Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 99

Nervous system Lyme disease JOHN J. HALPERIN* Department of Neurosciences, Overlook Medical Center, Summit, NJ, USA

HISTORY The term Lyme disease describes the clinical disorder attributable to infection with any of the Borrelia burgdorferi group of spirochetes, disorders transmitted exclusively by bites of infected hard-shelled Ixodes ticks. The name derives from the Connecticut town where a cluster of cases of what appeared to be juvenile rheumatoid arthritis led first, in 1975, to the recognition of a syndrome named Lyme arthritis (Steere et al., 1977), then to the recognition that this was actually a multisystem disease (Reik et al., 1979), and ultimately to the identification of the causative spirochete, Borrelia burgdorferi (Burgdorfer et al., 1982; Benach et al., 1983; Steere et al., 1983b). As so often happens when our understanding of a disease evolves from a syndromic definition to the use of newly available biologic markers, subsequent clarification of the true spectrum of disorders caused by this infection led to the recognition that the disease had in fact been present for decades, under a variety of other labels. In 1910, Afzelius first described the characteristic skin lesion now known as erythema migrans (Afzelius, 1910) – a lesion first reported in the US literature in 1970 (Scrimenti, 1970). In 1922, two French physicians (Garin and Bujadoux, 1922) described a retired French Foreign Legionnaire who, 3 weeks after a tick bite, developed a large erythematous rash accompanied initially by high fever, sciatica, and a diffuse, extremely painful multifocal neuropathy. He had a cerebrospinal fluid (CSF) pleocytosis and a slightly positive Wasserman test, and improved following treatment with arsenic and mercury. Although the authors confused this disorder with tick bite paralysis, they did assert that it was due to infection with a tick-borne nonsyphilitic spirochete – a truly remarkably prescient conclusion. In 1941, the German neurologist Bannwarth described a series of patients with the same syndrome, and

included the term “rheumatism” in the title, providing the first sense that joint symptoms were part of the syndrome (Bannwarth, 1941). By the mid 1950s, this primarily neurologic syndrome was well recognized in Europe, and was being treated with penicillin (Hollstrom, 1951). Although Lyme arthritis was first reported in the mid 1970s, clinical folklore in eastern Long Island, New York (an area now known to be highly endemic for Lyme disease), relates that in the 1950s many individuals were being diagnosed with “Montauk knee,” a relapsing remitting, nontraumatic large joint oligoarthritis that in retrospect almost certainly was Lyme arthritis. Following the recognition of Lyme arthritis in Connecticut, groups from both Long Island and Connecticut simultaneously reported identifying B. burgdorferi as the causative organism (Benach et al., 1983; Steere et al., 1983b). At the same time, Steere’s neurologic colleagues Lou Reik (Reik et al., 1979) and Andrew Pachner (Steere et al., 1983c) helped define the classic neurologic triad of Lyme disease, which was entirely congruous with the disorder first characterized by Garin and Bujadoux. The identification of the organism in the early 1980s has allowed improved diagnostics, better characterization of the illness, better therapeutics, and the development of animal models, all of which has permitted significant advances in our understanding of the biology of this infectious disease.

CLINICAL FINDINGS It is commonplace to hear the assertion that the range of clinical manifestations of Lyme disease is vast; this is a considerable overstatement. Clinical disease begins following the inoculation of B. burgdorferi spirochetes – something that occurs solely with bites of infected hard-shelled Ixodes ticks. These ticks typically attach for several days during which time they inject their

*Correspondence to: John J. Halperin, M.D., Chair, Department of Neurosciences, Overlook Medical Center, Summit NJ 07078, USA. Tel: þ1-908-522-3501, E-mail: [email protected]

