Baggio–Yoshinari syndrome

Localized acute infection

This stage includes flu-like symptoms and erythema migrans, the latter seen in 40-50% of the patients.^[6][8][3]The expanding skin lesion follows a latent period after the inoculation ranging from 4 to 30 days, around 10 days on average, and it lasts from 3 days to 3 months, generally around 4 weeks.^[3]

Early disseminate infection

Borrelia burgdorferi disseminates to various organs and tissues and patients can present clinically with symptoms as fever, enlarged lymph nodes, headaches,^[9] chills, nausea and vomiting,^[10] multiple anular EM-like lesions and, less commonly, borrelial lymphocytoma, a skin lesion typically associated with Borrelia afzelii infection. Sometimes, other skin lesions can be found.^[3][11][12]

Articular manifestations are found in around 40% of patients in the early disseminated stage, typically involving large joints such as the knee, presenting with considerable joint effusion. Arthritis lasts variable time amounts from a few weeks to a few months and resolves spontaneously. Analysis of the synovial fluid reveals inflammation and an elevated number of neutrophils.^[3]It's also possible for recurrent arthritic flares to evolve into chronic articular manifestations similar to rheumatoid arthritis. These molest both small and large joints and present with morning stiffness.^[3]

Neurological syndromes occur in around 35% of the patients in the early disseminated stage. Typically, it presents very similarly to the early triad of Lyme neuroborreliosis (LNB) manifestations and include cranial neuropathy,^[13]radiculopathy and lymphonomononuclear meningitis. The cerebrospinal fluid analysis reveals elevated proteins, increased number of mononuclear cells and sometimes the development oligoclonal bands. Other less typical manifestations include weakness, ptosis, mydriasis, dysarthria and inflammatory myositis.^[8][10] The diagnosis of BYS should be suggestive when bilateral cranial neuropathy is concomitant with meningitis.^[3]

Another notable characteristic of early Baggio-Yoshinari Syndrome is the presence of ocular involvement, being present in 43.8% of patients with early BYS neurological symptoms, often associated with cranial nerve inflammation and radiculopathy. The most common complaints are ptosis, strabismus, Claude Bernard Syndrome, corneal reflex disturbance, ophthalmoparesis, anisocoria, mydriasis, neuroretinitis, papilledema, uveitis, retinal lesions, retinal arteritis, chorioretinitis, optic neuritis, diplopia and photophobia.^[8][9][14]

Cardiac involvement is seen in less than 5% of the patients and it is clinically indistinguishable from Lyme Disease cardiac manifestations.^[3] Most often these involve conduction system abnormalities, commonly presenting as an atrioventricular conduction block.^[15]

Latent infection

Assays of PCR amplification works as a proof that Borrelia burgdorferi persist latently in the body of the patients just to reactivate later, causing the appearance of late stage and reactive manifestations. There are documented cases of PCR targeting the flgE gene in the synovial fluid and skin lesions of patients that were previously treated, sometimes extensively.^[3]

Reactive disease expression resembling CFS/ME

Symptoms typical of CFS/ME are often found in BYS patients, with prevalences being around 50-60%.^[16] CFS/ME is a syndrome that causes severe fatigue, cognitive dysfunction, post-exertional malaise, sleep disturbances, orthostatic intolerance and a myriad of other symptoms.^[17]Manifestations that look like post-treatment Lyme disease syndrome (PTLDS) are also commonly present in BYS patients. PTLDS is currently classified as a post-infectious syndrome that occurs in a subset of patients.^[18] Defining symptoms include impairing fatigue, musculoskeletal pain and neurocognitive dysfunction, but many others are often present, like sleep disturbances, paresthesia and autonomic dysfunction.^[19][20] Its prevalence varies widely, with the 10-20% range being a common estimation for ideally-treated early Lyme disease patients at the 6-12 month follow-up evaluation.^[21] PTLDS pathophysiology is still unclear, and proposed causes include persistent infection or debris, tissue damage, immune system dysfunction, autoimmunity and central sensitization.^{[22][23][24][25][26]} Brain white matter alterations^[27] and markers of microglial activation^[28] were found in some studies. Treatment options are currently limited or controversial, as repeated antibiotic treatment has been found to be helpful in some trials^[29][30] but not in others.^[31] Recently, psilocybin-assisted treatment was tested in a pilot study with promising benefits for overall symptom burden, fatigue, mental and physical quality of life, depression, sensory and affective pain and sleep disturbances.^[32][33] These manifestations happen most often in BYS patients who have not been treated or have undergone just a few days of treatment.^[3]

