Neurologic complications from B. henselae infection are infrequent, occurring in around 2–7% of infected persons. Neurological symptoms often manifest two weeks after the onset of fever and lymphadenopathy ^[1][2][87,88]. Recently, Bartonella infections have been related to a broader range of neurological symptoms, including hallucinations, loss of weight, muscular exhaustion, partial paralysis, and pediatric acute-onset neuropsychiatric syndrome (PANS) ^[3][89].

The findings imply that this species of bacteria may be capable of causing a spectral range of neurological symptoms, varied clinical features, and multi-organ system pathology that differs in intensity and screening difficulty across an extended time period, varying from weeks to years ^[4][5][52,54].

The majority of individuals with CSD who have central nervous system damage are children under the age of 18. One of the most common symptoms is encephalitis, although radiculitis, polyneuritis, myelitis, and cranial nerve involvement have all been described ^[6][7][90,91]. Neurologic alterations often occur about two weeks after the start of fever and significant lymphadenopathy, which are frequent in these patients. Seizures are the most frequent first symptom, but headaches, alterations in mental state, delirium, and coma are all possible ^[7][91]. Most individuals recover completely without complications in under a year ^[8][92]. Computed tomographic imaging revealed no abnormalities or localized low-density lesions; an electroencephalogram demonstrated generic, widespread slowness ^[7][91]. The pathologic characteristics of CSD in the brain are unknown, as these tissues are rarely biopsied.

However, granulomatous inflammation of the brain tissue involving meningitis has been demonstrated, and special stains and molecular testing have shown that organisms recover from such lesions ^[9][93]. Usually, the diagnosis is established based on the findings of a lymph-node biopsy or other supportive laboratory tests.

Except for the detection of B. henselae infection, the laboratory examination of infected individuals with encephalopathy usually produces inconsistent findings and is thus ineffective for diagnosis.

Electroencephalography conducted during the acute period of illness shows a widespread slowness in about 80% of patients, which resolves completely upon follow-up ^[10][33]. Approximately 19% of patients show abnormal results on a CT scan or magnetic resonance imaging (MRI) of the brain, which would include anomalies in the brain’s white matter, striatum, thalamus, and gray matter ^[11][94]. The outcome for individuals with encephalopathy is usually good, with 90% of patients recovering completely and spontaneously with no complications ^[2][88]. Just one case of fatal meningitis and encephalitis in an immunocompetent infant has been reported in the scientific literature as a consequence of B. henselae disease ^[12][95].

Examination of the cerebrospinal fluid may reveal moderate pleocytosis and increased protein content ^[7][91] but, frequently, CSF study findings are benign or suggest relatively moderate inflammation. Examination of the cerebrospinal fluid may reveal moderate pleocytosis and an increased protein content ^[7][91]. The human illness has some features in common with experimental cat-brain disease, including the temporary nature of the disruption, the existence of behavioral changes, a decline in alertness or convulsions, and the absence of major CSF irregularities. It is possible that B. henselae infects both species through comparable pathophysiologic processes.

With the development of increasingly accurate and precise screening procedures, recent microbiological studies have confirmed blood and cerebrospinal fluid (CSF) infections with one or more Bartonella species in patients with neurological, neuropsychological, and psychiatric manifestations ^[3][89]. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a medical illness in children and adolescents marked by the abrupt development of neuropsychiatric symptoms such as obsessions or compulsions or dietary restriction ^[13][96]. Depression, anger, anxiousness, and academic deterioration are frequently associated with PANS manifestations. PANS may be induced by infection, electrolyte imbalances, and other inflammatory responses ^[13][96]. After failing to react to psychiatric combination therapy and an immunomodulatory operator for suspected immune-driven encephalitis, Breitschwerdt and colleagues reported a case of Bartonella henselae bacteremia in a child with schizophrenia who had symptom remission after antibiotic treatment ^[3][89].