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saliva, containing, among other substances, local anesthetics and anticoagulants to permit prolonged feeding. Spirochetes reside in the tick gut; the ingested host’s blood triggers their proliferation and migration throughout the tick, eventually reaching the salivary glands from which they can be injected into the host. With US strains of ticks and B. burgdorferi this process requires at least 24–48 hours (Piesman and Dolan, 2002); in Europe this period is more variable. Once spirochetes enter the host’s skin, they multiply and migrate centrifugally. The resulting inflammatory response causes a slowly enlarging erythroderm, known originally as erythema chronicum migrans (ECM) but now just as erythema migrans (EM). This can become many centimeters in diameter. Central areas can lose their erythema by the time the advancing edge becomes red, resulting in a targetoid appearance (Fig. 99.1). The characteristics that differentiate EM from, for example, allergic reactions to tick saliva, are the large size (EM is typically more than 5 cm in diameter), relatively asymptomatic nature (EM is not typically pruritic or painful), and expansion and growth over many days to weeks (allergic reactions typically subside in a day or two). In some patients (about 25% in the US (Steere et al., 1983a), somewhat fewer in Europe), early hematogenous dissemination of spirochetes can lead to multifocal EM, with each satellite EM representing a new nidus of spirochetes, again proliferating and migrating centrifugally. Spirochete dissemination is often accompanied by typical symptoms of a bacteremia: fever, headache, malaise, diffuse aches and pains. Although these symptoms are often referred to as “flu-like,” importantly they generally do not include respiratory or gastrointestinal symptoms. The disseminating spirochetes have distinct organotropisms (Bacon et al., 2008), in particular the nervous system is symptomatically seeded in 10–15% of patients (polymerase chain reaction-based studies suggest that more may be seeded (Keller et al., 1992; Luft et al., 1992) but the infection is presumably

Fig. 99.1. Erythema migrans on the left thigh of a 5-year-old.

controlled by the host’s immune response in many). About 1–2% of infected patients will develop cardiac involvement, typically conduction block. This can be high grade and patients may require a temporary pacemaker. However, this is almost always reversible. Joint involvement, typically manifest somewhat later in infection, occurs in about one-third of US patients, but fewer than 10% in Europe. This can include nonspecific arthralgias but most typically is manifest as a large joint, relapsing oligoarthritis, with one large joint (knee, hip, etc.) at a time spontaneously becoming red and swollen, resolving over several weeks, with subsequent involvement of the same or a different joint months later. Nervous system involvement, termed neuroborreliosis, may take a number of different forms. Patients most commonly develop all or part of the triad first described by Garin and Bujadoux. Early seeding of the meninges can lead to a local inflammatory response with lymphocytic meningitis. Symptoms of this are highly variable, ranging from patients with an asymptomatic pleocytosis incidentally found to accompany a cranial neuritis, to others with an identical pleocytosis with severe headache, neck stiffness, photo- and phonosensitivity, typical of aseptic meningitis (occurring in isolation in approximately 2% of patients). In children, some with meningitis develop raised intracranial pressure, developing a syndrome clinically indistinguishable from pseudotumor cerebri (Jacobson and Frens, 1989; Belman et al., 1993; Zemel, 2000). Most reported patients have had a CSF pleocytosis at the time of presentation; a few have not. Regardless of whether the raised intracranial pressure is due to meningitis or another mechanism, affected children are at risk of visual loss and require monitoring and management identical to that of others with pseudotumor (in addition to being treated for the causative infection). More frequent manifestations include cranial neuritis in up to 8–10%, and radiculoneuritis, reported to occur in about 3% of confirmed cases (Bacon et al., 2007). Of patients with cranial neuritis, the facial nerve is involved in up to 80%, and may be bilateral (simultaneously or sequentially) in about 25% of these (Stiernstedt et al., 1988). Involvement of other cranial nerves is less common but primarily involves nerves to the extraocular muscles, the trigeminal, and the acousticovestibular. Lower cranial nerve involvement has only been reported anecdotally; optic neuritis probably occurs but is extremely rare (Sibony et al., 2005). Radiculoneuritis is probably the most frequently misdiagnosed disorder. As first described by Garin and Bujadoux, pain is severe and neuropathic in character, while objective sensory findings are mild. Motor deficits are common. Pain and motor deficits are classically dermatomal, and are said to preferentially affect the limb

