Infectious Diseases, 2015; 47: 1–6
REVIEW ARTICLE
Vasculitis and stroke due to Lyme neuroborreliosis – a review
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JOANNA ZAJKOWSKA1, ADAM GARKOWSKI1, ANNA MONIUSZKO1, PIOTR CZUPRYNA1, IWONA PTASZYŃSKA-SAROSIEK2, EUGENIUSZ TARASÓW3, ANDRZEJ USTYMOWICZ3, WOJCIECH ŁEBKOWSKI4 & SŁAWOMIR PANCEWICZ1 From the 1Department of Infectious Diseases and Neuroinfections, 2Department of Forensic Medicine, 3Department of Radiology, and 4Department of Neurosurgery, Medical University of Bialystok, Poland
Abstract Lyme neuroborreliosis (LNB) is a rare cause of vasculitis and stroke. It may manifest as subarachnoid hemorrhage, intracerebral hemorrhage, and most often ischemic stroke due to cerebral vasculitis. The vast majority of reported cases have been described by European authors. A high index of suspicion is required in patients who live or have traveled to areas with high prevalence of tick-borne diseases, and in the case of stroke-like symptoms of unknown cause in patients without cardiovascular risk factors. In this review, we also present four illustrative cases of vasculitis and stroke-like manifestations of LNB.
Keywords: Lyme neuroborreliosis, stroke, vasculitis, tick-borne disease
Introduction
History
Lyme neuroborreliosis (LNB) is a disease of the central nervous system (CNS) caused by the spirochete Borrelia burgdorferi sensu lato genospecies complex. B. burgdorferi sensu stricto is the main cause of Lyme borreliosis in the United States, whereas B. garinii and B. afzelii dominate in Europe. The aforementioned bacteria are transmitted by the bite of infected ticks (Ixodes ricinus, I. persulcatus, I. scapularis). Approximately 13% of patients with Lyme borreliosis developed neurologic manifestations, and this stage may occur in the absence of prior clinical symptoms. In Europe LNB usually manifests as Bannwarth’s syndrome including lymphocytic meningitis, cranial neuritis, and radiculoneuritis [1,2]. Stroke is one of the least common complications of B. burgdorferi infection and is rarely mentioned in medical articles about LNB. It may manifest as subarachnoid hemorrhage (SAH) [3], intracerebral hemorrhage (ICH) [4,5], and most often ischemic stroke due to cerebral vasculitis [6,7].
The first reported case of the ischemic stroke-like form of LNB was described by Uldry et al. in 1987 [8]. This was a 40-year-old woman who developed vasculitis with recurrent ischemic events during 3 years following a tick bite. Computed tomography (CT) revealed a bilateral hypodense area in the thalamus and in the right lenticular nucleus. Angiography showed severe segmental narrowing and segmental occlusion of cortical arterial vessels [8]. In the same year, Midgard and Hofstad reported a case of a 49-year-old patient who experienced sudden muscle weakness in both arms and dysphasia [9]. The symptoms resolved within 15 h and were interpreted as transient ischemic attack (TIA). CT of the brain showed infarction in the left capsula interna. Cerebral angiography showed multiple stenosis of small and large intracerebral arteries on both sides. The patient had a history of multiple tick bites and radicular pain. LNB was confirmed in laboratory studies. Other possible causes of stroke were excluded [9].
Correspondence: Adam Garkowski MD, Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Żurawia 14, Białystok 15-540, Poland. E-mail: [email protected] (Received 16 August 2014 ; accepted 27 August 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.961544
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As already stated, LNB can also lead to SAH and ICH, and so far five cases of hemorrhagic stroke and one case of uncomplicated aneurysm due to B. burgdorferi infection have been reported in the literature. All these patients fulfilled the diagnostic criteria for LNB. The first case of SAH was described by Chehrenama et al. in 1997. Magnetic resonance imaging (MRI) demonstrated diffuse pial enhancement along the entire cord surface and the focal spinal lesion [3]. Two other reported cases showed aneurysm-associated SAH, which were located in the internal carotid artery (ICA) and in the basilar artery. In the third case, the aneurysms located in the ICA did not rupture and underwent successful endovascular embolization [10]. In 2001, Seijo Martinez et al. reported the first documented case of ICH due to LNB [4]. The patient was a 48-year-old male with progressive spastic paraparesis lasting for months who presented acute headache, confusion, left-sided hemiparesis with sensory deficit, and homonymous hemianopsia. Cranial CT showed extensive right temporal lobe hemorrhage with subarachnoid invasion [4]. The second case of ICH was described by Scheid et al., where the patient complained of diffuse slowing of cognitive functions, and cerebral CT showed a right-sided atypical temporoparietal hemorrhage extending into the subarachnoid space [5].