Reactive disease expression resembling autoimmune or allergic diseases

As the disease progresses, some patients show clinical manifestations and laboratory signs of autoimmune or allergic diseases "which resemble Sjögren's syndrome; rheumatoid arthritis; inflammatory myositis similar to poly-dermatomyositis with increased muscle enzymes (creatine phosphokinase, aldolase) and electromyography alterations; panniculitis; localized scleroderma; venous thrombosis with antiphospholipid antibodies; clinical manifestations mimicking systemic lupus erythematosus such as Raynaud's phenomenon, alopecia and photosensitivity; sudden onset of drug or food allergies."^[3]Laboratory abnormalities that are seen in autoimmune diseases can also be seen at these patients, including antinuclear antibodies, hypergammaglobulinemia, anticardiolipin antibodies and antineutrophil cytoplasmatic antibodies (ANCA) and elevated IgE.^[3]

BYS patients may develop autoantibodies targeting skin and neural tissue. It was discovered that of early BYS patients, 30% test positive for antibodies against skin targets and 40% test positive against neural targets. For patients at the late stage, 38.4% test positive for antibodies against skin targets and 64.1% test positive for antibodies against neural targets. The difference in prevalence against neural targets when comparing early and late patients crossed the threshold for statistical significance.^[3]

Unclassified disease expression

This isn't exactly a stage, but rather a category for patients whose manifestations doesn't fit neatly in the aforementioned stages. It usually includes patients with severe and unremitting neuropsychiatric manifestations that look alike autoimmune and infectious encephalitis.^[3][34]

Distinctive characteristics

A distinctive feature of the syndrome is its prolonged clinical evolution, with relapsing episodes and autoimmune dysfunction. If diagnosed in its early stage, historically arbitrarily defined as less than 3 months after the inoculation, the symptoms respond well to antibiotics. If the disease progresses to the chronic phase, it can potentially cause chronic fatigue syndrome symptoms, autoimmune manifestations, arthritis, late neuroborreliosis and skin lesions such as acrodermatitis chronica atrophicans, erythema nodosum and reactive exantema, with the patient being at risk of developing both articular and neuropsychiatric sequelae.^[4]

Neurological manifestations

The neurological manifestations of BYS were first described by Yoshinari et al., including patients with the classical neurological triad of early neuroborreliosis: Radiculoneuritis, meningitis, and cranial neuritis. Inflammation and injury of any cranial nerve can be noted, but involvement of facial or oculomotor nerves is specially typical. These manifestations are not infrequently bilateral.^[8][3]In patients with meningoencephalitis, lymphomononuclear pleocytosis along with normal or mildly elevated protein is the most typical landscape.^[8][3] In some cases, oligoclonal bands are seen. Meningeal irritation signs are often mild.

Encephalomyelitis, presenting as a progressive inflammatory involvement of the brain white matter, was found in 33.3% of the patients with neurological symptoms. Progression is typically insidious, and patients can develop cerebellar syndromes, spastic paraparesis, cerebellar ataxia (30%), organic psychiatric manifestations (60%), seizures (10%), hemiparesis, sphincter dysfunction (20%), movement disorders and transverse myelitis.^[8] Notably, around half of the patients who present with encephalomyelitis have early BYS.^[8] Patients who display symptoms suggestive of encephalitic involvement can show repeated crisis of severe headaches.^[3] In some instances, these episodes are followed by muscle fasciculations, loss of equilibrium, gait disturbances and cognitive disturbances.^[8][3] MRI scans of these patients can occasionally show foci of demyelinization.^[3] Neurological manifestations can progress, and severe clinical pictures that resemble those of Guillain-Barre Syndrome, amyotrophic lateral sclerosis, multiple sclerosis, opsoclonus-myoclonus-ataxia syndrome^[34] and Parkinson's disease can take place during the disease evolution.^[3]

Psychiatric and psychosocial manifestations even in patients without relevant psychiatric history are a remarkable feature of Baggio-Yoshinari Syndrome neurological cases, seen in 12.5% of early BYS and in 28.5% of late BYS patients with neurological symptoms.^[8] These include aggressive behavior, suicidal attempt, depression, panic attacks, hallucinations, paranoia, catatonia, obsessive compulsive disorder, anorexia and social disability.^[8]

