Lyme Neuroborreliosis¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 30, 2026 STATUS: Approved
DIAGNOSIS: Lyme Neuroborreliosis
ICD-10: A69.22 (Other neurologic disorders in Lyme disease)
CPT CODES: 86618 (Lyme ELISA or EIA (serum)), 86617 (Lyme Western blot IgM and IgG (serum)), 85025 (CBC with differential), 80053 (CMP (BMP + LFTs)), 85651 (ESR), 86140 (CRP), 82947 (Blood glucose (paired with CSF if LP performed)), 87389 (HIV 1/2 antigen/antibody (4th generation)), 86592 (RPR or VDRL (serum)), 84443 (TSH), 82607 (Vitamin B12 level), 86235 (ANA), 82164 (ACE level (serum)), 83036 (HbA1c), 87798 (Babesia smear and PCR), 86666 (Anaplasma phagocytophilum PCR or IgG), 86255 (Autoimmune encephalitis panel (serum + CSF)), 70553 (MRI brain with and without contrast), 70450 (CT head without contrast), 72156 (MRI spine (cervical/thoracic) with contrast), 93000 (ECG (12-lead)), 95816 (EEG (routine or continuous)), 95930 (Evoked potentials (VEP, BAEP, SSEP)), 93306 (Echocardiogram (TTE)), 89051 (Cell count with differential (tubes 1 and 4)), 84157 (Protein), 82945 (Glucose with paired serum glucose), 87483 (BioFire FilmArray ME Panel), 83916 (Oligoclonal bands, IgG index), 88104 (Cytology), 87116 (AFB smear and culture), 96365 (Ceftriaxone)
SYNONYMS: Lyme neuroborreliosis, neurologic Lyme disease, Lyme meningitis, Lyme cranial neuropathy, Bannwarth syndrome, Lyme radiculoneuropathy, Lyme encephalomyelitis, Borrelia burgdorferi CNS infection, nervous system borreliosis, neuro-Lyme, Lyme facial palsy, Lyme meningoradiculitis
SCOPE: Evaluation and management of nervous system involvement by Borrelia burgdorferi infection, including early neuroborreliosis (cranial neuropathy, lymphocytic meningitis, painful radiculopathy/Bannwarth syndrome) and late neuroborreliosis (encephalomyelitis, peripheral neuropathy, encephalopathy). Includes diagnosis with two-tier serologic testing and CSF analysis, treatment with IV ceftriaxone and oral doxycycline, and management of post-treatment Lyme disease syndrome (PTLDS). Excludes non-neurologic Lyme disease (erythema migrans, Lyme arthritis, Lyme carditis) unless as context for neurologic presentation.
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
═══════════════════════════════════════════════════════════════ SECTION A: ACTION ITEMS ═══════════════════════════════════════════════════════════════
1. LABORATORY WORKUP¶
1A. Essential/Core Labs¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Lyme ELISA or EIA (serum) (CPT 86618) | First-tier screening test in two-tier algorithm; sensitivity 70-100% depending on disease stage (lower in early infection <2 weeks); high sensitivity in disseminated/late disease | Positive or equivocal (proceed to Western blot); negative in very early infection does not exclude | STAT | STAT | ROUTINE | STAT |
| Lyme Western blot IgM and IgG (serum) (CPT 86617) | Second-tier confirmatory test; IgM positive if >=2 of 3 bands (23, 39, 41 kDa); IgG positive if >=5 of 10 bands; IgM only reliable within first 4 weeks of illness | IgM: >=2 of 3 bands (early disease). IgG: >=5 of 10 bands (disseminated/late disease). IgM alone unreliable after 4 weeks | STAT | STAT | ROUTINE | STAT |
| CBC with differential (CPT 85025) | Baseline; infection markers; rule out hematologic mimics; lymphocytosis may be present | Normal or mild lymphocytosis | STAT | STAT | ROUTINE | STAT |
| CMP (BMP + LFTs) (CPT 80053) | Renal function for antibiotic dosing; hepatic function (Lyme hepatitis may coexist); electrolytes | Normal; document baseline Cr and LFTs | STAT | STAT | ROUTINE | STAT |
| ESR (CPT 85651) | Inflammatory marker; often elevated in disseminated Lyme disease | May be mildly to moderately elevated | URGENT | ROUTINE | ROUTINE | ROUTINE |
| CRP (CPT 86140) | Inflammatory marker; baseline | May be mildly elevated | URGENT | ROUTINE | ROUTINE | ROUTINE |
| Blood glucose (paired with CSF if LP performed) (CPT 82947) | CSF:serum glucose ratio interpretation | Document paired with LP | STAT | STAT | - | STAT |
1B. Extended Workup (Second-line)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Lyme C6 antibody index (serum) (CPT 86618) | Modified two-tier testing (MTTT); some labs now use C6 ELISA as first or second tier; may improve sensitivity in early disease | Positive supports Borrelia infection | - | ROUTINE | ROUTINE | - |
| Coagulation panel (PT/INR, aPTT) (CPT 85610+85730) | Before lumbar puncture; coagulopathy workup | Normal | STAT | STAT | ROUTINE | - |
| HIV 1/2 antigen/antibody (4th generation) (CPT 87389) | Immunosuppression may alter Lyme disease presentation and serologic response; co-infection consideration in endemic areas | Negative | - | ROUTINE | ROUTINE | - |
| RPR or VDRL (serum) (CPT 86592) | Neurosyphilis in differential (cranial neuropathies, meningitis, radiculopathy); must be excluded | Non-reactive | URGENT | ROUTINE | ROUTINE | - |
| TSH (CPT 84443) | Thyroid dysfunction in differential for fatigue, cognitive complaints, and neuropathy | Normal | - | ROUTINE | ROUTINE | - |
| Vitamin B12 level (CPT 82607) | B12 deficiency neuropathy in differential for peripheral neuropathy presentation | Normal | - | ROUTINE | ROUTINE | - |
| ANA (CPT 86235) | SLE and other autoimmune conditions in differential for cranial neuropathies, meningitis | Negative | - | ROUTINE | ROUTINE | - |
