central area on cross section. In 6 patients hyperintense signal was eccentric in location. MRI was normal in 4 cases of ATM. Thus ATM is the leading cause of non-compressive myelopathy. Clinical features combined with MRI findings are helpful in defining the cause of ATM.     

Atypical transverse myelitis due to cytomegalovirus in an immunocompetent patient

Abstract Cytomegalovirus (CMV)-associated transverse myelitis is rare in immunocompetent patients. We report a 73-year-old man with no evidence of immune compromise, who developed acute transverse myelitis. Cerebrospinal fluid pleocytosis indicated central nervous system inflammation, and spinal MRI showed weak signal hypointensity in T1, hyperintensity in T2 and DP between C7 and T2, but no contrast enhancement. High CSF anti- CMV IgG index with normal CSF IgG index indicated intact blood-brain barrier, and supported the diagnosis of CMV-induced myelitis in an immunocompetent patient.     

Transverse myelitis in systemic sclerosis

BACKGROUND: Neurological involvement occurs rarely with systemic sclerosis (SSc). Only a few cases of transverse myelopathy have been reported in the setting of SSc. OBJECTIVE: To describe a patient with SSc who developed transverse myelitis that improved during a course of immunosuppression. RESULTS: A 30-year-old woman with SSc presented with subacute onset of bilateral lower extremity weakness and numbness. Results of magnetic resonance imaging and cerebrospinal fluid studies supported a diagnosis of transverse myelitis. The patient responded favorably to a course of corticosteroids and cyclophosphamide. No overlapping autoimmune disorders were evident. Clinical follow-up showed significant recovery, with resolution of radiological abnormalities. CONCLUSION: Transverse myelitis can occur as a rare manifestation of SSc and may respond favorably to immunosuppressive therapy.     

Astroglial and neuronal proteins in cerebrospinal fluid as markers of CNS involvement in Lyme neuroborreliosis

Is Lyme neuroborreliosis, even in its early phase, a parenchymatous disorder in the central nervous system (CNS), and not merely a meningitic process? We quantified cerebrospinal fluid (CSF) levels of four nerve and glial cell marker proteins in Lyme neuroborreliosis patients with pretreatment durations of 7–240 days. AH 23 patients had meningo-radiculitis, and six had objective signs of encephalopathy. Glial fibrillary acidic protein (GFAp) pretreatment levels in CSF, and the light subunit of neurofilament protein (NFL) levels were related to clinical outcome and declined significantly after treatment (P < 0.001 and P < 0.01, respectively). NFL was detectable in 11 out of 22 patients, and pre-and post-treatment NFL levels were associated with the duration of neurological symptoms within 100 days prior to treatment. Neuron-specific enolase (NSE) concentrations also decreased after therapy (P < 0.001), while CSF levels of glial S-100 protein remained unchanged. The pretreatment duration of disease was related to postinfectious sequelae. GFAp, NSE and NFL levels in CSF are unspecific indicators of astroglial and neuronal involvement in CNS disease. The findings in the present study are in agreement with the hypothesis that early and late stages of Lyme neuroborreliosis damage the CNS parenchyma.     

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.     

Brain magnetic resonance imaging findings in acute relapses of neuromyelitis optica spectrum disorders

We studied cranial magnetic resonance imaging (MRI) lesions in three women with acute attacks of recurrent longitudinally extensive transverse myelitis (r-LETM), recurrent-optic neuritis (r-ON) and r-LETM-CNS. Neuromyelitis Optica -immunoglobulin (IgG) antibody was positive in all cases. Brain MRI (1.5 Tesla) was performed according to protocol from consortium MS centre. We described the cranial lesions in brain MRI of acute relapses. These lesions were different from MS, most had an asymptomatic course which disappeared with time, protocol from consortium of MS centre criteria for brain MRI and seropositivity of NMO-IgG are useful tools for differentiate acute lesions of NMO/MS.     

Lymphocyte subset numbers in cerebrospinal fluid: comparison of tick-borne encephalitis and neuroborreliosis

OBJECTIVE: The aim of this study was to analyze lymphocyte subset numbers in cerebrospinal fluid (CSF) from patients with tick-borne encephalitis (TBE) and acute neuroborreliosis. METHODS: CSF lymphocyte subsets were enumerated in 42 TBE and nine neuroborreliosis patients using flow cytometry. RESULTS: The CSF numbers of CD4+, CD8+, HLA-DR+ and total-T lymphocytes, B lymphocytes, and NK cells were all greater in neuroborreliosis patients than in TBE patients. Neuroborreliosis patients showed positive correlation of CSF protein levels with the numbers of CD4+, HLA-DR+ and total-T lymphocytes. Also, the numbers of CSF B lymphocytes correlated positively with intrathecal Borrelia burgdorferi-specific IgG antibodies. Conversely, TBE patients demonstrated intrathecal protein levels that correlated positively with all investigated CSF lymphocyte subsets. CONCLUSION: These results suggest an intensive recruitment of lymphocyte subsets into the central nervous system (CNS) during acute neuroborreliosis, whereas TBE is characterized by a lower accumulation of lymphocyte subsets in the CSF.     