Furthermore, individuals with bartonellosis with neurological symptoms may acquire autoantibodies, lacking normal clinical, pathological, and immunologic markers of bacteremia, and may be immunocompromised as a result of medication therapy or lengthy Bartonella spp. infection. When autoantibodies are documented in combination with negative indicators for inflammation, the clinical presumption of an infectious etiology in individuals with neuropsychiatric symptoms is reduced ^[14][61].

B. henselae was discovered to be the causal agent of this disease in only the past decade ^[49][128]. The infection is believed to be spread through direct conjunctival inoculation. Common symptoms include a foreign-body sensation, unilateral eye redness, serous discharge, and increased tear secretion. Patients usually present necrotic granuloma with conjunctival epithelium ulceration, and also local lymphadenopathy involving the preauricular, submandibular, or cervical lymphatic system ^[50][129]. After many weeks, the granuloma often resolves without scarring.

Ocular involvement develops in 5–10% of people with CSD ^[10][33]. The eye could serve as the major infection site, resulting in Parinaud oculoglandular syndrome, which is defined by the infection of the conjunctiva and eyelids, as well as local lymphadenopathy (Figure 1). Within 2–3 weeks of the onset of systemic illness, various ocular symptoms might arise. Neuroretinitis, optic neuropathy, and a variety of other kinds of intraocular inflammation are among these symptoms. Regarding the annexal manifestation, Parinaud Syndrome would be representative. Considering vitreous changes, intermediate uveitis and vitreous hemorrhage can be present. Inner retinitis and chorioretinitis can also be included in the retinal and/or choroidal manifestations. The retinal vascular manifestations are retinal vasculitis, angiomatous-like proliferation, retinal arteriolar branch occlusion and retinal vein branch occlusion. The macular complications include serous macular detachment, macular stars (stellar maculopathy), macular edema, and macular hole. The optic-nerve manifestations are considered to be neuroretinitis, optic-disc edema, and optic-nerve head mass.

The most frequent clinical observations in previous investigations have been neuroretinitis associated with macular stars ^[51][24] and/or isolated foci of retinitis or choroiditis ^[52][130]. Macular stars can become visible in a few days as vision loss begins and become increasingly apparent over the following two to three weeks. Isolated ocular neuritis was also reported before ^[53][131], highlighting the necessity of eliminating infectious agents such as Bartonella henselae prior to initiating therapy with pulse methylprednisolone, particularly in children.

The authors of a Turkish study of 13 eyes of 10 patients with ocular bartonellosis highlighted the variety of ocular symptoms, including an acute endophthalmitis case ^[53][131]. Nine patients had a history of cat interaction and systemic symptoms for up to three months before presenting with ocular symptoms, and three had them earlier, but they had initially been misinterpreted as noninfectious intraocular inflammation ^[53][131]. The lack of vitreous cells helped to distinguish these lesions from the retinitis/retinal infiltrates observed in Behcet disease or toxoplasmosis, the investigators reported. They advised the careful monitoring of retinal infiltrates simulating cotton-wool patches, since these may progress to a branch retinal artery occlusion ^[53][131].

Ocular CSD may potentially manifest as occlusion of the retinal artery, retinal infiltrates resembling cotton-wool exudates, or endophthalmitis ^[54][132]. The pathogenesis of retinal infiltrates is most likely related to ischemia caused by the occlusion of the retinal arterioles ^[55][19]. It is essential for the ophthalmologist to distinguish the superficial retinal infiltrates in ocular CSD from retinitis or retinal infiltrates seen in individuals with sarcoidosis, Adamantiades-Behcet’s disease, toxoplasmosis or rickettsia infection ^[53][131].

Previously, Eiger-Moscovich et al. ^[56][133] described the clinical course of BRAO (Branch Retinal Artery Occlusion) in six individuals (seven eyes). One suffered numerous arterial occlusions. BRAO was found in three eyes. In one patient with unilateral BRAO, the other eye had neuroretinitis and, in two cases, both appeared in the ipsilateral eye. BRAO developed focal retinal infiltrates in both eyes or in one eye. A central scotoma left just one eye with low visual acuity (1/60). However, BRAO caused persistent visual field reduction in both eyes ^[56][133]. The authors recommended careful history-taking and serologic testing for Bartonella infection, particularly in children with BRAO.