Case definitions for LNB According to the current European Federation of Neurological Societies (EFNS) guidelines for establishing a definite diagnosis of LNB, three conditions should be fulfilled: neurological symptoms suggestive of LNB without other obvious reasons, cerebrospinal fluid (CSF) pleocytosis, and intrathecal synthesis of B. burgdorferi antibodies. If only two criteria are fulfilled, LNB is possible [11].
Epidemiology It seems that LNB is a very rare cause of vasculitis and stroke, and exact epidemiological data are unavailable because only a few cases have been reported so far. In the study by Hammers-Berggren et al., including 281 patients with a diagnosis of stroke, 8% of the patients were positive for B. burgdorferi infection, but only 1 of them had stroke-like symptoms due to LNB [12]. Oschmann et al. reported 4 cases of stroke due to LNB among 330 patients diagnosed with LNB [13]. In another study including 125 patients with LNB, none of the patients had stroke-like symptoms or vasculitis [2]. The vast majority of reported cases have been described by European authors. Only three cases have been
described by American authors, but one of these patients was infected with Borrelia in Europe and diagnosed in the USA. The higher frequency of LNB in Europe than in the United States is related to the presence of B. garinii, which is the most neurotropic genospecies of Borrelia [3,7,14,15].
Pathogenesis The few cases of stroke described in the literature suggest that there is a meningovascular form of infection with B. burgdorferi. Inflammatory vasculitis is a known pathologic manifestation of LNB, and is the result of perivascular and vascular lymphocytic infiltration within leptomeningeal and brain parenchymal arteries induced by infection with B. burgdorferi. The intima of the medium and small-sized leptomeningeal arteries shows significant fibroplastic thickening, narrowing the vascular lumen. Some vessels can be completely obstructed by organized thrombus [16,17]. These findings are similar to those occurring in other spirochetal disease, in the meningovascular form of neurosyphilis described by Heubner with inflammatory changes of the leptomeningeal arteries causing vascular stenosis and thrombosis with subsequent ischemic stroke [17,18]. In the study by Oksi et al., the presence of B. burgdorferi spirochetes and B. burgdorferi DNA was detected in the tissue from areas of the brain with inflammatory changes of affected patients [16].
Clinical symptoms Although stroke due to LNB is very rare, some clinical features must be taken into account in the differential diagnosis of brain stroke [19]. Most stroke patients with LNB are relatively young (in one study the mean age was 62 years) [15]. From several weeks to months before the stroke happens, the patients may suffer from headache, malaise, cranial neuritis, radiculoneuritis or meningitis, suggesting LNB [5,9,19–21]. History taking may reveal the past history of tick bites or erythema migrans (EM). However, the denial of the above symptoms should not exclude testing for B. burgdorferi infection. [15,19]. It should be emphasized that the observation that the LNB-associated vasculitis is more common in young people is probably due to the fact that in this group a more accurate differential diagnosis of stroke is performed than in elderly patients. Since B. burgdorferii-associated vasculitis can affect small and large vessels, causing ischemic or hemorrhagic complications, clinical symptoms are variable and nonspecific, and include acute hemiparesis, hemiplegia, hemisensory deficits, headache,
Stroke due to Lyme neuroborreliosis fatigue, changes in mental status, ataxia, aphasia, dysmetria, vertigo, and nystagmus [3–7,12,20,21]. The patients may also experience TIA; however, this is less common than a typical ischemic stroke [15,22].
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Neuroimaging CT or MRI reveal abnormalities in most cases; however, they are not specific in revealing changes associated with vasculitis. MRI usually shows multiple and bilateral ischemic lesions, and sometimes the evidence of meningeal enhancement, suggesting coexisting inflammatory disease of the CNS. Previous publications indicate a predilection for the posterior circulation. Angiography often reveals different degrees and location of segmental stenosis, often with post-stenotic dilatations. The most commonly affected vessels visible by angiography and transcranial Doppler are the basilar artery, posterior cerebral artery (PCA), and middle cerebral artery (MCA) [6,8,9,15,19–25]. Extracranial arteries, including the ICA and vertebral artery, can also be affected. A negative angiogram does not exclude the vasculitis, because the narrowing of the small vessels may be invisible, due to the fact that they are smaller than the resolution of angiography. Magnetic resonance angiography (MRA) and CT-angiography have limited sensitivity and are mainly able to detect changes of the larger intracranial vessels. The most appropriate technique for the diagnosis of vasculitis is conventional angiography, because compared with MRA it is able to disclose pathology in smaller vessels [10,13,26,27]. It should be emphasized that the abovementioned features can also be seen in patients with other CNS vasculitides, e.g. in infections caused by Treponema pallidum, Bartonella henselae, Mycobacterium tuberculosis, Varicellazoster virus, cytomegalovirus, and HIV, and in systemic vasculitides and connective tissue diseases [28,29].