| ACE level (serum) (CPT 82164) | Neurosarcoidosis in differential (cranial neuropathies, meningitis, radiculopathy) | Normal | - | ROUTINE | ROUTINE | - |
| HbA1c (CPT 83036) | Diabetic neuropathy in differential if peripheral neuropathy presentation | <5.7% (normal) | - | ROUTINE | ROUTINE | - |
| Babesia smear and PCR (CPT 87798) | Co-infection with Babesia microti common in endemic areas (Northeast US); affects clinical presentation and treatment | Negative | - | ROUTINE | ROUTINE | - |
| Anaplasma phagocytophilum PCR or IgG (CPT 86666) | Co-infection with Anaplasma (human granulocytic anaplasmosis) common in endemic areas; thrombocytopenia, leukopenia suggest co-infection | Negative | - | ROUTINE | ROUTINE | - |
| Ehrlichia chaffeensis antibody (CPT 86666) | Tick-borne co-infection screening in endemic areas | Negative | - | ROUTINE | ROUTINE | - |
1C. Rare/Specialized (Refractory or Atypical)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Borrelia PCR (CSF) (CPT 87798) | Low sensitivity (10-30%) but high specificity; may be useful in seronegative early disease or when serologic interpretation is unclear | Negative (positive confirms B. burgdorferi DNA in CNS) | - | EXT | EXT | - |
| Borrelia PCR (blood) (CPT 87798) | Transient spirochetemia; low sensitivity; rarely positive in disseminated disease | Negative (positive confirms active infection) | - | EXT | EXT | - |
| CSF CXCL13 (B-cell chemokine) | Emerging biomarker for active neuroborreliosis; elevated in acute neuroborreliosis; declines with treatment; may be useful for early diagnosis and treatment monitoring; not widely available | Elevated (>250 pg/mL suggests active neuroborreliosis) | - | EXT | EXT | - |
| Autoimmune encephalitis panel (serum + CSF) (CPT 86255) | Autoimmune encephalitis in differential if encephalopathy or psychiatric symptoms | Negative | - | EXT | EXT | - |
| Paraneoplastic antibody panel (serum) (CPT 86255) | If rapidly progressive neurologic syndrome with atypical features | Negative | - | EXT | EXT | - |
| Anti-ganglioside antibodies (GM1, GD1b, GQ1b) (CPT 86255) | GBS in differential if ascending weakness or cranial neuropathy pattern | Negative | - | EXT | EXT | - |
| Aquaporin-4 (NMO-IgG) and MOG antibody (CPT 86235) | If myelopathy or optic neuritis component raises concern for NMOSD | Negative | - | EXT | EXT | - |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI brain with and without contrast (CPT 70553) | Within 24-48h; STAT if altered mental status, focal deficits, or concern for encephalomyelitis | Cranial nerve enhancement (especially CN VII); leptomeningeal enhancement; white matter lesions (late neuroborreliosis); may be NORMAL in early neuroborreliosis with isolated cranial neuropathy or meningitis | Pacemaker, metallic implants | STAT | STAT | ROUTINE | STAT |
| CT head without contrast (CPT 70450) | Immediate in ED if acute neurologic presentation (altered consciousness, focal deficit, papilledema) to rule out mass/hemorrhage before LP | Usually normal; excludes mass lesion before LP | Pregnancy (relative) | STAT | STAT | - | STAT |
2B. Extended¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI spine (cervical/thoracic) with contrast (CPT 72156) | If myelopathy symptoms (weakness, sensory level, bladder dysfunction) suggesting Lyme myelitis | Spinal cord T2 hyperintensity; nerve root enhancement (radiculitis); meningeal enhancement | Same as MRI | - | ROUTINE | ROUTINE | URGENT |
| Nerve conduction studies / EMG (CPT 95907+95861) | If peripheral neuropathy or radiculopathy symptoms to characterize pattern and severity | Axonal polyneuropathy (late neuroborreliosis); radiculopathy pattern (early); mononeuritis multiplex (rare) | Anticoagulation (relative for EMG) | - | ROUTINE | ROUTINE | - |
| ECG (12-lead) (CPT 93000) | Screen for Lyme carditis (AV block) which may coexist with neuroborreliosis; baseline before ceftriaxone | PR prolongation or AV block (Lyme carditis); baseline QTc | None | URGENT | ROUTINE | ROUTINE | STAT |
2C. Rare/Specialized¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| EEG (routine or continuous) (CPT 95816) | If seizures, altered mental status, or encephalopathy | Focal or generalized slowing (encephalopathy); epileptiform discharges (rare in Lyme) | None significant | URGENT | URGENT | ROUTINE | URGENT |
| Evoked potentials (VEP, BAEP, SSEP) (CPT 95930) | If subclinical demyelination suspected (late neuroborreliosis); optic nerve or brainstem involvement | Prolonged latencies suggesting demyelination | None significant | - | ROUTINE | ROUTINE | - |
| Echocardiogram (TTE) (CPT 93306) | If PR prolongation or AV block on ECG (Lyme carditis workup) | Normal or valvular abnormalities; evaluate cardiac function | None significant | - | ROUTINE | ROUTINE | - |
LUMBAR PUNCTURE¶
Indication: ALL patients with suspected neuroborreliosis and CNS symptoms (meningitis, encephalopathy, myelopathy). Recommended for patients with cranial neuropathy (especially bilateral facial palsy) to distinguish CNS involvement from peripheral nerve disease. LP helps determine whether IV (vs. oral) antibiotics are needed. CSF pleocytosis with intrathecal antibody production is the diagnostic hallmark.
Timing: URGENT in ED/inpatient if meningitis, encephalopathy, or myelopathy suspected. ROUTINE for outpatient evaluation of isolated facial palsy or late neuroborreliosis symptoms.