NERVOUS SYSTEM LYME DISEASE that was the site of the tick bite (Rupprecht et al., 2008). Other mononeuropathies and plexopathies occur as well; in fact, detailed neurophysiologic studies (Halperin et al., 1990c), and the few available histopathologic studies (Halperin et al., 1987; Vallat et al., 1987), suggest that all these patients actually have various manifestations of a mononeuropathy multiplex. Some patients with untreated disease of significant duration (rarely seen any more) can develop what appears to be a lengthdependent “stocking and glove” type neuropathy. Neurophysiologic studies in these individuals suggest that this is actually a confluent mononeuropathy multiplex (Halperin et al., 1990c), similar to that seen in a variety of vasculopathies. Although a few case reports and small series suggest an association with demyelinating neuropathies (Muley and Parry, 2009), reported cases are so infrequent as to be possible chance associations. There is now one informative animal model of nervous system Lyme disease – the rhesus macaque monkey (Philipp et al., 1993; Pachner et al., 1995). Notably virtually all experimentally infected monkeys develop a mononeuropathy multiplex (England et al., 1997). Despite the availability of this model, our understanding of the pathophysiology of neuroborreliosis remains quite limited. Intact spirochetes, their antigens, or even their DNA have never been demonstrated in peripheral nerve of patients or of experimentally infected animals. Limited observations in the rhesus model suggest possible infection in dorsal root ganglia (Cadavid et al., 2000), an observation that might explain the severe pain, but not the frequent motor concomitants. Central nervous system (CNS) involvement is much less common. Symptomatic isolated meningitis occurs in only 1–2% of confirmed cases. Years ago, when many patients went months or years without accurate diagnosis and appropriate treatment, rare patients developed inflammation and presumably infection in the brain and spinal cord. The European literature suggests that patients with Garin–Bujadoux–Bannwarth syndrome, with prominent radicular symptoms, often have spinal cord involvement at the involved level (Hansen and Lebech, 1992). Very rarely, patients were identified with inflammation in the brain (Ackermann et al., 1988; Halperin et al., 1988; Hansen and Lebech, 1992). This appeared to affect white matter more than gray both clinically and radiographically. Seizures were very rare; spasticity, ataxia, and other white matter tract signs were more typical. This disorder has largely disappeared, presumably as a result of better disease diagnosis and early treatment. However, it remains a theoretical possibility that gives rise to a great deal of concern. This encephalomyelitis was presumably caused by direct brain infection by spirochetes. Patients usually had evidence of a targeted immune response against

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the causative spirochetes within the central nervous system (Henriksson et al., 1986; Ackermann et al., 1988; Halperin et al., 1989), accompanied by typical evidence of CNS inflammation (CSF pleocytosis, increased protein, increased overall IgG synthesis, and even oligoclonal bands). Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans (Kalina et al., 2005) demonstrated contrast enhancing hypermetabolic areas (Fig. 99.2). The repeated observation that clinical, CSF, and imaging changes all resolve with antimicrobial therapy clearly indicates a necessary and sufficient role of active spirochetal infection in the maintenance of the process; yet, as in peripheral nerve, there has been little if any credible evidence of spirochetes in pathologic samples. This clinically rarely

Fig. 99.2. Imaging from a 28-year-old male with brainstem inflammation, strongly positive Lyme serology with intrathecal production of anti-B. burgdorferi antibodies, resolving after antimicrobial therapy (i.e., Lyme encephalomyelitis). (A) Fluid-attenuated inversion recovery MRI sequence. (B) PET scan. (Reproduced from Kalina et al., 2005, with permission; PET images courtesy of Ronald Van Heertum, M.D.)

