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Neurological Complications of Lyme DiseaseSyed Rizvi, MD, andAmanda Diamond, MD

A tick-bite associated rash with laterneurological manifestations, including paralysis and meningitis, had been documented in Europe for several years beforeLyme arthritis was recognized in the1970s.1-4 The illness was later understoodto be part of a multisysrem disease causedby spirochetae and transmitted by Ixodesticks. 5. " Borrelia burgdorferi, althoughinitially thought to be a single species, hasbeen found to have several sub-species.These subgroups may be responsible forthe variation in clinical symptoms observedin different parts of the world.7

The pathophysiology of neuroborreliosis is difficult to demonstrate, butmimics other spirochetal infections. Infection is local with subsequent dissemination. During this time spirochete numbers are high. B. burgdorferi componentsthat induce cytokine production by Tand B cells produce immune activationand indirect cell damage. Central nervous system involvement is common andclinical syndromes tend to occur instages. 7

Lyme disease has been implicated ina variety of peripheral and central nervous system disorders. The neurologicalsyndromes are often accompanied bymore general complaints (arthralgias, fa-tigue, myalgias). Earlier neurologicalsymptoms, or those occurring during dissemination within weeks to months, tendto be more clinically obvious and developin an estimated 15% to 20% of patients.4Several late syndromes seem to follow amore insidious course. 8 For purposes ofsimplification, disorders of the peripheraland central nervous systems will be reviewed separately.NEUROBORRELIOSIS OF THEPERIPHERAL NERVOUS SYSTEM

The most common peripheral manifestations of Lyme disease are cranial neuropathies, peripheral neuropathies andradicultis. However, many other syndromes, including a "Guillian Barre-like"syndrome, motor neuron disease,axonopathies, brachial and lumbarplexopathies, mononeuropathy multiplexand even myositis have been described. 7MEDICINE & HEALTH/RHODE ISLAND

Radiculoneuropathy. Painful radicu

litis is one of the most common early neurologic symptoms of Lyme disease in Europe. Incidentally, it was also part of thesymptom-complex described in the firstpatient reported with the syndrome. 1 Usually occurring within the first weeks tomonths in the infection, theradiculoneutopathies of Lyme disease haveincluded motor, sensory and mixed symptoms. They are usually self-limited and maybe easily mistaken for nerve-impingementsyndromes, with segmental symptoms ofweakness, sensory or reflex changes.9 Thesymptoms may not occur in the region ofthe tick bit. Electrodiagnostic testing usually shows multifocal mild sensorimotor involvement.lO. 11

Cranial neuropathies. Involvement ofcranial nerves, particularly the seventhnerve, may be present in up to 50%-75%of all patients experiencing neurologicsyrnptoms.4 Multiple cranial nerves maybe involved simultaneously.9 Reports include symptoms of evety cranial nerve ex-cept the olfactory nerve. The facial nerveinvolvement is reported to be bilateral inup to one third of cases. I I Facial nervesymptoms may not affect taste or hearing,indicating that involvement may be outsidethe subarachnoid space. Additionally, CSFanalysis in isolated Lyme disease facial palsymay be normal. Complete recovery occursin 80-90% of patients within weeks tomonths.

"Guillain Barre-like" syndrome.Although rare, an acute and severe syndrome of diffuse polyneuropathy, including bifacial weakness, may mimic thesymptoms of Guillan Barre. A CSF lymphocytic pleocytosis and/or neurophysiologic testing may help differentiate between the syndromes.?

Peripheral neuropathy. Symptomsof peripheral neuropathies in patientswith Lyme disease tend to be primarilysensory, occurring in a stocking-glove fashion, although patchy paresthesias mayalso be noted. In some European patients, a dermatologic manifestation isoften associated with the neuropathy.Labeled acrodermatitis atrophicans, theskin becomes tissue-thin and discolored.

tThe same patients have been discoveredto develop an axonal neuropathy* in theaffecred limb. 9. In the case of chronicinfection, it has been estimated that onein four patients may have peripheralnerve involvement. These patients maypresent with mainly sensory symptoms.10, 11 '

NEUROBORRELIOSIS OF THECENTRAL NERVOUS SYSTEM

Meningitis. Although many syndromes involving the central nervous system remain controversial, several havebeen well-defined. Certainly, the earlyappearance of lymphocytic meningitisis well recognized. Mildly increasedCS F pressure with headache andpapiledema may occur. The lymphocytic pleocytosis usually includes tens tohundreds of lymphocytic cells per mL.A mild elevation of protein may also beseen, with CSF glucose usually remaining wirhin a normal range to minimallydecreased. 12 Th e 'typical' symptomsthat usually occur with 'aseptic' meningitis, such as photophobia, headacheand neck stiffness, are extremely variablewith Lyme meningitis. II , 12

