What is the most likely diagnosis for a 46-year-old male with a history of a suspected insect or spider bite, initial symptoms of a large oval-shaped rash, fatigue, headaches, and subsequent neurological and psychiatric symptoms, despite negative MRI, CT scan, and bloodwork results?

Clinical Diagnosis: Lyme Disease (Lyme Borreliosis)

Based on the clinical presentation—particularly the large oval-shaped expanding rash following a suspected insect bite, the subsequent multisystem neurological and psychiatric manifestations occurring in a waxing and waning pattern, and the geographic location in New Zealand where Lyme disease vectors exist—this patient most likely has disseminated Lyme disease with chronic neurological involvement.

Primary Diagnostic Reasoning

The Initial Rash is Pathognomonic

• The description of a large oval-shaped rash expanding from 0 to 19cm x 7cm over 48-72 hours following a suspected insect/spider bite is classic for erythema migrans (EM), which is the only clinical manifestation sufficient to diagnose Lyme disease without laboratory confirmation 1
• The rash being warm to touch but not painful, itchy, or significantly swollen further supports EM rather than cellulitis 1
• The misdiagnosis as cellulitis is a common pitfall—cellulitis typically presents with more pronounced pain, warmth, and systemic signs of bacterial infection, whereas EM is characteristically non-painful 1
• The fact that IV flucloxacillin appeared to improve the rash is misleading; EM can spontaneously resolve even without appropriate antibiotic therapy, only to have the spirochete disseminate systemically 2

Neurological Dissemination Pattern Matches Lyme Disease

• The acute onset of meningitis-like symptoms 12 months after the initial bite (sore neck, photophobia, extreme headache, confusion, slurred speech) represents early disseminated neurological Lyme disease, which can occur within weeks to months after initial infection 3, 4
• Lyme disease has a latency period of months to years before late-stage symptoms emerge, similar to syphilis 3
• The Centers for Disease Control and Prevention notes that 10-15% of Lyme disease patients develop neuroborreliosis, with common manifestations including lymphocytic meningitis, cranial neuritis, and radiculoneuritis 4
• The subsequent chronic neuropsychiatric symptoms—including cognitive impairment, word-finding difficulty, memory issues, tremors, mood disturbances, anxiety, depression, and panic attacks—are well-documented in late Lyme disease, with depressive states occurring in 26-66% of patients 3

The Waxing and Waning Pattern is Characteristic

• The relapsing-remitting nature of symptoms over years is explained by the microbiology of Borrelia burgdorferi, which can evade normal immune surveillance and persist despite initial immune responses 3
• The multisystem involvement (neurological, psychiatric, musculoskeletal with joint pain, cardiac with chest pains) mirrors the known manifestations of disseminated Lyme disease 2, 1

Why Standard Testing Was Negative

• Normal MRI, CT, and bloodwork are common in neuroborreliosis—neuroimaging is typically unremarkable even with significant neurological symptoms 4
• The patient was never appropriately tested for Lyme disease with two-tier serologic testing (ELISA followed by Western blot confirmation) 1
• Serology can be falsely negative in early disease and requires both acute and convalescent samples 1

Alternative Diagnoses to Consider (But Less Likely)

Tickborne Rickettsial Diseases (Ehrlichiosis/Anaplasmosis)

• While the CDC guidelines emphasize considering ehrlichiosis and anaplasmosis in patients with fever, headache, and outdoor exposure 5, several features argue against these diagnoses:
• The incubation period for rickettsial diseases is typically 5-10 days, not the prolonged course seen here 5, 6
• Rickettsial diseases cause acute illness with characteristic laboratory abnormalities (leukopenia, thrombocytopenia, elevated transaminases) that resolve with treatment 7, 5
• The chronic, relapsing-remitting neuropsychiatric symptoms over years are not consistent with rickettsial disease 5, 6
• Rocky Mountain Spotted Fever rash appears 2-4 days after fever and progresses to involve palms and soles, which did not occur here 8, 6

Post-Viral Syndromes (Long COVID)

• While the patient had suspected COVID in March 2022, the symptoms began 18 months earlier in October 2020, making long COVID an incomplete explanation 2
• The initial expanding rash is not explained by COVID or vaccination 1

Chronic Fatigue Syndrome/Somatic Symptom Disorder

• These are diagnoses of exclusion and should not be made when an infectious etiology (Lyme disease) has not been adequately ruled out with appropriate testing 3
• The specific pattern of neurological findings and the initial EM rash point to an organic infectious process 3

Recommended Diagnostic Workup

Immediate Serologic Testing

• Order two-tier testing: ELISA for Borrelia burgdorferi antibodies followed by Western blot (both IgM and IgG) for confirmation if ELISA is positive or equivocal 1
• Given the chronic timeline (>4 years since initial infection), IgG antibodies are more likely to be positive than IgM 1
• Be aware that serology can have false positives if confirmatory Western blot is not performed 2

Consider PCR Testing

• If available, PCR testing for Borrelia burgdorferi DNA from blood or cerebrospinal fluid may provide additional diagnostic evidence, though sensitivity varies 5

Lumbar Puncture

• If neurological symptoms are prominent, lumbar puncture showing lymphocytic pleocytosis with positive Borrelia antibodies in CSF would confirm neuroborreliosis 4

Treatment Recommendation

Empiric Treatment Should Be Initiated Immediately

• Given the high clinical probability of disseminated Lyme disease with neurological involvement, treatment with doxycycline 100 mg orally twice daily should be initiated immediately without waiting for serologic confirmation 1, 4
• For confirmed neuroborreliosis with significant CNS involvement, intravenous ceftriaxone 2g daily for 2-4 weeks is the standard treatment 4
• One case report demonstrated complete resolution of neurological Lyme disease symptoms within 24 hours of starting ceftriaxone, with full recovery after 21 days of treatment 9
• Oral regimens appear as effective as parenteral ones in most instances of neuroborreliosis 4

Expected Clinical Response

• Clinical improvement should occur within days to weeks of appropriate antibiotic therapy 9, 4
• Neuroborreliosis can be microbiologically cured in virtually all patients using standard 2-4 week antimicrobial regimens 4

Critical Clinical Pitfalls to Avoid

• Do not dismiss the initial rash as simple cellulitis—the expanding oval shape over 48-72 hours without significant pain is classic for EM, not bacterial cellulitis 1
• Do not attribute chronic neuropsychiatric symptoms to psychiatric illness alone when there is a history of possible tick exposure and an expanding rash 3
• Do not wait for laboratory confirmation to initiate treatment when clinical suspicion is high—Lyme disease is a clinical diagnosis, and serology is confirmatory 1
• Do not accept "normal" imaging as ruling out neuroborreliosis—MRI and CT are typically unremarkable even with significant neurological involvement 4
• Psychiatrists and general practitioners in endemic areas must include Lyme disease in the differential diagnosis of any atypical psychiatric disorder 3