Volume Required: 10-15 mL (standard diagnostic)
| Study | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Opening pressure | Rule out elevated ICP; usually normal or mildly elevated in Lyme meningitis | Normal or mildly elevated (10-20 cm H2O) | URGENT | ROUTINE | ROUTINE | - |
| Cell count with differential (tubes 1 and 4) (CPT 89051) | CSF lymphocytic pleocytosis is the hallmark of neuroborreliosis; typically 10-1000 WBC/uL (lymphocyte predominant); distinguishes from bacterial meningitis | WBC typically 10-1000 cells/uL (lymphocyte predominant >80%); plasma cells may be present (suggestive of Lyme) | STAT | ROUTINE | ROUTINE | - |
| Protein (CPT 84157) | Elevated in neuroborreliosis (50-300 mg/dL typically) | Elevated (>45 mg/dL); typically 50-300 mg/dL | STAT | ROUTINE | ROUTINE | - |
| Glucose with paired serum glucose (CPT 82945) | Usually normal in Lyme meningitis (distinguishes from bacterial and TB meningitis where glucose is low) | Normal (>60% serum glucose ratio); low glucose suggests bacterial or TB meningitis, NOT Lyme | STAT | ROUTINE | ROUTINE | - |
| Gram stain and bacterial culture (CPT 87205+87070) | Exclude bacterial meningitis in acute presentation | No organisms | STAT | ROUTINE | - | - |
| CSF Lyme antibody index (CPT 86618) | GOLD STANDARD for neuroborreliosis diagnosis; compares CSF:serum antibody ratio to determine intrathecal antibody production; elevated index confirms CNS infection (not just passive diffusion from serum) | Elevated CSF:serum antibody index (>1.0-1.3 depending on lab) confirms intrathecal antibody production = neuroborreliosis | STAT | ROUTINE | ROUTINE | - |
| CSF Lyme IgM and IgG antibodies (CPT 86618) | Detect Borrelia-specific antibodies in CSF; must be interpreted alongside serum antibodies (CSF:serum index); isolated CSF positivity without elevated index may represent passive diffusion | Positive CSF Lyme antibodies (interpret with antibody index) | STAT | ROUTINE | ROUTINE | - |
| BioFire FilmArray ME Panel (CPT 87483) | Rapid multiplex PCR to exclude viral and bacterial meningitis pathogens; does NOT detect Borrelia | Negative (excludes common viral/bacterial pathogens) | STAT | ROUTINE | - | - |
| Oligoclonal bands, IgG index (CPT 83916) | Intrathecal immunoglobulin synthesis; positive in neuroborreliosis; also positive in MS (differential) | Often positive (intrathecal IgG synthesis); not specific | - | ROUTINE | ROUTINE | - |
| VDRL (CSF) (CPT 86592) | Exclude neurosyphilis (chronic lymphocytic meningitis differential) | Non-reactive | STAT | ROUTINE | - | - |
| Cytology (CPT 88104) | Leptomeningeal malignancy in differential for chronic meningitis | Negative | - | ROUTINE | - | - |
| AFB smear and culture (CPT 87116) | TB meningitis in differential if chronic lymphocytic meningitis | Negative | - | ROUTINE | - | - |
Special Handling: CSF Lyme antibody index requires paired serum and CSF samples drawn at the same time for accurate calculation. Ensure lab receives BOTH specimens labeled appropriately. CSF Lyme PCR has low sensitivity; antibody index is preferred.
Contraindications to LP: Coagulopathy (INR >1.5, platelets <50K) -- correct first if possible. Mass lesion with midline shift (CT first). Signs of impending herniation.
Diagnostic Interpretation Guide:
| Serum Lyme Serology | CSF Pleocytosis | CSF Lyme Antibody Index | Interpretation |
|---|---|---|---|
| Positive (two-tier) | Yes (lymphocytic) | Elevated | Confirmed neuroborreliosis |
| Positive (two-tier) | Yes (lymphocytic) | Not elevated or not available | Probable neuroborreliosis (treat as neuroborreliosis in endemic area with compatible syndrome) |
| Positive (two-tier) | No | Not elevated | Seropositive but no active CNS infection; consider alternative diagnosis or prior exposure |
| Negative | Yes (lymphocytic) | N/A | Very early neuroborreliosis possible (seroconversion may take 2-6 weeks); repeat serologies in 2-4 weeks; consider other causes of meningitis |
| Negative | No | N/A | Neuroborreliosis unlikely |
3. TREATMENT¶
3A. Acute/Emergent¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Ceftriaxone (CPT 96365) | IV | First-line treatment for neuroborreliosis with CNS involvement (meningitis, encephalomyelitis, encephalopathy) and cranial neuropathy with CSF pleocytosis; also for Lyme radiculopathy with CSF abnormalities | 2 g daily :: IV :: daily :: 2 g IV once daily for 14-28 days (most experts recommend 14-21 days); infuse over 30-60 min; standard duration 14 days for most cases, 21-28 days for late neuroborreliosis or encephalomyelitis | Cephalosporin anaphylaxis; severe penicillin allergy (cross-reactivity ~1-2%); caution with biliary disease (ceftriaxone can cause biliary sludge/pseudolithiasis) | Renal function (BUN, Cr) weekly; CBC weekly; LFTs; monitor for C. difficile diarrhea; biliary symptoms; IV site assessment | STAT | STAT | ROUTINE | STAT |
| Doxycycline | PO | First-line for isolated facial palsy WITHOUT CSF pleocytosis or other evidence of CNS involvement; also acceptable for Lyme radiculopathy without meningitis in European practice; IDSA/AAN guidelines support oral doxycycline for cranial neuropathy without meningitis | 100 mg BID :: PO :: BID :: 100 mg PO BID for 14-21 days; take with full glass of water; remain upright 30 min after dosing to prevent esophageal ulceration | Pregnancy; children <8 years; severe hepatic impairment; concurrent retinoids; esophageal stricture | GI tolerance; photosensitivity counseling; LFTs if prolonged course | STAT | STAT | ROUTINE | - |