Another relevant neurological manifestation is chronic encephalopathy.^[8]Lyme encephalopathy (LE) is a well-described, although somewhat controversial, late neurologic syndrome in the literature.^[35][36][37]It typically presents months to many years after the initial Lyme disease manifestations, sometimes in patients who had been previously treated,^[35] with symptoms as headaches, excessive daytime somnolence, depression, fatigue, sleep disturbances and cognitive deficits, most notably low verbal memory scores.^{[38][39][40][41]}The CSF analysis of these patients often show intrathecal antibody synthesis, elevated protein levels, normal glucose and less commonly, pleocytosis. Caution is warranted, as sometimes the CSF is normal.^[40] Often, an axonal sensorimotor radiculoneuropathy that causes spinal pain or distal paresthesia accompanies the syndrome.^[35][42]Patients with LE display hypoperfusion of cerebral frontal subcortical and cortical structures on SPECT that can partially reverse after antibiotic treatment.^[38]Patients with Lyme encephalopathy often do not respond fully to antibiotic treatment, typically IV ceftriaxone 2g/day for 2-4 weeks.^[35][40]In a case series study by Logigian et al., at a follow-up evaluation conducted at 12-24 months after a 4 week course of IV ceftriaxone, while all had improved, only 39% of the patients considered themselves as "normal".^[40] These results are even better than the ones from an earlier series, in which only 58% of the patients with encephalopathy showed sustained improvement at the 6 month follow-up examination after a shorter 2 week course of IV ceftriaxone.^[35] Some authors consider the patients whose objective cognitive deficits persist after treatment to have post-treatment Lyme encephalopathy (PTLE).^[30]These patients show cerebral hypoperfusion that is thought to be secondary to both metabolic and vascular factors, as seen on PET and SPECT scans, primarily in the temporal, parietal and limbic bilateral gray and white matter.^[43] It is still controversial if these patients respond to additional antibiotic treatment.^[44][45]In a series of patients with neurological symptoms of Baggio-Yoshinari Syndrome, encephalopathy was seen in 8 of 30 cases (26,7%).^[8]

Follow-up care of patients with neurological symptoms revealed that 55.6% of patients with early BYS and 90% of patients with late BYS had episodes of recurrence, with the first relapsing episode occurring months to years after the first treatment.^[8] Patients who initially presented with neurologic manifestations do not relapse necessarely showing involvement of the same system. However, there seems to exist a correlation, especially in patients whose diagnosis was made in the late stage of the disease. In a series, among patients whose disease relapsed at least once, repeated neurological symptoms were noted in 88.9% in patients who had been firstly diagnosed in the late stage, whereas for those who were diagnosed in early stage, they were seen in 44.4%.^[8] Typically, the relapsing episodes features a clinical picture that mixes articular and neurological symptoms. Notably, the incidence of some manifestations considered typical of Lyme disease decreased in the subsequent relapsing episodes during long-term follow up. Meningitis and cranial neuritis became more infrequent and cutaneous disease became progressively rarer, severely hampering the diagnosis of BYS.^[8]

Comparison with STARI

Some features of BYS also resemble those found in the Southern tick-associated rash illness (STARI, also known as Master's Disease), which is found in the Southern United States. However, there are distinctive differences; e.g., Baggio-Yoshinari Syndrome cause systemic symptoms but STARI do not.^[46]

Major parameters

• Epidemiology (tick bite or contact with wild or domestic animals in risk areas);

• Erythema migrans or systemic manifestations (arthritis, neurological abnormalities, cardiac involvement);

• Positive serology for Borrelia burgdorferi (HCFMUSP criteria).

Minor parameters

• Relapsing symptoms;

• Chronic fatigue or cognitive disturbances;

• Identification of spirochete-like structures by dark-field microscopy or Giemsa staining.

Serology

The serology is considered positive if the ELISA or the Western blot is positive, combination that occurs in 64.7% of patients.^[3]False positives occur in 16% of the healthy controls.^[3] The Western blot is interpreted with the HCFMUSP criteria that says that the test is positive if four IgG bands are positive, if two IgM bands are positive or if two IgG bands and one igM band is positive.^[3][8]Sometimes, antibody synthesis is detected only in the cerebrospinal fluid.^[10]

PCR assays

Since the discovery of a target, PCR tests have been used to identify Baggio-Yoshinari Syndrome patients, mainly targeting the flgE gene as it was found to return positive in 29.3% ^[48]of the samples and agreed with serological results. Recently, patients could be identified with PCR tests targeting the main flagellin gene (FlaB).^[47]