Imaging in Lyme neuroborreliosis
Lyme neuroborreliosis (LNB) is a tick-borne spirochetal infection with a broad spectrum of imaging pathology. For individuals who live in or have travelled to areas where ticks reside, LNB should be considered among differential diagnoses when clinical manifestations from the nervous system occur. Radiculitis, meningitis and facial palsy are commonly encountered, while peripheral neuropathy, myelitis, meningoencephalitis and cerebral vasculitis are rarer manifestations of LNB. Cerebrospinal fluid (CSF) analysis and serology are key investigations in patient workup. The primary role of imaging is to rule out other reasons for the neurological symptoms. It is therefore important to know the diversity of possible imaging findings from the infection itself. There may be no imaging abnormality, or findings suggestive of neuritis, meningitis, myelitis, encephalitis or vasculitis. White matter lesions are not a prominent feature of LNB. Insight into LNB clinical presentation, laboratory test methods and spectrum of imaging pathology will aid in the multidisciplinary interaction that often is imperative to achieve an efficient patient workup and arrive at a correct diagnosis. This article can educate those engaged in imaging of the nervous system and serve as a comprehensive tool in clinical cases.
• Diagnostic criteria for LNB emphasise exclusion of an alternative cause to the clinical symptoms.
• MRI makes a crucial contribution in the diagnosis and follow-up of LNB.
• MRI may have normal findings, or show neuritis, meningitis, myelitis, encephalitis or vasculitis.
• White matter lesions are not a prominent feature of LNB.
KeywordsLyme neuroborreliosis MRI Neuritis Myelitis Encephalitis
American Academy of Neurology
Apparent diffusion coefficient
Cenhancement responsive to steroids
Central nervous system
European Federation of Neurological Societies
Fluid attenuated inversion recovery
Magnetic resonance imaging
Positron emission tomography
Single photon emission computed tomography
Lyme borreliosis is an infection with the spirochete Borrelia burgdorferi (Bb). It is transmitted through tick bites, and is the most common vector-borne disease in Europe and North America [1, 2]. Estimates of prevalence are 100-130 per 100,000 in Europe, and 20-100 cases per 100,000 people in the United States (US) . Involvement of the nervous system is reported to occur in 10-15% of patients with borreliosis .
Lyme neuroborreliosis (LNB) is an important differential diagnosis in patients with nonspecific nervous system MRI findings and possibility of previous exposure to tick bite. In this article, we explain the diagnostic criteria, summarise and discuss current knowledge of imaging and pathology in LNB and describe the imaging findings in a spectrum from the typical presentations (meningoradiculitis, cranial nerve involvement), to less common (myelitis, peripheral neuropathy) and rare disease courses (meningoencephalitis, vasculitis).
The clinical presentation of LNB can vary widely, partly due to the genetic differences in spirochetal strains. Individual variations in immunological response and the possibility of co-infections may also explain the wide spectrum of symptoms that can be encountered. The skin is primarily affected, and erythema migrans can be observed. About one third to half of patients with LNB recall a tick bite or a rash [7, 8]. The most common neurological manifestation of LNB in adults is the Bannwarth syndrome with painful radiculoneuritis and aseptic meningitis, the former is most prominent in Europe and the latter in North America . LNB with facial nerve palsy is commonly encountered in both continents. Rarer manifestations from the nervous system are meningoencephalitis, encephalomyelitis, cerebral vasculitis and peripheral neuropathy . LNB may rarely present to the ophthalmologist with optic neuropathies and papilledema due to raised intracranial pressure . The distinction between early and late LNB is made from duration of neurological symptoms of less or more than 6 months, and more than 95% of cases are classified as early disease . Most LNB patients respond well to antibiotic treatment, but some experience persistent complaints [11, 12]. A definition for post-Lyme disease syndrome has been suggested to include subjective symptoms of fatigue, cognitive symptoms and/or widespread musculoskeletal pain starting within 6 months after completed treatment . Post-Lyme disease syndrome is not discussed in this article.