| Cefotaxime (alternative to ceftriaxone) | IV | Alternative parenteral beta-lactam for neuroborreliosis when ceftriaxone is contraindicated (biliary disease) or unavailable; equivalent CNS penetration | 2 g q8h :: IV :: q8h :: 2 g IV every 8 hours for 14-28 days | Cephalosporin anaphylaxis; severe penicillin allergy | Renal function; CBC; LFTs; C. difficile monitoring | STAT | STAT | - | STAT |
| Penicillin G (aqueous crystalline) | IV | Alternative parenteral antibiotic for neuroborreliosis; effective but less commonly used than ceftriaxone due to q4h dosing requirement; reserved for beta-lactam-tolerant patients when ceftriaxone unavailable | 18-24 million units/day :: IV :: divided q4h :: 3-4 million units IV q4h (total 18-24 million units/day) for 14-28 days | Penicillin anaphylaxis | Renal function; serum potassium (high-dose penicillin contains potassium); seizure risk at very high doses | STAT | STAT | - | STAT |
| Dexamethasone (if bacterial meningitis not excluded) | IV | Empiric adjunctive therapy if bacterial meningitis cannot yet be excluded pending culture results; give BEFORE or WITH first antibiotic dose; discontinue if Lyme meningitis confirmed (no role for steroids in Lyme meningitis) | 0.15 mg/kg q6h x 4 days :: IV :: q6h :: 0.15 mg/kg IV q6h for 4 days (discontinue if Lyme meningitis confirmed); administer before or with first antibiotic dose | Active untreated infection (relative); uncontrolled diabetes | Glucose; blood pressure; discontinue when Lyme confirmed | STAT | STAT | - | STAT |
3B. Symptomatic Treatments¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Ibuprofen | PO | Headache and pain management in Lyme meningitis; radicular pain | 400-600 mg q6-8h :: PO :: q6-8h :: 400-600 mg PO q6-8h as needed; max 2400 mg/day; take with food | Renal impairment; active GI bleed; aspirin-exacerbated respiratory disease; third trimester pregnancy | GI symptoms; renal function; blood pressure | STAT | ROUTINE | ROUTINE | - |
| Acetaminophen | PO/IV | Headache and pain management; fever reduction; alternative if NSAIDs contraindicated | 650-1000 mg q6h :: PO :: q6h :: 650-1000 mg PO/IV q6h; max 3 g/day (2 g/day if hepatic impairment) | Severe hepatic disease; active liver failure | LFTs; hepatic function | STAT | ROUTINE | ROUTINE | - |
| Gabapentin | PO | Neuropathic pain (Lyme radiculopathy; painful radiculoneuritis/Bannwarth syndrome; peripheral neuropathy) | 300 mg :: PO :: TID :: Start 300 mg qHS; titrate by 300 mg q1-3d to 300 mg TID; target 900-1800 mg/day divided TID; max 3600 mg/day; dose adjust for CrCl <60 | Severe renal impairment (dose adjust: CrCl <60) | Sedation; dizziness; edema; renal function | - | ROUTINE | ROUTINE | - |
| Pregabalin | PO | Neuropathic pain (Lyme radiculopathy; peripheral neuropathy); alternative to gabapentin | 75 mg :: PO :: BID :: Start 75 mg BID; may increase to 150 mg BID after 1 wk; max 300 mg BID (600 mg/day); dose adjust for renal impairment | Severe renal impairment (dose adjust); angioedema history | Sedation; weight gain; edema; renal function | - | ROUTINE | ROUTINE | - |
| Duloxetine | PO | Neuropathic pain (late Lyme peripheral neuropathy); concurrent depression | 30 mg :: PO :: daily :: Start 30 mg daily x 1 wk; increase to 60 mg daily; max 120 mg/day | Severe hepatic impairment; concurrent MAOIs; uncontrolled narrow-angle glaucoma | LFTs; blood pressure; serotonin syndrome symptoms | - | ROUTINE | ROUTINE | - |
| Amitriptyline | PO | Neuropathic pain (Lyme radiculopathy; chronic pain); may also help with insomnia | 10 mg :: PO :: qHS :: Start 10-25 mg qHS; titrate by 10-25 mg q1-2wk; target 50-75 mg qHS; max 150 mg/day | Cardiac conduction abnormality; recent MI; urinary retention; glaucoma; elderly (anticholinergic risk) | ECG if dose >100 mg/day; anticholinergic effects; sedation; weight | - | ROUTINE | ROUTINE | - |
| Prednisone (facial palsy adjunctive -- controversial) | PO | Short course for acute facial nerve palsy to reduce inflammation and improve recovery; evidence extrapolated from Bell's palsy data; NOT standard of care for Lyme facial palsy and NOT recommended by most experts; discuss with specialist | 60 mg :: PO :: daily x 5 days :: 60 mg daily x 5 days, then taper over 5 days; controversial in Lyme -- some experts avoid due to concern for impaired immune clearance of Borrelia; use ONLY with concurrent antibiotics | Active untreated infection without antibiotics; uncontrolled diabetes | Glucose; blood pressure; GI prophylaxis | - | ROUTINE | ROUTINE | - |
| Artificial tears (lubricant eye drops) | TOP | Eye protection for facial palsy (incomplete eye closure); prevents exposure keratopathy and corneal abrasion | 1-2 drops :: TOP :: q1-2h while awake :: Apply lubricant drops q1-2h while awake; use lubricant ointment at bedtime; tape eye closed at night if unable to fully close | None significant | Corneal integrity; refer ophthalmology if corneal exposure | STAT | ROUTINE | ROUTINE | - |
| Ondansetron | IV/PO | Nausea and vomiting associated with Lyme meningitis or vertigo | 4 mg q6-8h PRN :: IV :: PRN :: 4-8 mg IV/PO q6-8h as needed; max 24 mg/day | QT prolongation; severe hepatic impairment (max 8 mg/day) | QTc if risk factors | STAT | ROUTINE | ROUTINE | - |
| Meclizine | PO | Vertigo associated with cranial nerve VIII involvement (vestibulocochlear nerve) | 25 mg q6-8h PRN :: PO :: PRN :: 25 mg PO q6-8h as needed for vertigo; max 100 mg/day | Urinary retention; glaucoma | Sedation; anticholinergic effects | STAT | ROUTINE | ROUTINE | - |