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Pediatric patients with CNS manifestations (including vasculitis) should be treated with IV ceftriaxone (2 g daily) for 14 days [11]. However, a recent important study by Bremell and Dotevall shows that treatment with oral doxycycline has the same efficacy as IV ceftriaxone, irrespective of the severity of symptoms, including CNS vasculitis [30]. Some authors additionally used steroids [15,20,22,25]. In two reported cases, clinical improvement was observed only after the use of cyclophosphamide, despite prior treatment with ceftriaxone and prednisolone [31,32]. Several reports in the literature indicate that undiagnosed and untreated LNB may lead to recurrent cerebral ischemia [7,8,23,33]. Patients with stroke due to LNB require immediate antibiotic treatment because this condition is potentially lifethreatening; two fatal cases of cerebral vasculitis induced by LNB have been reported. In the first case, the patient died due to extensive basilar artery thrombosis [15]. The second patient was a 25-yearold male, who experienced an infarction in the territory of the left anterior cerebral artery (ACA) and extensive changes in the basilar artery and both MCAs; the ACA was occluded [24].
Conclusion Vasculitis and stroke are rare consequences of LNB, which should be considered in differential diagnosis, especially in areas with a high prevalence of tick-borne diseases, and in the case of stroke-like symptoms of unknown cause in patients without cardiovascular risk factors.
Illustrative cases Below we present four illustrative cases of patients who were hospitalized due to stroke-like manifestations of LNB in the Department of Infectious Diseases and Neuroinfections of the Medical University in Bialystok.
Management
Case 1
As in the cases described in the literature, appropriate antibiotic treatment results in the recovery of the patients, with regression of neurological deficits, improvements in the CSF examination findings, and no recurrence of cerebral ischemia [6,7,22,23]. According to the EFNS guidelines, adult patients with early LNB with CNS manifestations (including vasculitis), should be treated with intravenous (IV) ceftriaxone (2 g daily) for 14 days. Adult patients with late LNB with CNS manifestations should be treated with IV ceftriaxone (2 g daily) for 3 weeks.
A previously healthy 27-year-old female with a history of multiple tick bites (2 months before hospitalization), was admitted to the Department of Neurology, presenting with a sudden onset severe headache with dizziness, vomiting, and blurred vision. The physical examination showed double vision while looking to the right, horizontal nystagmus, anizokoria, a positive Romberg’s test, superficial sensory disturbance of the left side of the body, right-sided hemiparesis, bilateral Babinski’s sign, and atactic gait. CT of the brain did not reveal
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abnormalities. MRI of the brain revealed a lesion in the brainstem, initially assumed to be demyelination (Figure 1). CT-angiography detected segmental stenosis of the initial segment of the left ACA and the right PCA. Carotid artery color Doppler ultrasound was normal. The CSF examination revealed inflammatory features: pleocytosis – 63 cells/mm3, 91% lymphocytes; protein, 0.92 g/L. The patient had no risk factors for stroke. Transthoracic echocardiogram (TTE) and Holter monitor were normal. Three pulses of intravenous methylprednisolone were given because of suspected multiple sclerosis. However, the therapy was discontinued because it was poorly tolerated by the patient. Serum ELISA test showed positive high titers of B. burgdorferi antibodies (IgM, 41 Biomedica Borrelia units (BBU)/ml and IgG, 59 BBU/ml). CSF examination was performed again (pleocytosis – 62 cells/mm3, 94% lymphocytes; protein, 52.1 mg/dl) and intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. An immunoblot (Virotech, Rüsselsheim, Germany) analysis identified antibodies directed against immunodominant antigens (in both CSF and serum): IgM to VlsE and OspC, and IgG to VlsE, p83, and iv3(Crasp3). The patient’s history was negative for EM. The patient was treated with ceftriaxone for 21 days and was discharged with substantial neurological improvement. At the follow-up visit after 4 months, except for delayed closure of the right eyelid there were no neurological deficits.