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occurring disorder has not, to date, been identified in any animal model. One other early observation gave rise to tremendous subsequent controversy. In the 1980s, when there were still many patients whose active infection went undiagnosed and untreated for months or years, many infected individuals, symptomatic with arthritis or other manifestations of an ongoing inflammatory disorder, described difficulty with memory, mental focus, and cognitive processing (Halperin et al., 1988, 1990b; Logigian et al., 1990; Krupp et al., 1991). Early studies indicated that, although a very small number of such individuals had evidence of brain infection, the vast majority had a “toxic metabolic” encephalopathy, comparable to that seen in innumerable other systemic (extraneurologic) infections or inflammatory states (e.g., pneumonia, urinary tract infections, active rheumatoid arthritis, etc.). Some assumed that these symptoms had a high degree of specificity for Lyme disease, and in particular for nervous system involvement, and began diagnosing neuroborreliosis in individuals in whom there was no plausible evidence to support this assertion (Cameron et al., 2004). This incorrect attribution of these nonspecific symptoms to neuroborreliosis was then coupled with the not surprising observation that most of these individuals had negative Lyme blood tests and normal spinal fluid and failed to respond to conventional courses of antibiotics. Rejecting the simpler conclusion that the premise was incorrect, this then led to the assertion that testing was flawed and conventional treatment ineffective. This in turn resulted in the use – in patients without evidence of Lyme disease – of ever more prolonged and complex treatment regimens, all of which are illogical based on the biology of the organism, not to mention demonstrably unhelpful and often harmful. The mechanism of this encephalopathy remains unclear, as it does in other circumstances. In patients who develop it during infection there is evidence soluble neuroimmunomodulator molecules can diffuse across the blood–brain barrier, altering brain physiology without there being a brain infection or other potentially brain damaging process (Halperin and Heyes, 1992). The more challenging issue has been an entity labeled by some as “post Lyme disease syndrome” (Feder et al., 2007). As had been observed previously following other infections, there has been anecdotal evidence that some patients who receive usually curative courses of antibiotics will subsequently have – either persistent or newly developing – fatigue, malaise, and symptoms of cognitive slowing and memory difficulty. Although the mechanism of this disorder is unknown, several important observations bear on its pathophysiology. First, there is no biologically plausible evidence that this disorder responds in a meaningful fashion to additional

or prolonged antibiotic treatment. Second, this disorder appears to be extremely infrequent in that studies that attempted to study it have had tremendous difficulty recruiting sufficient numbers of patients (Krupp et al., 2003; Fallon et al., 2008). Third, in studies with control populations, it is not at all clear that these symptoms are any more common among individuals treated for Lyme disease than in controls (Skogman et al., 2008; Cerar et al., 2010). Finally, identical symptoms affect about one-third of the general population at any give time (Luo et al., 2005), significantly impacting quality of life in up to 2% (Luo et al., 2005), making it very challenging to determine if this syndrome is related to Lyme disease, or simply occurring in these individuals by chance. Disease manifestations are comparable in patients in the US and Europe, although the frequency of specific ones probably differs somewhat. Multifocal EM and arthritis are probably more common in US patients; painful radiculitis is said to be more common in Europe. All of these observations are subject to some ascertainment bias, given the historical perspective of this being considered a neurologic disease in Europe and a rheumatologic one in the US. Notably the responsible organisms do differ slightly. The broad group of spirochetes is now known as B. burgdorferi sensu lato with the sole strain found in the US referred to as B. burgdorferi sensu stricto. Although this strain is found in Europe, it is responsible for only a minority of European borreliosis. Most European infections are caused by B. garinii, which often causes neurologic disease, and B. afzelii, particularly likely to cause a number of cutaneous abnormalities. These strain differences could be responsible for somewhat different ranges of disease manifestations in the two geographically distinct populations, and could even cause differences in treatment responsiveness.

LABORATORY INVESTIGATIONS Laboratory support for the diagnosis of Lyme disease relies primarily on the demonstration of a serologic response to the causative organism. Unlike the related spirochete, Treponema pallidum, B. burgdorferi can be grown in culture. However, this is clinically impractical. The organism is very slow growing and requires special medium, BSK II, not typically available in clinical laboratories. Moreover sensitivity of culture is quite low in systemic disease – typically only about 10% in CSF in Lyme meningitis (Karlsson et al., 1990), even when enhanced by the use of polymerase chain reaction (PCR) (Keller et al., 1992), presumably because of the low number of organisms present in readily available fluids or tissues. The one exception to this is erythema