Can electromyography predict the prognosis of transverse myelitis?

The role of clinical and magnetic resonance imaging (MRI) features on the prognosis of acute transverse myelitis has been studied, but the role of electromyography (EMG) changes, although reported, has not been investigated. Seventeen patients with acute transverse myelitis were subjected to clinical evaluation, MRI scanning and concentric needle EMG. The outcome was defined on the basis of a 3-month Barthel Index (BI) score as good or poor. The EMG changes in these groups were compared. All of the patients had complete paraplegia (power grade 0), except 1 who had grade III power. Mild upper limb weakness was present in 6 patients. Joint position and vibration sense were impaired in the lower limbs, and a horizontal limit to sensory loss to pinprick was present in all of the patients. Spinal MRI was abnormal in 12 of 14 patients. EMG of the lower limb muscles in the acute stage (within 15–30 days of onset) revealed fibrillations or sharp waves or both in 11 patients. At 3-month follow-up, the lower limb power had improved in 8 and upper limbs in all 6 patients. The EMG changes also improved in 6 patients; fibrillations either disappeared or were markedly reduced. The motor unit potentials (MUPs) were of long duration, polyphasic with reduced recruitment. In 5 patients, however, no MUPs could be recorded and fibrillations persisted. Lower limb hypotonia and fibrillations on EMG were significantly related to the 3-month outcome. EMG evidence of denervation in the lower limb muscles in acute transverse myelitis suggests a poor outcome as assessed by 3-month Barthel index score. Received: 16 December 1998 Received in revised form: 3 April 1998 Accepted: 5 April 1998     

Concentration of interleukin-18, interleukin-1beta, soluble receptor for interleukin-1 (sIL-1RII) and C-reactive protein in patients with neuroborreliosis

BACKGROUND AND PURPOSE: The aim of the present study was to determine the role of interleukin-18 (IL-18), interleukin-1beta (IL-1beta) and its soluble receptor sIL-1RII in the pathogenesis of neuroborreliosis as well as the usefulness of C-reactive protein (CRP) determination in the diagnosis and monitoring of treatment of Lyme neuroborreliosis. MATERIAL AND METHODS: The study group consisted of 20 patients with Lyme meningitis (age range 16-72 years, mean age 42.6 years). For measurements of IL-18, IL-1beta and sIL-1RII levels in serum and cerebrospinal fluid (CSF) the control group consisted of 10 healthy volunteers and 10 patients with infection of the central nervous system ruled out, respectively. Cytokines and sIL-1RII levels in serum and CSF were measured twice, before and after the 30-day treatment period. Serum and CSF levels of IL-18, IL-1beta and sIL-1RII were measured using ELISA, and CRP serum levels were measured using the immunoturbidimetric method. RESULTS: Before the treatment the concentration of IL-18, IL-1beta and sIL-1RII in serum as well as in CSF was significantly higher as compared to the controls. After the treatment end the level of IL-18, IL-1beta and sIL-1RII was reduced but the serum level of sIL-1RII and CSF level of IL-18 and sIL-1RII remained significantly higher than in the control group. The serum level of CRP was increased only in 15% of patients and after the treatment CRP concentration returned to a basal level (except one patient in whom CRP was slightly higher than in the control group). No correlation between CRP and IL-18, IL-1beta and sIL-1RII was observed. CONCLUSIONS: Our results confirm the involvement of IL-18, IL-1beta and sIL-1RII in the pathogenesis of neuroborreliosis and uselessness of CRP determination in the diagnosis of Lyme meningitis.     

Neuromyelitis optica IgG status in acute partial transverse myelitis

BACKGROUND: Neuromyelitis optica (NMO) IgG is a specific marker for NMO. Furthermore, a high proportion of patients with longitudinally extensive transverse myelitis (characterized by spinal cord lesions extending 3 vertebral segments or more on magnetic resonance imaging) are seropositive for NMO-IgG and are considered to have a limited form of NMO. The NMO-IgG status in mild cases of acute partial transverse myelitis asociated with minimal magnetic resonance imaging abnormalities (spinal cord lesions <2 vertebral segments on magnetic resonance imaging) is unknown. OBJECTIVE: To investigate the NMO-IgG status of patients with acute partial transverse myelitis and a normal cerebral magnetic resonance image. DESIGN: Observational, retrospective consecutive case series with longitudinal follow-up. SETTING: Allegheny Multiple Sclerosis Treatment Center. PATIENTS: Three groups of patients were tested for NMO-IgG. Group 1 consisted of 22 patients with acute partial transverse myelitis, group 2 consisted of 4 patients with definite NMO (by 1999 criteria of Wingerchuk et al), and group 3 consisted of 6 patients with definite multiple sclerosis. MAIN OUTCOME MEASURE: NMO-IgG status. A commercially available assay for NMO antibodies was performed at the Mayo Clinic. Testing was performed during the convalescent stage of the illness. RESULTS: Of the 22 patients with acute partial transverse myelitis, only 1 was seropositive for NMO-IgG at presentation. This patient subsequently developed recurrent episodes of longitudinally extensive transverse myelitis that are typicaly seen in association with NMO-IgG. Three of the 4 patients meeting criteria for NMO were seropositive. None of the patients with multiple sclerosis had NMO-IgG detected. CONCLUSION: NMO-IgG is rarely encountered in patients with acute partial transverse myelitis, which is in sharp contrast to the high frequency of this antibody in patients with NMO and longitudinally extensive transverse myelitis.     