3C. Second-line/Refractory¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Doxycycline (extended course for late neuroborreliosis) | PO | Late neuroborreliosis with encephalopathy or peripheral neuropathy; some European guidelines support oral doxycycline for all neuroborreliosis (including meningitis); may be used as step-down therapy after initial IV ceftriaxone | 100 mg :: PO :: BID :: 100 mg PO BID for 21-28 days (some European protocols use 200 mg BID); IDSA 2020 guidelines suggest oral doxycycline may be equivalent to IV ceftriaxone for neuroborreliosis | Pregnancy; children <8 years; severe hepatic impairment | LFTs; GI tolerance; photosensitivity counseling | - | ROUTINE | ROUTINE | - |
| Azithromycin (third-line alternative) | PO | Third-line alternative ONLY when both ceftriaxone and doxycycline are contraindicated; inferior CNS penetration; less well-studied for neuroborreliosis | 500 mg daily :: PO :: daily :: 500 mg PO daily for 14-21 days; limited evidence for CNS disease; use only if no other option | QT prolongation; hepatic impairment; concurrent QT-prolonging drugs | LFTs; QTc; GI tolerance; hearing (rare ototoxicity) | - | ROUTINE | ROUTINE | - |
| IV immunoglobulin (IVIG) (for severe Bannwarth syndrome -- rare) | IV | Severe, refractory painful radiculoneuritis (Bannwarth syndrome) not responding to antibiotics and analgesics; limited evidence; case reports only | 0.4 g/kg/day x 5 days :: IV :: daily x 5 days :: 0.4 g/kg/day IV for 5 days; infuse slowly starting at 0.5 mL/kg/h; premedicate with acetaminophen and diphenhydramine | IgA deficiency (anaphylaxis risk); renal impairment; hypercoagulability | Renal function; infusion reactions; CBC; consider IgA level before first dose | - | EXT | - | - |
| Carbamazepine | PO | Lancinating/paroxysmal neuropathic pain in Lyme radiculopathy (similar mechanism to trigeminal neuralgia pain) refractory to gabapentin/pregabalin | 100 mg :: PO :: BID :: Start 100 mg BID; titrate by 200 mg/day q1wk; target 400-800 mg/day divided BID; max 1200 mg/day | AV block; history of bone marrow suppression; concurrent MAOIs; HLA-B*1502 positive (Asian descent -- screen before starting) | CBC with differential q2wk x 2 months then q3 months; LFTs; sodium (SIADH); drug level (target 4-12 ug/mL) | - | ROUTINE | ROUTINE | - |
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Infectious disease consultation for treatment optimization, duration guidance, co-infection management, and complex diagnostic interpretation | URGENT | ROUTINE | ROUTINE | STAT |
| Neurology consultation for diagnosis confirmation, CSF interpretation, differentiation from MS and other neurologic mimics, and management of neurologic complications | STAT | STAT | ROUTINE | STAT |
| Ophthalmology evaluation for ALL patients with incomplete eye closure from facial palsy to assess corneal exposure risk and recommend eye protection strategy | URGENT | URGENT | ROUTINE | - |
| Audiology evaluation for patients with hearing loss, tinnitus, or vestibular symptoms (cranial nerve VIII involvement) for baseline audiometry | - | ROUTINE | ROUTINE | - |
| Physical therapy for gait training and balance rehabilitation if ataxia or weakness from myelopathy or peripheral neuropathy | - | ROUTINE | ROUTINE | - |
| Occupational therapy for ADL assessment and adaptive strategies for patients with hand weakness or fine motor deficits from peripheral neuropathy | - | ROUTINE | ROUTINE | - |
| Neuropsychology for formal cognitive testing if encephalopathy or cognitive complaints persist after antibiotic treatment to establish baseline and guide rehabilitation | - | ROUTINE | ROUTINE | - |
| Pain management referral for refractory neuropathic pain not responding to first-line and second-line analgesics | - | ROUTINE | ROUTINE | - |
| Cardiology consultation if ECG shows PR prolongation or AV block (Lyme carditis may coexist with neuroborreliosis and requires separate management) | URGENT | URGENT | ROUTINE | STAT |
| Social work for discharge planning, home health services coordination, and support resources for prolonged IV antibiotic therapy | - | ROUTINE | ROUTINE | - |
4B. Patient Instructions¶
| Recommendation | ED | HOSP | OPD |
|---|---|---|---|
| Return to ED if: worsening headache, new weakness, vision changes, difficulty breathing, chest pain (Lyme carditis), high fever, or worsening confusion (may indicate disease progression or alternative diagnosis) | STAT | STAT | ROUTINE |
| Complete the FULL course of antibiotics as prescribed (14-28 days); do NOT stop treatment early even if symptoms improve, as incomplete treatment may lead to persistent or late neurologic complications | - | ROUTINE | ROUTINE |
| Facial palsy from Lyme disease has an excellent prognosis; most patients recover fully within weeks to months with appropriate antibiotic treatment; tape affected eye closed at night and use lubricant drops to protect the cornea | STAT | ROUTINE | ROUTINE |
| Some symptoms (fatigue, pain, cognitive difficulty) may persist for weeks to months after completing antibiotics (post-treatment Lyme disease syndrome/PTLDS); this does NOT indicate ongoing infection and does NOT require additional antibiotics | - | ROUTINE | ROUTINE |
| Follow-up with neurology in 2-4 weeks after completing antibiotics for clinical reassessment; additional follow-up at 3 and 6 months to confirm resolution | - | ROUTINE | ROUTINE |
| Report any new neurologic symptoms (numbness, weakness, cognitive changes, hearing loss, visual changes) between follow-up visits as they may indicate treatment failure or alternative diagnosis | - | ROUTINE | ROUTINE |