contrast enhancement. Carotid duplex ultrasonography showed hard atherosclerotic plaques of carotid arteries with normal blood flow. TTE and Holter monitor were normal. The patient had complete resolution of paresis and was discharged in good general condition. LNB was not considered in the differential diagnosis. A month later, the patient was hospitalized for the third time. Examination showed bilateral hemiparesis, bilateral Babinski’s sign, and imbalance. CT and MRI of the brain showed multifocal cerebral ischemia in both hemispheres of the brain. This time he reported a tick bite about 7 months ago. Serum anti-B. burgdorferii IgM (11 BBU/ml) and IgG (78 BBU/ml) were positive (ELISA test). The patient was transferred to the Department of Infectious Diseases and Neuroinfections of the Medical University in Bialystok where the CSF examination showed: pleocytosis – 22 cells/mm3, 87% lymphocytes; protein, 0.584 g/L; glucose, 50 mg/dl. An immunoblot analysis (Microgen, Microgen, Neuried, Germany) identified antibodies directed against immunodominant antigens (in both CSF and serum): IgG to VlsE, iv1(BBA36), and iv2(BBO323). Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. The patient was treated with ceftriaxone for 21 days. After that, there was no recurrence of cerebral ischemia. Over several weeks, the patient showed gradual improvement of the hemiparesis. Case 3
Case 2 A 56-year-old man with a history of hypertension and smoking was hospitalized twice within 7 months in the Department of Neurology due to acute bilateral hemiparesis and imbalance. CT and MRI of the brain revealed multifocal cerebral ischemia in the white matter in both hemispheres, located in the subcortical and paraventricular regions. These changes were hyperintensity on T2 images on MRI without
Figure 1. MRI, T2-weighted image for case 1: hyperintense lesion in the brainstem, on the dorsal side of the medulla.
A 59-year-old female with a history of hypertension was admitted to the hospital due to imbalance with throwing to the left, short-term memory loss, spatial orientation disorder, psychomotor impairment, and left-sided hemiparesis. The patient reported a 2-week history of muscle weakness in the left limbs. Shortly after admission short-term memory loss and psychomotor retardation progressed and confabulation was observed. The patient experienced urinary incontinence. Transcranial Doppler (TCD) demonstrated low blood flow velocity in both the MCAs and in the vertebrobasilar system, as well as high blood flow velocity in the left ACA. CT and MRI of the brain showed multiple vascular changes in the thalamus and pons on the right side, as well as a few peripherally located changes in both cerebral hemispheres and around the brain ventricles. These lesions were hyperintense on T1-weighted images (Figure 2). MRA demonstrated narrowing of the right posterior communicating artery and irregular pattern of intracranial vessels. A cardiac source of embolism was excluded by TTE and Holter monitor. The CSF examination showed the
Stroke due to Lyme neuroborreliosis
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Figure 2. MRI, T2-weighted image for case 3: hyperintense lesion in the thalamus on the right side. Hyperintense areas around the lateral ventricles – chronic vascular changes (leukoaraiosis).
following features: pleocytosis – 23 cells/mm3, 68% lymphocytes; protein, 0.218 g/L. A diagnosis of LNB was confirmed by positive serologic findings of the serum (IgM, 65 BBU/ml and IgG, 27 BBU/ ml) and CSF for IgG on both ELISA and Western blot (Microgen), which showed bands to protein p100, VlsE, p41, p39, and OspC. Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. Therapy with ceftriaxone was initiated and a sudden and complete leftsided hemiparesis occurred after 2 days of this therapy. CSF analysis after a 21-day treatment with ceftriaxone revealed significant improvement, with cytosis of 3 cells/mm3 and protein concentration of 0.358 g/L. Case 4 A 65-year-old female was referred to the hospital with a 3-day history of peripheral bilateral facial nerve palsy and an incomplete left-sided hemiparesis, which occurred about 6 h before admission. A similar episode of transient left-sided hemiparesis had occurred 1 day before admission to hospital and resolved within 10 min. The patient had a history of hypertension. The hemiparesis, which was the reason for this hospitalization, remitted about 3 h after admission. CT of the brain showed no pathology. Duplex ultrasound of the neck showed hard atherosclerotic plaques of carotid arteries with normal blood flow. TTE, Holter monitor, and coagulation tests showed no abnormalities. The follow-up MRI revealed no pathology. The patient’s history was positive for recent tick bites (1 year before admission to hospital) but she could not recall having an EM at the time or a past history of meningitis or radiculitis. Serum ELISA test showed positive results for B. burgdorferi antibodies (IgM, 50 BBU/ml and IgG, 35 BBU/ml). The CSF examination before treatment revealed: pleocytosis – 112 cells/mm3, 81% lymphocytes; protein, 1.059 g/L; glucose, 62 mg/dl. An
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immunoblot test (Microgen) identified the following antigens of B. burgdorferi in the CSF and serum: OspC, VIsE, p39, p83, iv1(BBA36), iv2(BBO323), iv3(Crasp3), and iv4(pG). Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. The patient was treated with ceftriaxone for 21 days. At the patient’s discharge, the neurological recovery was good and slight persistence of facial nerve palsy was observed. At the follow-up visit after 2 months, there were no detectable symptoms except facial nerve palsy, slightly less than in the previous examination. CSF examination disclosed improvement in the CSF profile; there was residual pleocytosis (19 cells/mm3). The patient experienced no further cerebrovascular events.
Acknowledgements The authors would like to thank Mateusz Fórmanek (Poznań) for his help in translating this article. Declaration of interest: The authors have no disclosures or conflicts of interest.