Acute severe spinal cord dysfunction in bacterial meningitis in adults: MRI findings suggest extensive myelitis

BACKGROUND: Bacterial meningitis is rarely complicated by acute spinal cord involvement (eg, myelitis, ischemic infarction, spinal abscess, or epidural hemorrhage). In spinal cord dysfunction, magnetic resonance imaging (MRI) is the imaging modality of choice. Still, MRI findings of myelitis due to bacterial meningitis in adults have not been reported. METHODS: Spinal MRIs were obtained during the acute stage of meningitis and on follow-up in 3 adults with bacterial meningitis that was complicated by paraparesis or tetraparesis and bowel and bladder incontinence. The causative pathogens were Streptococcus pneumoniae and Neisseria meningitidis; in 1 patient, the pathogen was not identified. RESULTS: In all cases, spinal MRI ruled out a compression of the cord by an extramedullary mass but demonstrated hyperintensities on T2-weighted images that predominantly involved the gray matter and extended from the cervical to the lumbar cord. Leptomeningeal and discrete nodular intramedullary enhancement on T1-weighted images was detected only in 1 patient. Follow-up examinations revealed that hyperintensities resolved completely in 1 patient, while a central cavitation developed in the cervical spinal cord of another, and the MRI findings were progressive during the first 4 weeks in the third patient. In all cases, severe paresis and bowel and bladder incontinence persisted. CONCLUSION: We demonstrate for the first time the MRI findings of adults with acute spinal cord involvement during bacterial meningitis. Magnetic resonance imaging showed central intramedullary hyperintensities on T2-weighted images that extended from the cervical to the lumbar cord, indicating myelitis. Clinical follow-up examinations suggest that myelitis during bacterial meningitis has an unfavorable prognosis.     

Diagnosis and treatment of CNS parasite infection with special reference to parasitic myelitis]

The occurrence of visceral larva migrans due to Ascaris suum (A. suum) and Toxocara canis (T. canis) has occasionally been reported in Japan, although parenchymatous involvement of the CNS is extremely rare in A. suum/T. canis visceral larvae migrans. Recently we experienced 7 cases with myelitis caused by visceral larva migrans due to A. suum/T. canis (parasite myelitis). The characteristics of this myelitis are: (1) sensory disturbances (Lhermitte's sign, paresthesia, and hypesthesia) are predominant symptoms, while severe motor weakness is rare, (2) spinal cord lesions on T2-weighted MRI show more extensive lesions compared with mild symptoms, (3) Gadolinium enhancement of spinal cord lesions are limited as compared with spinal cord lesions on T2-weighted MRI lesions, (4) Some cases show the presence of eosinophils in CSF, while others show Th2 deviation in CSF supernatant, and (5) Tests for anti-A. suum/T. canis IgG antibody are strongly positive in serum and CSF. Moreover, 6 percent of 108 consecutive cases with non-compression myelopathy presenting at the Department of Neurology at Kyushu University Hospital from January, 1998 to December, 2002 had parasitic myelitis. Myelitis from visceral larva migrans due to A. suum/T. canis might be overlooked because of its mild neurologic impairment without systemic symptoms, but should be considered as one of the differential diagnoses in non-compression myelopathy.     

Follow-up of antibiotically treated and untreated neuroborreliosis

Follow-up of 57 patients who suffered from antibiotically untreated acute, monophasic neuroborreliosis 5 to 27 years ago shows no significant difference in comparison with the follow-up of 66 patients who suffered from antibiotically treated acute, monophasic neuroborreliosis during the last 5 years. In both groups, the involution of clinical symptoms and the normalization of pathological CSF findings were nearly identical. We found no significant difference of sequelae between the groups. Following acute neuroborreliosis, neither the antibiotically untreated nor the antibiotically treated patients developed chronic neuroborreliosis. Only in rare cases of primary chronic neuroborreliosis with CNS involvement did we observe convincing effects of antibiotics, which were given mostly in combination with glucocorticosteroids.