EFNS diagnostic criteria for LNBa 
1) Neurological symptoms suggestive of LNB without other obvious reasons
2) Cerebrospinal fluid pleocytosisb
3) Intrathecal Bb antibody production
All three criteria fulfilled
Clinical criteria and one of two laboratory criteria fulfilled
A recent study with inoculation of Bb infection in the central nervous system (CNS) of rhesus macaques resulted in lymphocytic neuritis and ganglionitis, and neuronal degeneration and demyelination in the peripheral nervous system. In brainstem and medulla there were lesions with focal malacia and nerve fibre degeneration, and some subjects had myelitis with necrosis and degeneration . The experiment gave evidence that the nerve injuries are mainly due to immune mediated mechanisms. Human studies are limited, but have pointed mainly to axonal damage in LNB mononeuropathy and plexopathy [4, 17]. The myelitis seen in most LNB cases could be the inflammation of radiculoneuritis extending to the spinal cord, CNS parenchymal involvement is otherwise considered rare in LNB . Bb invasion into the human brain has been reported in four cases with biopsy from MRI enhancing lesions [18, 19, 20].
Imaging in Lyme neuroborreliosis
Early imaging reports, starting with Halperin et al. in 1988 and 1989, focused on non-specific white matter changes in Lyme encephalopathy, considered a late phase of LNB with mild cognitive deficits [21, 22]. These and six other studies published between 1990 and 2007 included 10-27 subjects, and white matter lesions were found in 15-63% of the patients [23, 24, 25, 26, 27, 28]. The diagnostic criteria in these reports varied, and for many cases would not fulfil the EFNS or AAN criteria of today. Sequence development and higher resolution of MRI have constantly evolved with increased sensitivity of this imaging method, and knowledge of age-related white matter changes has also changed throughout this time. Therefore, the claim that LNB causes non-specific white matter changes should be considered based on weak scientific evidence. In 2009 Agarwal and Sze reported imaging data in 66 patients with LNB. Seven patients, but also six out of the 50 healthy control subjects, had white matter lesions, and the result suggests that white matter lesions are not a feature of LNB. One patient had an enhancing parenchymal lesion and three had meningeal or cranial nerve enhancement . Numerous case reports demonstrate that LNB has a wide spectrum of imaging entities, including diffuse or tumour-like affection in brain or spinal cord [19, 20, 29, 30, 31, 32, 33, 34], meningeal and/or nerve enhancement [33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43], as well as vascular affection with stroke-like presentation [44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54] or haemorrhage [35, 55, 56]. Overlap of imaging findings between LNB and multiple sclerosis (MS) has been discussed [1, 57], but is understudied.
There is limited knowledge of structural and functional changes in LNB with quantitative MRI techniques. Three studies have reported structural changes, and no difference between the patients and controls was found [23, 27, 28]. However, these studies included a limited number of subjects and controls (n = 6-20), so they probably lacked power to show subtle changes. Functional studies have been conducted with PET [58, 59] and with SPECT [26, 60, 61, 62]. These studies reported regional hypoactivity and hypoperfusion, but were hampered by heterogeneous study populations with non-specific symptoms and included individuals with uncertain diagnoses. Larger, prospectively conducted case-control studies are needed to learn more about imaging abnormalities in LNB.
Non-specific imaging findings are a constant challenge to radiologists. Insight into clinical disease courses and laboratory test methods will aid in the multidisciplinary interaction that often is imperative to achieve an efficient patient workup and arrive at a correct diagnosis. This is especially true in LNB, where a wide spectrum of neurological, and sometimes general and cognitive symptoms can be encountered, as well as diverse imaging pathology from neuritis to meningitis, encephalitis and vasculitis. The primary role of imaging is to look for other causes to explain the clinical symptoms. This article can educate those engaged in imaging of the nervous system and serve as a comprehensive tool when LNB is in question.
Thanks to Christian G. Lund, Anne-Helene Moksness and Karen Herlofsson for conveying and discussing cases, Harald Reiso for management of the BorrSci project, and to the patients for permission to publish.
Research fellowship for Elisabeth S. Lindland, Anne Marit Solheim and Silje Andreassen is funded by the Norwegian Multiregional Health Authorities through the BorrSci project (Lyme borreliosis; a scientific approach to reduce diagnostic and therapeutic uncertainties, project 2015113). Postdoctoral fellowship for Åslaug R. Lorentzen is funded by the South-Eastern Norway Regional Health Authority (project 2013089).
Compliance with ethical standards
Conflict of interest
Mona K Beyer received minor grants or speaker’s fees from Biogen Idec, Merck and Novartis. Hanne F. Harbo received minor grants or speaker’s fees from Biogen, Sanofi Genzyme, Merck, Novartis and Teva. The other authors do not report any disclosures.
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