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REVIEW ARTICLE
Vasculitis and stroke due to Lyme neuroborreliosis – a review
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JOANNA ZAJKOWSKA1, ADAM GARKOWSKI1, ANNA MONIUSZKO1, PIOTR CZUPRYNA1, IWONA PTASZYŃSKA-SAROSIEK2, EUGENIUSZ TARASÓW3, ANDRZEJ USTYMOWICZ3, WOJCIECH ŁEBKOWSKI4 & SŁAWOMIR PANCEWICZ1 From the 1Department of Infectious Diseases and Neuroinfections, 2Department of Forensic Medicine, 3Department of Radiology, and 4Department of Neurosurgery, Medical University of Bialystok, Poland
Abstract Lyme neuroborreliosis (LNB) is a rare cause of vasculitis and stroke. It may manifest as subarachnoid hemorrhage, intracerebral hemorrhage, and most often ischemic stroke due to cerebral vasculitis. The vast majority of reported cases have been described by European authors. A high index of suspicion is required in patients who live or have traveled to areas with high prevalence of tick-borne diseases, and in the case of stroke-like symptoms of unknown cause in patients without cardiovascular risk factors. In this review, we also present four illustrative cases of vasculitis and stroke-like manifestations of LNB.
Keywords: Lyme neuroborreliosis, stroke, vasculitis, tick-borne disease
Introduction
History
Lyme neuroborreliosis (LNB) is a disease of the central nervous system (CNS) caused by the spirochete Borrelia burgdorferi sensu lato genospecies complex. B. burgdorferi sensu stricto is the main cause of Lyme borreliosis in the United States, whereas B. garinii and B. afzelii dominate in Europe. The aforementioned bacteria are transmitted by the bite of infected ticks (Ixodes ricinus, I. persulcatus, I. scapularis). Approximately 13% of patients with Lyme borreliosis developed neurologic manifestations, and this stage may occur in the absence of prior clinical symptoms. In Europe LNB usually manifests as Bannwarth’s syndrome including lymphocytic meningitis, cranial neuritis, and radiculoneuritis [1,2]. Stroke is one of the least common complications of B. burgdorferi infection and is rarely mentioned in medical articles about LNB. It may manifest as subarachnoid hemorrhage (SAH) [3], intracerebral hemorrhage (ICH) [4,5], and most often ischemic stroke due to cerebral vasculitis [6,7].
The first reported case of the ischemic stroke-like form of LNB was described by Uldry et al. in 1987 [8]. This was a 40-year-old woman who developed vasculitis with recurrent ischemic events during 3 years following a tick bite. Computed tomography (CT) revealed a bilateral hypodense area in the thalamus and in the right lenticular nucleus. Angiography showed severe segmental narrowing and segmental occlusion of cortical arterial vessels [8]. In the same year, Midgard and Hofstad reported a case of a 49-year-old patient who experienced sudden muscle weakness in both arms and dysphasia [9]. The symptoms resolved within 15 h and were interpreted as transient ischemic attack (TIA). CT of the brain showed infarction in the left capsula interna. Cerebral angiography showed multiple stenosis of small and large intracerebral arteries on both sides. The patient had a history of multiple tick bites and radicular pain. LNB was confirmed in laboratory studies. Other possible causes of stroke were excluded [9].
Correspondence: Adam Garkowski MD, Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, Żurawia 14, Białystok 15-540, Poland. E-mail: [email protected] (Received 16 August 2014 ; accepted 27 August 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.961544
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As already stated, LNB can also lead to SAH and ICH, and so far five cases of hemorrhagic stroke and one case of uncomplicated aneurysm due to B. burgdorferi infection have been reported in the literature. All these patients fulfilled the diagnostic criteria for LNB. The first case of SAH was described by Chehrenama et al. in 1997. Magnetic resonance imaging (MRI) demonstrated diffuse pial enhancement along the entire cord surface and the focal spinal lesion [3]. Two other reported cases showed aneurysm-associated SAH, which were located in the internal carotid artery (ICA) and in the basilar artery. In the third case, the aneurysms located in the ICA did not rupture and underwent successful endovascular embolization [10]. In 2001, Seijo Martinez et al. reported the first documented case of ICH due to LNB [4]. The patient was a 48-year-old male with progressive spastic paraparesis lasting for months who presented acute headache, confusion, left-sided hemiparesis with sensory deficit, and homonymous hemianopsia. Cranial CT showed extensive right temporal lobe hemorrhage with subarachnoid invasion [4]. The second case of ICH was described by Scheid et al., where the patient complained of diffuse slowing of cognitive functions, and cerebral CT showed a right-sided atypical temporoparietal hemorrhage extending into the subarachnoid space [5].