NERVOUS SYSTEM LYME DISEASE migrans, which, much like the syphilitic chancre, contains innumerable readily demonstrable spirochetes. However, EM is typically so characteristic that laboratory confirmation is unnecessary. Serologic testing for Lyme disease is much maligned but actually is both reliable and necessary to establish the diagnosis (CDC, 1995) in all but one circumstance, namely the first few weeks of disease (Nowakowski et al., 2001). As in all infections, it takes time – typically several weeks – for B cells to develop a measurable and specific antibody response. When patients present with erythema migrans, which typically develops within the first 30 days of infection, half or more may not yet have a measurable antibody titer (Aguero-Rosenfeld et al., 1996; Nowakowski et al., 2001). Occasionally patients can develop Lyme-related facial nerve palsy or meningitis before the antibody response is demonstrable (Halperin, 2003); in patients in whom this is a consideration, comparing acute and convalescent titers can be informative, just as with all other serologic testing. In the early years of serologic testing there was a concern that some patients might remain permanently seronegative (Dattwyler et al., 1988). These observations appear to have been based on shortcomings of early serologic techniques; this appears not to be an issue with current techniques. The current recommendation is to use a two-tier serologic technique (CDC, 1995), starting with an ELISA (enzyme linked immunosorbent assay) as a sensitive but somewhat nonspecific screening test, then proceeding to a Western blot in individuals with positive or borderline ELISAs (terms that are defined statistically). Western blots should generally not be performed in individuals in whom the ELISA is negative, as false-positives in this setting – in which low level background crossreactivity to B burgdorferi-specific epitopes can be misinterpreted as positivity – can be very misleading. Criteria for interpretation of Western blots have been developed based on statistical studies of large populations of patients with and without Lyme disease. Some epitopes that are relatively selective for B. burgdorferi are not included because these antibodies are so rarely present as to provide no discriminant value. Rather, specific combinations were identified (Table 99.1) that accurately predict which patients do or do not actually have infection. While some laboratories use their own criteria for interpretation, these have not been validated and cannot be relied upon for accurate diagnosis until or unless this is done. Western blots are usually performed for both IgM and IgG antibodies. As in all infections, the normal sequential antibody response is first, to produce comparatively nonspecific IgM antibodies, then within weeks refine the response switching to much more targeted

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Table 99.1 Western blot criteria for the serologic diagnosis of Lyme disease

Positive

IgM (2 of 3)

IgG (5 of 10)

24, 39, 41

18, 21, 28, 30, 39, 41, 45, 58, 66, 93

Only in first few weeks of disease (CDC, 1995.)

IgG antibodies. Because of this, IgM criteria are only useful in patients whose illness is of less than 3 to at most 6 weeks’ duration. Beyond this early window, IgM antibodies are far more likely to represent nonspecific crossreactivity and should not be considered diagnostic. When the central nervous system is involved, additional laboratory support for the diagnosis is available. As in any other bacterial CNS infection, there is almost always a CSF pleocytosis and elevated protein. As in neurosyphilis, CSF glucose is depressed minimally if at all. Also similar to neurosyphilis, B. burgdorferi stimulates a prominent B cell response in the CNS, often leading to an increased CSF IgG index or IgG synthesis rate, and even oligoclonal bands (the latter reported more often in Europe than the US). As in other CNS infections, this increased B cell response within the CNS can result in local synthesis of antibodies specific to B. burgdorferi. This can be assessed by measuring the proportion of CSF IgG that is specific to B. burgdorferi, comparing this to the proportion in the serum. This index of specific intrathecal antibody production – which can be performed by a capture assay, by appropriately diluting CSF and serum to match IgG concentrations and then performing conventional ELISAs, or by mathematical calculation – is highly specific but has a sensitivity that has been challenging to define (Henriksson et al., 1986; Halperin et al., 1989; Hansen et al., 1990; Steere et al., 1990). False-positives occur in just two settings: neurosyphilis and past neuroborreliosis. The first can generally be differentiated from neuroborreliosis by measuring reaginic antibodies such as the VDRL (Venereal Disease Research Laboratory), which is rarely if ever elevated in Lyme disease. The latter, which is not really a false-positive but rather an irrelevant one, can be more challenging. Longitudinal studies indicate that apparent intrathecal antibody production can persist up to a decade following successful treatment (Hansen and Lebech,