Numerous case reports and series on ophthalmic vascular occlusions as a result of CSD have been published ^{[56][57][58][59]}[133,134,135,136]. Surprisingly, the changes and distortions in visual acuity are location-dependent. In some instances of secondary epiretinal membranes, the epiretinal membrane (ERM) spontaneously releases. The therapy, it has been claimed, may promote this occurrence ^[60][61][62][137,138,139]. The release of the ERM (epiretinal membrane) results in a reduction or elimination of the macula’s tractional pressures, thus allowing the macular hole to close.

When a persistent tractional epiretinal membrane develops (as a consequence of uveitis), even without the formation of a macular hole, pars plana vitrectomy and ERM peeling are the recommended treatment options. In immunocompromised or immunosuppressed individuals, CSD is anticipated to present a more severe systemic effect. It has been observed that, in HIV-positive individuals, it causes bacillary angiomatosis ^[63][140].

Best et al. ^[64][141] reported a case in which a patient came to the emergency department with a unilateral central scotoma and no prodromal symptoms, a rare presentation for this illness. The patient was afebrile and had no visible skin lesions associated with a cat scratch or bite, nor did she have lymphadenopathy. An ophthalmologic examination revealed findings suggestive of retinal edema.

Suhler et al. ^[65][142] discovered that B. henselae infection was the most frequently observed etiology of neuroretinitis in their clinic in the northwestern USA. The degree to which these results apply to certain other areas is unclear.

Tey et al. ^[66][143] found that 10 out of 13 patients (76.9%) exhibited posterior segment symptoms, whereas three (23.1%) had Parinaud’s oculoglandular syndrome, lacking the participation of the posterior segment. Eighty-two percent of the eyes had small foci of retinal white lesions. Subretinal fluid (SRF) beneath the fovea was visible on SD-OCT in eight eyes (34.8%), and Parinaud’s oculoglandular syndrome, in four eyes (17.4%).

In the case described by Annoura et al. ^[67][144], Parinaud oculoglandular syndrome, anterior uveitis, neuroretinitis, a serous retinal detachment, and a flame-like retinal hemorrhage suggesting retinal vein blockage were all identified. Additionally, the frequency of concurrent eye disorders in the anterior and posterior chambers is notable. Additionally, the present instance was noteworthy in that ocular involvement occurred in the absence of systemic diseases, and neither lymphatic nor systemic disease emerged.

Fundus imaging, optical coherence tomography (OCT), and fluorescence angiography can aid in the diagnosis and treatment of CSD ^[85][161]. Late leakage from the optic disc is the most frequently observed finding in FA. Peripapillary angiomatosis and peripapillary serous retinal detachment are additional FA observations ^[50][86][129,162]. Although neuroretinitis is a well-described complication of B. henselae infection, angiomatous lesions remain uncommon.

Habot-Wilner et al. ^[87][88][163,164] have shown the use of retinal OCT in evaluating macular alterations in CSD. The research discovered a lowering of the foveal contour, hypertrophy of the neurosensory retina, and production of subretinal fluid in each of the tested eyes. In the outer plexiform layer, the retinal exudates looked hyperreflective. Follow-up examinations revealed that the macula was normal. The authors also recommended the use of OCT in conjunction with other imaging modalities to monitor patients with CSD neuroretinitis ^[87][88][163,164].

B. henselae-induced ocular inflammation is often benign and self-limiting, with good visual outcomes. However, significant, irreversible visual loss is possible. The indication for therapy varies according to the severity of the condition (Table 14). In vitro, Bartonella henselae is sensitive to a variety of antibiotics ^[89][165]. There is no conclusive randomized clinical research demonstrating the effectiveness of antibiotic or corticosteroid therapy for B. henselae infection, but an uncontrolled study indicated the effectiveness of antibiotic therapy ^[89][165].