Case definitions for LNB According to the current European Federation of Neurological Societies (EFNS) guidelines for establishing a definite diagnosis of LNB, three conditions should be fulfilled: neurological symptoms suggestive of LNB without other obvious reasons, cerebrospinal fluid (CSF) pleocytosis, and intrathecal synthesis of B. burgdorferi antibodies. If only two criteria are fulfilled, LNB is possible [11].
Epidemiology It seems that LNB is a very rare cause of vasculitis and stroke, and exact epidemiological data are unavailable because only a few cases have been reported so far. In the study by Hammers-Berggren et al., including 281 patients with a diagnosis of stroke, 8% of the patients were positive for B. burgdorferi infection, but only 1 of them had stroke-like symptoms due to LNB [12]. Oschmann et al. reported 4 cases of stroke due to LNB among 330 patients diagnosed with LNB [13]. In another study including 125 patients with LNB, none of the patients had stroke-like symptoms or vasculitis [2]. The vast majority of reported cases have been described by European authors. Only three cases have been
described by American authors, but one of these patients was infected with Borrelia in Europe and diagnosed in the USA. The higher frequency of LNB in Europe than in the United States is related to the presence of B. garinii, which is the most neurotropic genospecies of Borrelia [3,7,14,15].
Pathogenesis The few cases of stroke described in the literature suggest that there is a meningovascular form of infection with B. burgdorferi. Inflammatory vasculitis is a known pathologic manifestation of LNB, and is the result of perivascular and vascular lymphocytic infiltration within leptomeningeal and brain parenchymal arteries induced by infection with B. burgdorferi. The intima of the medium and small-sized leptomeningeal arteries shows significant fibroplastic thickening, narrowing the vascular lumen. Some vessels can be completely obstructed by organized thrombus [16,17]. These findings are similar to those occurring in other spirochetal disease, in the meningovascular form of neurosyphilis described by Heubner with inflammatory changes of the leptomeningeal arteries causing vascular stenosis and thrombosis with subsequent ischemic stroke [17,18]. In the study by Oksi et al., the presence of B. burgdorferi spirochetes and B. burgdorferi DNA was detected in the tissue from areas of the brain with inflammatory changes of affected patients [16].
Clinical symptoms Although stroke due to LNB is very rare, some clinical features must be taken into account in the differential diagnosis of brain stroke [19]. Most stroke patients with LNB are relatively young (in one study the mean age was 62 years) [15]. From several weeks to months before the stroke happens, the patients may suffer from headache, malaise, cranial neuritis, radiculoneuritis or meningitis, suggesting LNB [5,9,19–21]. History taking may reveal the past history of tick bites or erythema migrans (EM). However, the denial of the above symptoms should not exclude testing for B. burgdorferi infection. [15,19]. It should be emphasized that the observation that the LNB-associated vasculitis is more common in young people is probably due to the fact that in this group a more accurate differential diagnosis of stroke is performed than in elderly patients. Since B. burgdorferii-associated vasculitis can affect small and large vessels, causing ischemic or hemorrhagic complications, clinical symptoms are variable and nonspecific, and include acute hemiparesis, hemiplegia, hemisensory deficits, headache,
Stroke due to Lyme neuroborreliosis fatigue, changes in mental status, ataxia, aphasia, dysmetria, vertigo, and nystagmus [3–7,12,20,21]. The patients may also experience TIA; however, this is less common than a typical ischemic stroke [15,22].
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Neuroimaging CT or MRI reveal abnormalities in most cases; however, they are not specific in revealing changes associated with vasculitis. MRI usually shows multiple and bilateral ischemic lesions, and sometimes the evidence of meningeal enhancement, suggesting coexisting inflammatory disease of the CNS. Previous publications indicate a predilection for the posterior circulation. Angiography often reveals different degrees and location of segmental stenosis, often with post-stenotic dilatations. The most commonly affected vessels visible by angiography and transcranial Doppler are the basilar artery, posterior cerebral artery (PCA), and middle cerebral artery (MCA) [6,8,9,15,19–25]. Extracranial arteries, including the ICA and vertebral artery, can also be affected. A negative angiogram does not exclude the vasculitis, because the narrowing of the small vessels may be invisible, due to the fact that they are smaller than the resolution of angiography. Magnetic resonance angiography (MRA) and CT-angiography have limited sensitivity and are mainly able to detect changes of the larger intracranial vessels. The most appropriate technique for the diagnosis of vasculitis is conventional angiography, because compared with MRA it is able to disclose pathology in smaller vessels [10,13,26,27]. It should be emphasized that the abovementioned features can also be seen in patients with other CNS vasculitides, e.g. in infections caused by Treponema pallidum, Bartonella henselae, Mycobacterium tuberculosis, Varicellazoster virus, cytomegalovirus, and HIV, and in systemic vasculitides and connective tissue diseases [28,29].