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1992; Hammers Berggren et al., 1993). This obviously makes this method unhelpful for judging treatment efficacy. However, as in other CNS infections, improvement and ultimately resolution of the CSF pleocytosis and protein elevation serve as reliable markers of disease resolution. Defining sensitivity is far more challenging due to the absence of an alternative “gold standard” marker of neuroborreliosis. Originally, European investigators required the demonstration of intrathecal synthesis of specific antibody to make the diagnosis, hence the sensitivity was, by definition, 100%. One small US study of patients with acute Lyme meningitis indicated a sensitivity of about 90% (Halperin et al., 1989). A subsequent US study with a more diverse group of patients, some of whom may not have had CNS infection, indicated sensitivity of about 50% (Steere et al., 1990). The issue remains unresolved. That notwithstanding, there is one subgroup of patients in whom sensitivity should be close to 100%. In individuals with active CNS inflammation (with or without parenchymal abnormalities on MRI scan), with increased overall IgG synthesis in the CSF and oligoclonal bands, if this inflammatory response is in response to a particular infection, logic would dictate that the bulk of the locally synthesized antibodies should be specific for the causative organism. Thus in those individuals with a multiple sclerosis (MS)like illness or otherwise prominent intrathecal IgG synthesis, measuring Lyme-specific intrathecal antibody production should be highly reliable. The one other obvious limitation is that if B. burgdorferi infection is limited to the peripheral nervous system, or does not affect the nervous system at all, there should be no expectation of abnormal antibody measures in the CSF.

NEUROIMAGING Neuroimaging is straightforward but, like so many other aspects of this disease, has been the subject of much debate that is only loosely rooted in reality. Central nervous system infection can, on very rare occasion, cause parenchymal inflammation of the brain or spinal cord. Like any other inflammatory CNS disease this can result in focal areas of increased T2 signal on MRI scans, with contrast enhancement and even bright signal on diffusion-weighted sequences (Halperin et al., 1989). The spirochete does appear to have an affinity for oligodendroglia (Garcia-Monco et al., 1989) so these abnormal areas are more likely to occur in white matter than gray. When active, these areas appear hypermetabolic on brain PET imaging (Kalina et al., 2005). Importantly, the presence of such abnormalities reflects the presence of an active infection and inflammatory

response within the CNS, and as such should almost invariably be accompanied by inflammatory CSF. Unfortunately, the prevalence of nonspecific white matter abnormalities on brain MRIs leads to frequent MRI reports suggesting the latter could be attributable to Lyme disease – a largely spurious suggestion. Most unfortunate has been the use of brain singlephoton emission computed tomography (SPECT) imaging. One carefully performed study used a sophisticated statistical analysis of quantitative brain SPECT scans in a well defined population of patients with Lyme disease and suggested that some might have areas of hypometabolism, of unclear etiology (Logigian et al., 1997). This has resulted in the use of qualitative SPECT, in which patchy metabolic changes are far too easy to infer incorrectly, to not only diagnose nervous system Lyme disease, but to serve as the primary basis for a diagnosis of Lyme disease in the absence of any other support for the diagnosis. This approach is both unfortunate and unsupported by any rigorous scientific evidence.

PATHOLOGYAND PATHOGENESIS Very few pathologic specimens have been studied. Peripheral nerve in both affected patients (Halperin et al., 1987; Vallat et al., 1987; Meier et al., 1989) and experimentally infected rhesus monkeys (England et al., 1997) typically demonstrates perivascular inflammatory infiltrates without vessel wall necrosis, with multifocal axonal changes, all suggestive of a mononeuropathy multiplex. Parenchymal brain involvement has not been demonstrated to date in any published animal studies. A few human biopsies have purported to show glial nodules or other nonspecific changes (Oksi et al., 1996; Bertrand et al., 1999). In neither human nor animal model material has there been compelling evidence of intact spirochetes, spirochetal antigens, or DNA. On the other hand, antimicrobial therapy is rapidly effective in reversing neuroborreliosis in virtually all instances. Thus the ongoing presence of viable spirochetes must be necessary. The prominent immune response appears to be out of proportion to the very small number of organisms demonstrable (a few in CSF and none in tissue); presumably this plays an important role in pathogenesis (Rupprecht et al., 2008, 2009). Yet the rapid resolution with antibiotics indicates that this immune response is not self-perpetuating and presumably not due to crossreacting epitopes (molecular mimicry). There is evidence that following entry of B. burgdorferi into the CNS, there is very rapid local production of CXCL13, a B cell attracting chemokine, presumably triggering local production of antibodies (Rupprecht et al., 2009). Other evidence points to local production of quinolinic acid within the CNS in response to infection (Halperin and Heyes,

NERVOUS SYSTEM LYME DISEASE 1992). This small molecule, produced in response to TNF-a and g-IFN can act at the NMDA receptor, presumably altering neuronal function or even being neurotoxic. The role of these or other mechanisms in the pathogenesis of this disease requires considerable additional clarification.