While B. henselae seems to be the most frequently observed infectious cause of neuroretinitis, treatment persists due to the disease’s self-limiting nature. Thus, according to two specialists, the rarity of Bartonella neuroretinitis complicates treatment ^[90][166]. Lee et al. believe that antimicrobial treatment reduces the duration of the disease symptoms and that, therefore, it should be treated with antibiotics until the laboratory testing is completed ^[91][167].

On the other hand, Bhatti asserts that therapy has no effect on the cure rate ^[90][166]. Given the rarity of Bartonella neuroretinitis, recruiting participants for a randomized clinical study would be very challenging and would require multicenter research ^[92][168]. Reed et al. ^[93][48] found that antibiotics resulted in a faster visual recovery and a shorter duration of illness. Chiu et al. ^[43][122] found no difference in visual results between treated and untreated patients (antibiotics, CS, or both). Rostad et al. cured an eight-year-old child of B. henselae with oral doxycycline (60 mg) every 12 h ^[94][169].

Chiu et al. found no link between systemic corticosteroid usage and visual results ^[43][122]. Meanwhile, Habot-Wilner et al. ^[87][88][163,164] found, in a multicenter retrospective cohort analysis, that a combination antibacterial and systemic corticosteroid regimen was related to a better visual result than an antibiotic-only regimen in patients with BCVA worse than 6/9 at presentation. Kodoma et al. described a case study of 14 patients in Japan, 13 of whom received systemic steroids and two of whom received 1000 mg of methylprednisolone pulse treatment ^[95][170].

In Garcia’s case report, oral doxycycline and rifampicin were effectively used to treat an elderly patient with a parotid abscess and aseptic meningitis ^[96][13]. The majority of the complications resolve spontaneously, while recovery from central nervous system symptoms might take up to a year ^[97][4]. There is insufficient evidence to support the advantages of particular antibiotic treatment in immunocompetent individuals with uncommon CSD manifestations ^[98][171]. Numerous antibiotic treatments, particularly gentamicin, trimethoprim/sulfamethoxazole, azithromycin, ciprofloxacin, erythromycin, doxycycline, and rifampin, were utilized in atypical CSD, alone or in various combinations.

Bejarano et al. reported a case in which a child presenting fever and tonic–clonic seizures was effectively treated with an approximately four-month course of azithromycin and rifampin ^[99][172].

Taking into consideration the available research, status epilepticus caused by this illness is often resistant to anticonvulsant medication. Even with the prompt initiation of treatment and the usage of various anticonvulsants, seizure management might not be achieved for several hours ^[100][173].

Due to their deep penetration of the central nervous system, the majority of researchers and doctors strongly advise a protocol of doxycycline and rifampin for 10–14 days ^[21][102], with a treatment course of 2–4 weeks in immunocompetent individuals and four months in immunosuppressed patients, but the antibiotic treatments used may vary in terms of the drug category and length of time. Antiepileptics usually cure the majority of patients within three days to two years ^[99][172]. Bogue et al. revealed that clinical signs of systemic CSD rapidly resolved in three critically sick patients following intravenous gentamicin-sulfate therapy ^[101][174].

The course of therapy would be determined by the responsiveness and the awareness that, in the normal course of the illness, recuperation from CSDE is typically quick (4–14 days). Collipp ^[102][175] noted an outstanding recovery due to trimethoprim–sulfamethoxazole in 11 CSD cases. Along with seizure management and respiratory assistance, the most critical part of treating individuals with encephalopathy is establishing a diagnosis as soon as possible. This may minimize lengthy and unsatisfying investigations that may cause the patient distress. During a coma, supporting measures such as adequate nursing care and constant monitoring of the patient are suggested.

Balakrishnan et al. ^[20][101] reported on an 11-year-old girl who suffered from a variety of neurological symptoms, which included migraines, multisensory hallucinations, nervousness, visual impairment affecting both eyes, episodes of generalized paralysis, VII-th nerve palsy, severe sleeping problems, convulsions, extreme fatigue, cognitive deficits, and memory problems. Physiopathologically, originally, B. henselae generated vasculitis, which resulted in subsequent cerebral ischemia, tissue destruction, and surgical excision.