Intracranial hypertension syndrome. A rare complication of Lyme disease resulting in headache and potentialpapilledema, this syndrome seems to beassociated more otten with children andadolescents. CSF abnormalities may occur. There does no t appear to be a correlation with female sex or obesity, as withpseudotumor cerebri. ll , 13

Encephalomyelitis. A chronicmanifestation of Lyme disease, encephalitis is rare in North American (nearly allcases have been reported in Europe). OnMRI there is evidence of parenchymalinvolvement. This can include hemispheric or brainstem abnormalities andis usually nonspecific, although maymimic ischemic patterns. 1l

Myelopathy. Patients may presentwith symptoms of transverse myelitis sothat Lyme disease should be consideredin the diagnosis of these patients. 11, 14Rarely, a transverse myelopathy may accompany Lyme radiculoneuritis. This

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typically occurs at the same level as radicu- lar involvement and may be preceededby a leptomeningitis. 12

Lyme encephalopathy. This may bethe most common late neurologic manifestation of Lyme disease. Patients expressdifficulties with concentration, sleep disturbance, emotional lability, memory andattention. I , I; , Ii, Despite studies including requirements for CSF abnormalitiesand SPECT imaging, the definitive diagnosis of Lyme encephalopathy remainselusive. i, In the consideration of acuteencephalopathy, one should note thatpersons with Lyme-induced cognitivechanges likely have a mild encephalitis;these patients should not be confusedwith mental status changes associatedwith systemic symptoms. I? Such patientsare likely to have objective findings onneuropsychiatric testing and such a diagnosis should only be made in the presence of appropriate findings after testing has been performed by a qualifiedprofessional. This is distinct from themore subjective symptoms patients oftenexperience for weeks to months following an episode of acute infection with B.burgdorferi (discussed below).

Post-Lyme disease. Several patientswho have had Lyme disease have beennoted to have other psychiatric and cognitive symptoms, such as fatigue, cognitive slowing and depression. These patients are sometimes diagnosed with postLyme disease. It is unlikely that thesesymptoms indicate persistem neurologicinfection, and studies have not shownthat antimicrobial therapy is helpful inthese patients. ISDIAGNOSIS OF NEUROLOGIC LYMEDISEASE

The crucial element for the consideration of neurologic Lyme disease is thepresence of an indicative neurologicsymptom. Laboratory data should becomplimentary and supportive of clinical findings. In evaluating response totherapy, the clinician must rememberthar many neurologic illnesses improvewith time, regardless of treatent. ? Unfortunately, sensitivity of culture in nervous system infections is Jow (only about10% in CSF in Lyme meningitis). Thesensitivity of PCR testing appears to below as well. Confirmation of the diagnosis, therefore, relies largely on serologic

testing. Spinal fluid can, however, betested for the presence of anti-B.burgdorferi antibodies.] 9

The American Academy of Neurology (AAN) guidelines for the diagnosisof neurologic Lyme disease include theconsideration of exposure to ticks in anendemic region, clinical abnormalitiesother than those affecting the nervoussystem (including cardiac, rheumatologicand dermatologic symptoms), and adequate laboratory support (proof of thepresence of B. burgdorferi or immunologic evidence of exposure) in additionto the causally-related neurologic diseaseor syndrome. 20

...prolonged coursesof antibiotics do notimprove outcomes

and are notrecommended.

Additionally, the US Centers forDisease Control and Prevention (CDC)has recommended a two-tier system to testfor anti-B. burgdorferi antibodies. Serologic testing starts with enzyme-linkedimmunosorbent assay (ELISA), withusually high sensitivity depending onacuity of infection and organ systems involved, and low specificity due to crossreacting antigens. 21 Seropositivity mayremain for years and can occur in up to10% of the asymptomatic population inendemic areas. The antibody may notbe detected within the first 2 to 6 weeksafter exposure, so retesting (or treatmentwithout testing in cases with Erythemamigricans) may be important in cases ofhigh clinical suspicion. Borderline orpositive results are then confirmed byWestern blot. IgM testing is recommended only acutely in disease, whenclinical history is limited to 1 to 2 months,and requires 2 of 3 possible bands (sensitivity 32%). Confirmatory testing ofIgGpresence requires 5 of 10 possible bands(sensitivity 83%). Given lower sensitivities, clinical judgment should in used inpatients with positive ELISA whom donot meet Western blot criteria. Also,positive Western blot performed withoutELISA may be deceptive and should notbe used. J9, 20, 21