DIFFERENTIAL DIAGNOSIS As with any neurologic diagnosis, the clinical syndromes associated with neuroborreliosis suggest a range of possible disorders and are not diagnostic in and of themselves. If the three most distinctive manifestations of nervous system Lyme disease – lymphocytic meningitis, cranial neuritis, and radiculoneuritis – occur simultaneously in an individual with possible exposure in an endemic area, the diagnosis is highly probable. If, as usually occurs, only one or two elements are present, the diagnosis must be confirmed and other possibilities excluded. Lyme meningitis occurs in warm weather months and overlaps epidemiologically with enteroviral meningitis. Studies in children (Tuerlinckx et al., 2003, 2009; Shah et al., 2005) indicate that in Lyme meningitis symptoms evolve over days instead of hours (the latter more typical of enteroviral infection). Probably the best differentiator is if the patient develops a cranial neuropathy, something that occurs rarely, if ever, in viral meningitis. Although facial nerve palsies and other cranial neuropathies occur frequently in Lyme disease, a study in a highly endemic region indicated that even in the summer months, Lyme disease was responsible for no more than 25% of facial nerve palsies (Halperin et al., 1990a). The presence of multiple cranial neuropathies, particularly bilateral facial nerve palsies – or for that matter, a facial nerve palsy in a child – substantially increases the likelihood that the disorder is due to Lyme disease. Even in these circumstances though, other potential causes of cranial neuropathies need to be considered: in the appropriate context possibilities include bacterial meningitis, sarcoidosis, HIV infection, and even Guillain–Barre´ syndrome. Symptoms of Lyme radiculoneuropathy are generally indistinguishable from those of a mechanical radiculopathy. Clues that B. burgdorferi infection might be responsible include normal imaging studies of the responsible root, involvement of several myotomes clinically or by EMG, and presence of a CSF pleocytosis. In all instances B. burgdorferi antibodies should be evident in serum by two-tier testing, except that occasionally these disorders occur very early in infection, before the humoral response has developed sufficiently for antibody to be detectable. In such circumstances a follow-up sample in several weeks will typically be strongly positive. In all instances, possible exposure to Ixodes ticks in an area endemic for Lyme disease is

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essential as there are no other known means of transmission of infection. In patients with less characteristic presentations of neuroborreliosis, establishing the diagnosis can be more challenging. Again, plausible exposure in an appropriate geographic location at an appropriate time of year is a prerequisite. Patients suspected of having peripheral nervous system manifestations almost always have a mononeuropathy multiplex (Halperin et al., 1990c) demonstrable neurophysiologically. In such patients, confirmation of the infection with positive ELISA and Western blot, and exclusion of other common causes of vasculitis, generally is sufficient to establish the diagnosis. In the very rare patients with inflammatory parenchymal CNS disease, CSF examination is usually required. Although the overall sensitivity of measurement of intrathecal antibody production is still debated, in those patients with evidence of chronic CNS inflammation (i.e., increased IgG synthesis and/or oligoclonal bands in the CSF), if the immune stimulation is the result of a particular infection, the increased antibodies that are evident should be specific to the causative organism. In these patients, the diagnosis should only be considered definite if the production of specific anti-B. burgdorferi antibody is demonstrable in the CSF.

MANAGEMENT B. burgdorferi remains highly sensitive to commonly available antibiotics; no clinically relevant resistance has been demonstrated. Doxycycline, penicillin, and cefuroxime axetil (Table 99.2) remain the agents of choice for most disease (Wormser et al., 2006; Halperin et al., 2007). Severe disease can be treated with parenteral ceftriaxone, cefotaxime, or high-dose penicillin. Of these, ceftriaxone is usually the easiest to use, as its pharmacokinetics permit once a day dosing. When used either in higher than the conventional dose of 2 g/day, or for an extended period of time, it can lead to precipitates in the gall bladder; patients have required cholecystectomies. Optimal treatment of nervous system Lyme disease remains to be defined. No studies have specifically addressed parenchymal CNS disease so, by analogy to other CNS infections, this is conventionally treated parenterally. European studies have clearly shown that oral doxycycline is as effective as parenteral regimens in Lyme meningitis, cranial neuritis, and radiculitis (Halperin et al., 2007). Comparable studies have not been conducted in the US; given the difference in responsible strains of B. burgdorferi it is theoretically possible that parenteral treatment might be necessary. However, the organism differences are slight so this seems unlikely. It has long been debated whether CSF should be examined in patients thought to have Lyme disease-related