| Tick prevention: use DEET-based repellent, wear long sleeves/pants in wooded areas, perform daily tick checks, shower within 2 hours of outdoor activity in endemic areas, and check pets for ticks | - | ROUTINE | ROUTINE |
| Remove attached ticks promptly with fine-tipped tweezers by grasping close to skin and pulling straight out; risk of Lyme transmission is low if tick is removed within 36 hours of attachment | - | ROUTINE | ROUTINE |
| Driving restrictions if significant cognitive impairment, seizures, or visual deficit until cleared by neurology | - | ROUTINE | ROUTINE |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD |
|---|---|---|---|
| Tick bite prevention in endemic areas (Northeast US, upper Midwest, Pacific Northwest): use permethrin-treated clothing, DEET or picaridin repellent, avoid tall grass/leaf litter during peak season (May-September) | - | ROUTINE | ROUTINE |
| Yard maintenance to reduce tick habitat: keep grass short, remove leaf litter, create gravel/wood chip barriers between lawn and wooded areas, consider professional tick treatment | - | - | ROUTINE |
| Pet tick prevention with veterinarian-recommended tick control products, as pets can carry ticks into the home environment | - | - | ROUTINE |
| Gradual return to physical activity as symptoms improve; rest during acute illness; avoid strenuous exercise until neurologic symptoms have stabilized | - | ROUTINE | ROUTINE |
| Adequate sleep and stress management to support immune recovery during and after treatment | - | ROUTINE | ROUTINE |
| Alcohol avoidance during antibiotic treatment (potential hepatotoxicity with doxycycline; general immune recovery support) | - | ROUTINE | ROUTINE |
| No reinfection immunity: prior Lyme disease does NOT prevent future infections; continue tick prevention measures indefinitely in endemic areas | - | ROUTINE | ROUTINE |
═══════════════════════════════════════════════════════════════ SECTION B: REFERENCE (Expand as Needed) ═══════════════════════════════════════════════════════════════
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| Bell's palsy (idiopathic facial nerve palsy) | Unilateral facial weakness without other neurologic findings; no tick exposure or erythema migrans; no meningeal symptoms; BILATERAL facial palsy strongly favors Lyme in endemic areas | Lyme serologies (two-tier); CSF analysis (pleocytosis favors Lyme); MRI brain |
| Viral meningitis (enterovirus, HSV-2, VZV) | Acute febrile illness with headache, neck stiffness; CSF lymphocytic pleocytosis; season (summer/fall for enterovirus); no tick exposure history | BioFire ME panel; viral CSF PCR; Lyme serologies; enterovirus typically has lower CSF protein than Lyme |
| Neurosyphilis | Cranial neuropathies; meningitis; CSF pleocytosis; may be clinically indistinguishable; different risk factors (sexual exposure vs. tick exposure) | RPR/VDRL; FTA-ABS; CSF VDRL; Lyme serologies; may coexist |
| Multiple sclerosis | Relapsing neurologic deficits; optic neuritis; myelopathy; white matter lesions; younger women; oligoclonal bands positive | MRI brain/spine (periventricular lesions, Dawson fingers); CSF oligoclonal bands; Lyme serologies (must exclude in endemic areas before MS diagnosis) |
| Neurosarcoidosis | Cranial neuropathies (CN VII common); chronic meningitis; granulomatous inflammation; systemic involvement (lungs, skin, eyes) | Chest CT (hilar adenopathy); serum/CSF ACE; biopsy; Lyme serologies negative |
| Guillain-Barre syndrome (GBS) | Ascending symmetric weakness; areflexia; cytoalbuminous dissociation (high protein, normal WBC); facial diplegia variant exists | CSF analysis (GBS: high protein, <5 WBC; Lyme meningitis: elevated WBC AND protein); NCS/EMG; anti-ganglioside antibodies; Lyme serologies |
| Tuberculous meningitis | Subacute chronic meningitis; basilar predominance; cranial neuropathies; very low CSF glucose; very high protein; exposure/travel history | AFB culture; TB PCR (GeneXpert); CSF ADA; chest X-ray; PPD/IGRA; Lyme CSF glucose is NORMAL |
| Sarcoidosis (facial nerve) | Bilateral facial palsy (like Lyme); uveoparotid fever (Heerfordt syndrome); erythema nodosum; no tick exposure | Chest imaging; ACE level; biopsy; Lyme serologies negative |
| Lymphomatous meningitis | Chronic meningitis; cranial neuropathies; constitutional symptoms; immunocompromised host | CSF cytology; flow cytometry; brain MRI with contrast; Lyme serologies negative |
| Autoimmune encephalitis | Subacute psychiatric symptoms; seizures; movement disorders; may present with encephalopathy similar to late neuroborreliosis | Autoimmune encephalitis panel (serum + CSF); MRI; EEG; Lyme serologies |
| West Nile virus neuroinvasive disease | Summer/fall; mosquito exposure; acute flaccid paralysis; meningoencephalitis; CSF pleocytosis | WNV IgM (serum and CSF); Lyme serologies; WNV PCR |
6. MONITORING PARAMETERS¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Neurologic exam (cranial nerves, motor, sensory, gait, mental status) | q8-12h inpatient; each outpatient visit | Stable or improving | If declining: reassess diagnosis; repeat imaging; repeat LP; consider treatment failure or alternative diagnosis | STAT | STAT | ROUTINE | STAT |
| Facial nerve function (House-Brackmann scale) | Daily inpatient; each outpatient visit for facial palsy patients | Progressive improvement; most recover within 1-2 months | If no improvement by 3 months: repeat Lyme serologies; consider EMG; ophthalmology for corneal protection; neurology reassessment | - | ROUTINE | ROUTINE | - |