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Pediatric patients with CNS manifestations (including vasculitis) should be treated with IV ceftriaxone (2 g daily) for 14 days [11]. However, a recent important study by Bremell and Dotevall shows that treatment with oral doxycycline has the same efficacy as IV ceftriaxone, irrespective of the severity of symptoms, including CNS vasculitis [30]. Some authors additionally used steroids [15,20,22,25]. In two reported cases, clinical improvement was observed only after the use of cyclophosphamide, despite prior treatment with ceftriaxone and prednisolone [31,32]. Several reports in the literature indicate that undiagnosed and untreated LNB may lead to recurrent cerebral ischemia [7,8,23,33]. Patients with stroke due to LNB require immediate antibiotic treatment because this condition is potentially lifethreatening; two fatal cases of cerebral vasculitis induced by LNB have been reported. In the first case, the patient died due to extensive basilar artery thrombosis [15]. The second patient was a 25-yearold male, who experienced an infarction in the territory of the left anterior cerebral artery (ACA) and extensive changes in the basilar artery and both MCAs; the ACA was occluded [24].
Conclusion Vasculitis and stroke are rare consequences of LNB, which should be considered in differential diagnosis, especially in areas with a high prevalence of tick-borne diseases, and in the case of stroke-like symptoms of unknown cause in patients without cardiovascular risk factors.
Illustrative cases Below we present four illustrative cases of patients who were hospitalized due to stroke-like manifestations of LNB in the Department of Infectious Diseases and Neuroinfections of the Medical University in Bialystok.
Management
Case 1
As in the cases described in the literature, appropriate antibiotic treatment results in the recovery of the patients, with regression of neurological deficits, improvements in the CSF examination findings, and no recurrence of cerebral ischemia [6,7,22,23]. According to the EFNS guidelines, adult patients with early LNB with CNS manifestations (including vasculitis), should be treated with intravenous (IV) ceftriaxone (2 g daily) for 14 days. Adult patients with late LNB with CNS manifestations should be treated with IV ceftriaxone (2 g daily) for 3 weeks.
A previously healthy 27-year-old female with a history of multiple tick bites (2 months before hospitalization), was admitted to the Department of Neurology, presenting with a sudden onset severe headache with dizziness, vomiting, and blurred vision. The physical examination showed double vision while looking to the right, horizontal nystagmus, anizokoria, a positive Romberg’s test, superficial sensory disturbance of the left side of the body, right-sided hemiparesis, bilateral Babinski’s sign, and atactic gait. CT of the brain did not reveal
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abnormalities. MRI of the brain revealed a lesion in the brainstem, initially assumed to be demyelination (Figure 1). CT-angiography detected segmental stenosis of the initial segment of the left ACA and the right PCA. Carotid artery color Doppler ultrasound was normal. The CSF examination revealed inflammatory features: pleocytosis – 63 cells/mm3, 91% lymphocytes; protein, 0.92 g/L. The patient had no risk factors for stroke. Transthoracic echocardiogram (TTE) and Holter monitor were normal. Three pulses of intravenous methylprednisolone were given because of suspected multiple sclerosis. However, the therapy was discontinued because it was poorly tolerated by the patient. Serum ELISA test showed positive high titers of B. burgdorferi antibodies (IgM, 41 Biomedica Borrelia units (BBU)/ml and IgG, 59 BBU/ml). CSF examination was performed again (pleocytosis – 62 cells/mm3, 94% lymphocytes; protein, 52.1 mg/dl) and intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. An immunoblot (Virotech, Rüsselsheim, Germany) analysis identified antibodies directed against immunodominant antigens (in both CSF and serum): IgM to VlsE and OspC, and IgG to VlsE, p83, and iv3(Crasp3). The patient’s history was negative for EM. The patient was treated with ceftriaxone for 21 days and was discharged with substantial neurological improvement. At the follow-up visit after 4 months, except for delayed closure of the right eyelid there were no neurological deficits.
contrast enhancement. Carotid duplex ultrasonography showed hard atherosclerotic plaques of carotid arteries with normal blood flow. TTE and Holter monitor were normal. The patient had complete resolution of paresis and was discharged in good general condition. LNB was not considered in the differential diagnosis. A month later, the patient was hospitalized for the third time. Examination showed bilateral hemiparesis, bilateral Babinski’s sign, and imbalance. CT and MRI of the brain showed multifocal cerebral ischemia in both hemispheres of the brain. This time he reported a tick bite about 7 months ago. Serum anti-B. burgdorferii IgM (11 BBU/ml) and IgG (78 BBU/ml) were positive (ELISA test). The patient was transferred to the Department of Infectious Diseases and Neuroinfections of the Medical University in Bialystok where the CSF examination showed: pleocytosis – 22 cells/mm3, 87% lymphocytes; protein, 0.584 g/L; glucose, 50 mg/dl. An immunoblot analysis (Microgen, Microgen, Neuried, Germany) identified antibodies directed against immunodominant antigens (in both CSF and serum): IgG to VlsE, iv1(BBA36), and iv2(BBO323). Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. The patient was treated with ceftriaxone for 21 days. After that, there was no recurrence of cerebral ischemia. Over several weeks, the patient showed gradual improvement of the hemiparesis. Case 3
Case 2 A 56-year-old man with a history of hypertension and smoking was hospitalized twice within 7 months in the Department of Neurology due to acute bilateral hemiparesis and imbalance. CT and MRI of the brain revealed multifocal cerebral ischemia in the white matter in both hemispheres, located in the subcortical and paraventricular regions. These changes were hyperintensity on T2 images on MRI without
Figure 1. MRI, T2-weighted image for case 1: hyperintense lesion in the brainstem, on the dorsal side of the medulla.