Rosas et al. ^[103][176] described a case of cat-scratch-illness encephalitis associated with left-arm flaccid paralysis. The patient manifested an altered mental state and a probable seizure during the acute phase. Initially, hemiparesis was thought to be a sign of Todd’s paralysis. Clinically, the patient recovered on the fifth day of hospitalization, regaining use of her left arm, and recovered completely a week afterwards with doxycycline and levetiracetam treatment.

Raihan et al. reported four instances in which patients had a background of interaction with cats, had a fever prior to developing ocular symptoms, had optic-disc enlargement and macular edema, and tested positive for B. henselae ^[104][177].

Zakhour et al. ^[105][178] described a 10-year-old girl who had transverse myelitis and Guillain–Barré syndrome as a consequence of cat-scratch illness. Lower-extremity weakness and sensory loss, as well as lower-extremity discomfort, were all associated with the symptomatology. The treatment consisted of doxycycline for 14 days and five days of rifampin and intravenous immunoglobulin, and the case evolution was positive; at the end of the treatment, the patient only presented mild sensory deficits.

In the study conducted by Bilavsky et al. ^[106][179], over a period of 11 years, of cat-scratch disease in eight pregnant women, it was found that five of the eight had classic cat-scratch illness, including regional lymphadenitis; two experienced local lymphadenitis accompanied by arthralgia, myalgia, and erythema nodosum; and one had neuroretinitis.

This disease is especially concerning when it occurs in pregnancy because the course of cat-scratch disease is longer and frequently febrile, lasting weeks or months. B. henselae DNA was found in postmortem cells of a neonate delivered by a mother who had been diagnosed with B. henselae infection; the baby died nine days after birth. These findings indicate that B. henselae infection could be detrimental to the fetus, explicitly or implicitly, and might even present a danger of horizontal transmission ^[3][89].

4. Conclusions

By and large, medical information concerning neurobartonellosis is restricted to case reports and case series, and a clear molecular mechanism behind the emergence of symptoms and pathogenesis of the lesions has not been discovered.

Neurological and ophthalmological symptoms and syndromes can develop at the same time. The period between the beginning of CSD and the commencement of encephalopathy is between days and two months. Encephalopathy is often signaled by disorientation, which might be followed by a decreased state of awareness, varying from sleepiness to a comatose state. Around 50% of individuals have seizures, which vary from localized, self-limited clonic convulsions to status epilepticus. Aphasia, hemiparesis, cranial nerve palsy, and ataxia are all examples of focal neurological symptoms that occur in a minority of individuals. Despite Bartonella henselae infrequently generating encephalopathy and meningitis, a favorable prognosis following antibiotic therapy requires clinicians to consider them in routine practice.

Infected individuals may have a variety of visual symptoms of Bartonella infections. Neuroretinitis, optic neuritis, focal retinitis, choroiditis, chorioretinitis, exudative maculopathy, serous retinal detachment, and vitritis have all been described in the literature. Other ocular issues, such as branch retinal artery blockage, macular holes, and peripapillary angiomatosis, have also been reported. There have also been reports of conjunctival symptoms such as Parinaud’s oculoglandular syndrome and nonspecific follicular conjunctivitis.

B. henselae is the most often identified cause of neuroretinitis, with about two-thirds of patients exhibiting serologic evidence of prior B. henselae infection. Patients with ocular bartonellosis may also present with a variety of posterior segment symptoms, such as posterior uveitis, neuroretinitis, optic neuritis/papillitis, optic disc granuloma, retinal vasculitis, retinal venous or arteriolar occlusions, angiomatosis, acute multifocal inner retinitis or retinal white-dot syndrome and/or retinal infiltrates.

Whenever a patient presents with injected conjunctivae and granulomatous follicular conjunctivitis, the possibility of Parinaud’s oculoglandular syndrome must be considered, especially if the patient has indicated interaction with cats or kittens.