Given the high incidence of B.burgdorferi antibody in the CSF of patients who are seropostive bu t withoutneuroborreliosis, other tests for the diagnosis of central nervous system diseasehave been evaluated. A recent study byBlanc, et.al. 22 suggested the use of ananti-Borrelia antibody index (AI). TheAI is the ratio of anti-Borrelia IgG inCSF to ami-Borrelia IgG in the serumand is considered positive if greater thanor equal to two. The study noted 74 patients wi th diagnoses of other neurologicdiseases all had positive CSF Lyme antibodies; only two of those patients had apositive AI (specificiry of97%). The sensitivity of positive AI was determined tobe 75%. Th e authors suggested the following criteria for diagnosis ofneuroborreliosis: presence of four of thefollowing five items. 1) no past historyof neuroborreliosis, 2) positive CSF antiBorrelia antibodies, 3) positive anti-Borrelia antibody index, 4) favorable outcome after specific antibiotic treatment,5) no other etiologic diagnosis. 22

Researchers have also described aB-cell-tropic chemokine, CXCLl3,which appears abnormally elevated inCS F of patients with Lymeneuroborreliosis. If confirmed, thiscytokine might serve as a marker to as-sist in the confirmation of the diagnosisof neuroborreliosis.21TREATMENT OF NEUROBORRELIOSIS

Although the general recommendation in the US is to use parenteral antibiotics whenever the nervous system isinvolved, there is considerable evidencein the European literature suggestingoral doxycycline (200-400mg/day) maybe equally effective in most patients. Atthe recommended doses it appears thatthe CSF concentrations of doxycyclineexceed minimum inhibitory concentration for most strains. Although there arestrain differences between United Statesand Europe, thete probably is not a significant difference in antimicrobial susceptibiliry. 24 Also, prolonged courses ofantibiotics do not improve outcomes andare not recommended. The duration ofparenteral treatmem suggested is 2 to 4weeks, with no data showing any definiteadvantage of prolonged treatment. 2j ,2 6Oral regimens are generally given for 30days.

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Table 1. Antimicrobial regimens for the treatment ofnervous system Lyme disease

MedicationOral regimens Adult dose Pediatric doseDoxycycl ine 100 (-200) mg BID Aged = 8 years:4 mg/kg/day in

2 divided doses;max 200mg/dose

Amoxicill in (when 500 mg TID 50 mg/kg/day indoxycycline 3 divided doses;contraindicated) max 500 mg/doseCefuroxime (when 500 mg BID 30 mg/kg/day indoxycycline 2 divided doses;contraindicated) max 500 mg/doseParenteral regimensCeftriaxone 2 9 IV daily 50-75 mg/kd/d insingle dose, max 2 9Cefotaxime 2 9 IV Q8H 150-200 mg/kg/day in3-4 divided doses;

max 6 g/dayPenicillin G 18-24 MU/day, 200-400,000 U/kg/day

divided doses Q4H divided Q4H, max 18-24MU/day

The AAN published practice parameters for the treatment of nervous sys-tem Lyme disease in March, 2007. It recommended:I) Parenteral penicillin, ceftriaxone,

and cefotaxime are probably safeand effective treatments for peripheral nervous system Lyme diseaseand for CNS Lyme disease with orwithout parenchymal involvement(Level B recommendation).

2) Oral doxycycline is probably a safeand effective treatment for peripheral nervous system Lyme diseaseand for CNS Lyme disease withoutparenchymal involvement (Level Brecommendation). Amoxicillin andcefuroxime axetil may provide alternatives bu t supporting data arelacking.

3) Prolonged courses of antibiotics donot improve the outcome of postLyme syndrome, are potentially as-sociated with adverse events, and aretherefore not recommended (LevelA recommendarion).Treatmenr regimens are listed I I I

Table I.

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Syed Rizvi, MD, is Director, RhodeIsland Hospital Multiple Scferosis Center,and Assistant Professor ofClinical Neurosciences. warren Alpert Medical School ofBrown University.

Amanda Diamond, MD, is a Neurology Fellow, Warren Alpert MedicalSchool of Brown UnilJersity.Disclosure of FinancialInterests

Syed Rizvi, MD, has no financialinterests to disclose.Amanda Diamond, MD . Consultant: Guidant, Teva, Berlex (Bayer),Genentech, Cordis.Discussion of drug used off-label or under investigation:

Doxycycline, amoxicillin, ceftriaxone,ceftriaxime and penicillin are nor FDAapproved for the treatment of Lyme disease, but all have been shown either effective or have evidence indicating efficacy.CORRESPONDENCE:Syed Rizvi, MD2 Dudley Street, suite 555Providence RI 02903Phone: (401) 444-3799e-mail: SRizvi@lifespan.org

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