| Temperature | q4-8h inpatient | Afebrile; fever resolves within 48-72h of antibiotics | Persistent fever >48h: reassess diagnosis; evaluate for co-infection (Babesia, Anaplasma); blood cultures | STAT | ROUTINE | - | STAT |
| ECG (PR interval) | Admission and daily if PR prolonged; repeat if palpitations or syncope | PR <300 ms; no high-degree AV block | If PR >300 ms or Mobitz II/complete heart block: cardiology STAT; temporary pacemaker may be needed; IV ceftriaxone continues | URGENT | ROUTINE | ROUTINE | STAT |
| Serum Lyme serologies (follow-up) | 4-6 weeks after treatment; 3 and 6 months | Declining antibody titers over time (IgM resolves; IgG may persist for years) | Persistent IgG is common and does NOT indicate treatment failure; clinical improvement is the primary measure of treatment response | - | - | ROUTINE | - |
| Renal function (BUN, Cr) | Baseline, then weekly during IV antibiotics | Stable; CrCl >60 | Dose adjust antibiotics if renal function declines | - | ROUTINE | ROUTINE | ROUTINE |
| Hepatic function (LFTs) | Baseline, then weekly during doxycycline; at completion of therapy | Normal | If transaminases >3x ULN: consider switching antibiotic; evaluate for hepatotoxicity | - | ROUTINE | ROUTINE | - |
| CBC | Baseline, then weekly during antibiotic therapy | Normal | Leukopenia/thrombocytopenia may suggest co-infection (Anaplasma/Ehrlichia); C. difficile if diarrhea | - | ROUTINE | ROUTINE | ROUTINE |
| Pain scores (VAS or NRS) | Each visit; daily inpatient if neuropathic pain | Decreasing pain scores | Escalate analgesic therapy per Section 3B; consider pain management referral | STAT | ROUTINE | ROUTINE | ROUTINE |
| Cognitive function (if encephalopathy) | Baseline and at follow-up visits; formal testing at 3-6 months if persistent | Improvement; return to baseline | If persistent cognitive deficits >6 months after treatment: neuropsychology evaluation; consider PTLDS; supportive care | - | ROUTINE | ROUTINE | ROUTINE |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Discharge home with oral antibiotics | Isolated facial palsy WITHOUT CSF pleocytosis; normal mental status; no meningeal signs; able to take oral medications; reliable follow-up arranged; Lyme serologies sent or positive |
| Discharge home with IV antibiotics (OPAT) | Neurologically stable after initial inpatient treatment; PICC line placed; home infusion services arranged; reliable patient with follow-up arranged; no complications of IV therapy |
| Admit to floor | Confirmed or suspected neuroborreliosis with meningitis, encephalopathy, or myelopathy requiring IV antibiotics; bilateral facial palsy (warrants LP and IV treatment); significant radicular pain requiring parenteral pain management; new Lyme carditis with PR prolongation requiring monitoring |
| Admit to ICU | Lyme carditis with high-degree AV block requiring temporary pacemaker; severe encephalopathy with altered consciousness (GCS <13); respiratory compromise from myelopathy or ascending weakness; status epilepticus (rare) |
| Transfer to higher level | Need for temporary pacemaker not available at current facility; need for neurology/infectious disease consultation not available; MRI not available for suspected myelopathy |
| Outpatient management | Late neuroborreliosis with peripheral neuropathy or mild encephalopathy; follow-up after completed inpatient treatment; PTLDS management; oral doxycycline for isolated facial palsy |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| IV ceftriaxone 2g daily x 14-28 days for neuroborreliosis with CNS involvement | Class I, Level A | Halperin et al. Neurology 2007 (AAN Practice Parameter); Wormser et al. CID 2006 (IDSA Guidelines) |
| Oral doxycycline 100 mg BID adequate for isolated facial palsy without CSF abnormalities | Class I, Level B | Halperin et al. Neurology 2007; Ljøstad et al. Eur J Neurol 2008 |
| Oral doxycycline non-inferior to IV ceftriaxone for European neuroborreliosis | Class I, Level A | Ljøstad et al. Eur J Neurol 2008; Karlsson et al. Neurology 1994 |
| Two-tier serologic testing (ELISA then Western blot) is standard for Lyme diagnosis | Class I, Level A | CDC MMWR 2019; Moore et al. CID 2016 |
| CSF Lyme antibody index (intrathecal antibody production) confirms neuroborreliosis | Class I, Level B | Halperin et al. Neurology 2007; Blanc et al. CID 2007 |
| CSF pleocytosis (lymphocytic) is the hallmark of active neuroborreliosis | Class I, Level B | Halperin JJ. Handb Clin Neurol 2014 |
| Bilateral facial palsy in endemic area should prompt Lyme testing (present in ~25% of Lyme facial palsy cases) | Class IIa, Level B | Halperin et al. Neurology 2007; Clark et al. Pediatrics 1985 |
| Prolonged antibiotic courses (>28 days) provide no additional benefit for post-treatment Lyme disease syndrome (PTLDS) | Class I, Level A | Klempner et al. NEJM 2001; Krupp et al. Neurology 2003; Berende et al. NEJM 2016 |
| Co-infection with Babesia and Anaplasma should be considered in endemic areas as it affects clinical presentation and treatment | Class IIa, Level B | Wormser et al. CID 2006 |
| Lyme carditis with high-degree AV block may require temporary pacemaker; IV ceftriaxone is treatment | Class IIa, Level B | Fishe et al. Am J Emerg Med 2015; Wormser et al. CID 2006 |
| Facial palsy from Lyme disease has excellent prognosis; >95% recover fully with appropriate antibiotics | Class I, Level B | Halperin et al. Neurology 2007; Bagger-Sjöbäck et al. Otol Neurotol 2005 |