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Table 99.2 Nervous system Lyme disease: treatment recommendations{ Disorder

Adults

Children

Acute neuroborreliosis (meningitis, radiculitis, cranial neuritis)

Ceftriaxone{ 2 g/day IV; 2–4 weeks OR Cefotaxime 2 g q8/IV; 2–4 weeks OR Penicillin, 20–24 million units IV/day; 2–4 weeks OR Probably doxycycline* 100 mg PO b.i.d. to 4 times/day for 3–4 weeks Possible alternatives: Amoxicillin 500 mg PO t.i.d.; 21 days OR Cefuroxime axetil 500 mg PO b.i.d.; 21 days Ceftriaxone{ OR cefotaxime OR penicillin IV – as above Ceftriaxone{ OR cefotaxime IV – as above

50–75 mg/kg/day

Encephalomyelitis

Chronic or recurrent neuroborreliosis (e.g., treatment failure after 2 weeks of treatment)

150–200 mg/kg/day in 3–4 divided doses 300 000 units/kg/day

 8 years 1–2 mg/kg b.i.d.

50 mg/kg/day in three divided doses 30 mg/kg/day in 3–4 divided doses

(Reproduced from Halperin, 2010, by permission of the Journal of the Royal College of Physicians of Edinburgh.) *Doxycycline should not be used in pregnant women or children under the age of 8 years. { Ceftriaxone should not be used late in pregnancy. { Pediatric weight-based doses should never exceed the recommended adult dose. IV, intravenous; q, each; b.i.d., twice daily; PO, orally.

cranial neuropathies. This can certainly be helpful in assessing the extent of disease, and remains reasonable as long as the efficacy of oral doxycycline is unclear in US patients. However, if in fact these disorders are shown to be highly responsive to oral antibiotics, the information obtained from the lumbar puncture would become largely superfluous. Regardless of the regimen chosen, treatment should generally be for 2–4 weeks. While some advocate prolonged antibiotic treatment, particularly for individuals with chronic nonspecific symptoms that they attribute to Lyme disease, there are now multiple well performed trials that demonstrate that this not only provides no substantive or long-term benefit, but carries substantial risk of harm (Klempner et al., 2001; Krupp et al., 2003; Oksi et al., 2007; Fallon et al., 2008). Complications have been reported in up to 43% of patients (Krupp et al., 2003). In one study (Fallon et al., 2008) side-effects were sufficiently severe in 24% that these patients had to withdraw from the study, stop treatment, or be hospitalized. With rates such as this under the meticulously controlled circumstances of US National Institutes of Health (NIH)-funded clinical trials, one can only assume that standard clinical practice would carry even greater risk.

Finally, a potential role for corticosteroids has been debated in this disorder. There are studies suggesting that, used in conjunction with antibiotics, they can shorten the duration of radicular pain in Garin– Bujadoux–Bannwarth syndrome (Pfister et al., 1988). Given that steroids are now recommended to improve outcome in facial nerve palsy(Sullivan et al., 2007), it is not unreasonable to use them in conjunction with antibiotics in this setting as well. Early Lyme disease studies (before the infectious etiology was ascertained) using steroids in the absence of antibiotics clearly showed less favorable outcomes (Steere et al., 1983c). However, despite concerns based on anecdotal observations, most studies and guidelines suggest that using steroids adjunctively in combination with appropriate antibiotics does not worsen outcomes in any way.

CONCLUSION Lyme disease is a multisystem infectious disease caused by the tick-borne spirochete B. burgdorferi. The nervous system is involved in 10–15%, typically causing meningitis, cranial neuritis, radiculoneuritis, and mononeuropathy multiplex. Accurate diagnostic tools are readily available,

NERVOUS SYSTEM LYME DISEASE primarily based on measuring the antibody response in serum, CSF, or both. Standard antimicrobial regimens are well tolerated and highly effective. Prolonged antibiotic treatment adds no significant benefit but carries substantial risk.

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