A 59-year-old female with a history of hypertension was admitted to the hospital due to imbalance with throwing to the left, short-term memory loss, spatial orientation disorder, psychomotor impairment, and left-sided hemiparesis. The patient reported a 2-week history of muscle weakness in the left limbs. Shortly after admission short-term memory loss and psychomotor retardation progressed and confabulation was observed. The patient experienced urinary incontinence. Transcranial Doppler (TCD) demonstrated low blood flow velocity in both the MCAs and in the vertebrobasilar system, as well as high blood flow velocity in the left ACA. CT and MRI of the brain showed multiple vascular changes in the thalamus and pons on the right side, as well as a few peripherally located changes in both cerebral hemispheres and around the brain ventricles. These lesions were hyperintense on T1-weighted images (Figure 2). MRA demonstrated narrowing of the right posterior communicating artery and irregular pattern of intracranial vessels. A cardiac source of embolism was excluded by TTE and Holter monitor. The CSF examination showed the
Stroke due to Lyme neuroborreliosis
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Figure 2. MRI, T2-weighted image for case 3: hyperintense lesion in the thalamus on the right side. Hyperintense areas around the lateral ventricles – chronic vascular changes (leukoaraiosis).
following features: pleocytosis – 23 cells/mm3, 68% lymphocytes; protein, 0.218 g/L. A diagnosis of LNB was confirmed by positive serologic findings of the serum (IgM, 65 BBU/ml and IgG, 27 BBU/ ml) and CSF for IgG on both ELISA and Western blot (Microgen), which showed bands to protein p100, VlsE, p41, p39, and OspC. Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. Therapy with ceftriaxone was initiated and a sudden and complete leftsided hemiparesis occurred after 2 days of this therapy. CSF analysis after a 21-day treatment with ceftriaxone revealed significant improvement, with cytosis of 3 cells/mm3 and protein concentration of 0.358 g/L. Case 4 A 65-year-old female was referred to the hospital with a 3-day history of peripheral bilateral facial nerve palsy and an incomplete left-sided hemiparesis, which occurred about 6 h before admission. A similar episode of transient left-sided hemiparesis had occurred 1 day before admission to hospital and resolved within 10 min. The patient had a history of hypertension. The hemiparesis, which was the reason for this hospitalization, remitted about 3 h after admission. CT of the brain showed no pathology. Duplex ultrasound of the neck showed hard atherosclerotic plaques of carotid arteries with normal blood flow. TTE, Holter monitor, and coagulation tests showed no abnormalities. The follow-up MRI revealed no pathology. The patient’s history was positive for recent tick bites (1 year before admission to hospital) but she could not recall having an EM at the time or a past history of meningitis or radiculitis. Serum ELISA test showed positive results for B. burgdorferi antibodies (IgM, 50 BBU/ml and IgG, 35 BBU/ml). The CSF examination before treatment revealed: pleocytosis – 112 cells/mm3, 81% lymphocytes; protein, 1.059 g/L; glucose, 62 mg/dl. An
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immunoblot test (Microgen) identified the following antigens of B. burgdorferi in the CSF and serum: OspC, VIsE, p39, p83, iv1(BBA36), iv2(BBO323), iv3(Crasp3), and iv4(pG). Intrathecal synthesis of B. burgdorferi antibodies was confirmed by a positive IgG antibody index. The patient was treated with ceftriaxone for 21 days. At the patient’s discharge, the neurological recovery was good and slight persistence of facial nerve palsy was observed. At the follow-up visit after 2 months, there were no detectable symptoms except facial nerve palsy, slightly less than in the previous examination. CSF examination disclosed improvement in the CSF profile; there was residual pleocytosis (19 cells/mm3). The patient experienced no further cerebrovascular events.
Acknowledgements The authors would like to thank Mateusz Fórmanek (Poznań) for his help in translating this article. Declaration of interest: The authors have no disclosures or conflicts of interest.
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