| Modified two-tier testing (MTTT) with two EIA tests improves early sensitivity over standard two-tier | Class IIa, Level B | Branda et al. CID 2011 |
| CXCL13 in CSF is an emerging biomarker for active neuroborreliosis | Class IIb, Level B | Rupprecht et al. Neurology 2005 |
| Lyme disease serology (IgG) may remain positive for years after successful treatment; clinical improvement is the primary outcome measure | Class I, Level B | Wormser et al. CID 2006 |
| AAN/IDSA 2020 updated guidelines for prevention, diagnosis, and treatment of Lyme disease | Class I, Level A | Lantos et al. CID 2021 (IDSA/AAN/ACR Guidelines) |
CHANGE LOG¶
v1.1 (January 30, 2026) - Fixed section dividers to Unicode format per style guide - Added ICU setting coverage across all applicable sections (labs, imaging, treatments, referrals, monitoring) - Updated frontmatter setting field to include ICU - Fixed structured dosing format for gabapentin, pregabalin, duloxetine, amitriptyline, carbamazepine, prednisone, artificial tears (standardized to dose :: route :: frequency :: instructions) - Corrected doxycycline extended course dosing to standard 100 mg BID (200 mg BID noted as European alternative) - Added ICU coverage for ceftriaxone, cefotaxime, penicillin G, dexamethasone in Section 3A - Added ICU coverage for ID, neurology, and cardiology consults in Section 4A - Added ICU coverage for neurologic exam, temperature, ECG, renal function, CBC, pain scores, cognitive function in Section 6 - Added OPD and ICU coverage for EEG in Section 2C - Added ICU coverage for ECG and MRI spine in Section 2B
v1.0 (January 30, 2026) - Initial template creation - Comprehensive coverage of early and late neuroborreliosis - Includes Bannwarth syndrome (painful radiculoneuropathy) - CSF diagnostic interpretation guide with antibody index - Two-tier serologic testing algorithm - Treatment with IV ceftriaxone and oral doxycycline - Post-treatment Lyme disease syndrome (PTLDS) guidance - Tick-borne co-infection screening (Babesia, Anaplasma) - Tick prevention counseling - PubMed citation links for all major references
APPENDIX A: NEUROBORRELIOSIS CLINICAL SYNDROMES¶
| Syndrome | Timing After Tick Bite | Key Clinical Features | Typical CSF Findings | Treatment |
|---|---|---|---|---|
| Cranial neuropathy (facial palsy) | 2-8 weeks | Unilateral or bilateral (25%) facial weakness; may be only neurologic finding; often preceded by erythema migrans | Lymphocytic pleocytosis (may be absent in isolated peripheral CN VII); normal glucose; mildly elevated protein | Oral doxycycline if no CSF pleocytosis; IV ceftriaxone if CSF pleocytosis present |
| Lymphocytic meningitis | 2-10 weeks | Headache; neck stiffness (often mild); photophobia; low-grade fever; may present with cranial neuropathy | Lymphocytic pleocytosis (10-1000 WBC); elevated protein (50-300); normal glucose; positive Lyme antibody index | IV ceftriaxone 14-21 days |
| Painful radiculoneuropathy (Bannwarth syndrome) | 2-12 weeks | Severe radicular pain (often nocturnal, migratory); motor weakness in affected dermatome; more common in European neuroborreliosis (B. garinii) | Lymphocytic pleocytosis; elevated protein; positive Lyme antibody index | IV ceftriaxone 14-21 days (or oral doxycycline per European guidelines) |
| Acute myelitis | Weeks to months | Spastic paraparesis; sensory level; bladder dysfunction; may mimic transverse myelitis or MS | Lymphocytic pleocytosis; elevated protein; Lyme antibody index elevated | IV ceftriaxone 21-28 days |
| Encephalomyelitis (late) | Months to years | Progressive spastic paraparesis; cognitive decline; cranial neuropathies; white matter lesions on MRI (may mimic MS) | Lymphocytic pleocytosis (may be mild); elevated protein; intrathecal antibody production | IV ceftriaxone 21-28 days |
| Peripheral neuropathy (late) | Months to years | Distal sensory polyneuropathy; asymmetric; often with encephalopathy; intermittent limb paresthesias | CSF may be normal or mildly abnormal | IV ceftriaxone 14-28 days |
| Encephalopathy (late) | Months to years | Subtle cognitive impairment; memory difficulties; fatigue; sleep disturbance; NO CSF pleocytosis (distinguishes from encephalomyelitis) | CSF usually NORMAL; may have elevated protein without pleocytosis | IV ceftriaxone 14-28 days; cognitive rehabilitation |
APPENDIX B: POST-TREATMENT LYME DISEASE SYNDROME (PTLDS)¶
Definition: Persistent symptoms (fatigue, musculoskeletal pain, cognitive difficulty) lasting >6 months after completion of appropriate antibiotic therapy for confirmed Lyme disease.
Key Points: - Occurs in approximately 10-20% of treated Lyme disease patients - NOT due to persistent active infection (multiple RCTs demonstrate no benefit of prolonged antibiotics) - Thought to be related to post-infectious immune dysregulation, not active spirochetal infection - Symptoms are real and can be debilitating, but are self-limited in most patients
Management: - Supportive care and symptom management only - Graduated exercise program - Cognitive behavioral therapy for persistent fatigue and pain - Sleep hygiene optimization - Neuropathic pain management if applicable (gabapentin, pregabalin, duloxetine) - Neuropsychological rehabilitation for cognitive complaints - NO role for prolonged, repeated, or combination antibiotics (Class I evidence: Klempner 2001, Krupp 2003, Berende 2016) - NO role for alternative therapies (bismacine, colloidal silver, ozone therapy, hyperthermia) -- these are harmful and unsupported
Prognosis: Most patients with PTLDS improve gradually over months to years. Complete resolution is expected in the majority.