Cranial nerve neuropathies: a rare manifestation of cat scratch disease

Abstract

Background

Cranial nerve neuropathies represent a rare manifestation of cat scratch disease (CSD). Only a few case reports have been published, and the full clinical spectrum remains poorly characterized. We aimed to describe the clinical presentation, diagnostic approach, and prognosis of cat scratch disease (CSD)-associated cranial nerve neuropathies, a manifestation that is poorly characterized.

Methods

Using data from a national CSD surveillance study, we identified patients with CSD-associated cranial neuropathies confirmed by serology and/or PCR for Bartonella henselae. Clinical, epidemiological, and imaging data were analyzed. Follow-up was conducted.

Results

Seven immunocompetent patients with cranial nerve neuropathies were identified among approximately 4100 CSD patients diagnosed over a 28-year period (1997–2025). Affected cranial nerves included the facial (n = 3), abducens (n = 2), oculomotor (n = 1), and glossopharyngeal (n = 1) nerves, the latter two not previously reported in patients with CSD. All patients reported cat exposure. Neuropathies were accompanied by other CSD-related features, including fever (71%), lymphadenitis (57%), neuroretinitis (43%), and encephalitis (14%). Three patients received antibiotic therapy and five were treated with systemic corticosteroids. Six patients fully recovered within a median of 4 weeks; one patient showed marked improvement after 3 months and was subsequently lost to follow-up.

Conclusion

CSD-associated cranial neuropathies are rare and possibly underdiagnosed. Diagnostic clues include cat contact and concurrent CSD features such as fever, lymphadenopathy, or neuroretinitis. These findings are hardly observed in idiopathic cranial nerve palsies such as Bell’s palsy, for which guidelines recommend against routine serologic evaluation. Although outcomes are generally favorable, optimal treatment remains undefined. We suggest testing for B. henselae infection in patients with cranial neuropathies when CSD is suspected. Increased clinical awareness is warranted to facilitate timely diagnosis and management.

Background

Cat scratch disease (CSD), caused by Bartonella henselae, is a zoonotic infection primarily transmitted through cat scratches or bites. Fleas (Ctenocephalides felis) play a key role in the transmission cycle among cats, and humans become infected when a scratch or bite is contaminated with flea feces containing the organism [1]. Approximately 90% of CSD cases present with Typical CSD characterized by regional lymphadenopathy or lymphadenitis, often preceded by a primary inoculation skin lesion [2]. Atypical CSD presentations are diverse and may include fever of unknown origin (FUO), erythema nodosum, neuroretinitis, osteomyelitis, hepatosplenic involvement, Parinaud’s oculoglandular syndrome, encephalitis and others [3–5]. CSD-associated cranial nerve neuropathy or palsy has been rarely described; previously reported cases will be reviewed in the Discussion. Utilizing data from a large national CSD surveillance study conducted since 1991, and performing long-term follow-up, we aimed to characterize CSD-associated cranial nerve neuropathies with respect to diagnosis, clinical features, and long-term outcomes.

Methods

Patient Population and study design. A detailed description of the CSD National Surveillance Study patient population has been published before [3]. Briefly, a case of CSD was defined as a patient presenting with a clinical syndrome consistent with CSD, in the absence of another diagnosis, and meeting at least one of the following laboratory criteria: positive serology for anti–B. henselae antibodies (immunoglobulin [Ig] M and/ or IgG) utilizing enzyme immunoassay (EIA) [6] or a positive PCR for B. henselae DNA in clinical specimens, primarily lymph node tissue, lymph node pus aspirates, or primary skin lesions. PCR were performed and interpreted as previously reported [7]. Serologic testing was performed while the patients were symptomatic, sometimes weeks after onset of clinical presentation. Testing was conducted using EIA for detection of anti–B.henselae IgM and/or IgG antibodies, as previously described [6]. An IgG titer ≥ 1:100 or a positive IgM result was considered diagnostic for recent or active infection. The assay demonstrated a sensitivity of approximately 84% and specificity of 95% for confirmed CSD, based on prior validation studies using PCR-confirmed cases [6].

Epidemiologic, demographic and clinical data were obtained from community and hospital-based physicians, medical records, and directly from patients and their families.

Cranial nerve neuropathies were identified through the national registry. Clinical diagnosis was essentially based on neurologic examination. All patients were evaluated by a neurologist and underwent brain imaging.

Follow-up was conducted using reports from hospital and outpatient clinics, and direct contact with the patients and their families by email/telephone surveys. Doxycycline, macrolides and rifampin, were considered as antimicrobials potentially active against B. henselae [8].

Results

During a 28-year period (1997–2025), approximately 4500 patients were diagnosed with CSD in the National Surveillance Study. Eight B. henselae-seropositive patients with cranial neuropathies were identified in the national registry. One, a 10-month-old with abducens nerve palsy, was excluded due to lacks proper validation in this age group, and preliminary evidence of increased false seropositivity in children ≤ 1 year-old (Giladi, personal communication). All patients with cranial neuropathy were serologically tested for cytomegalovirus, Epstein Barr virus, West-Nile virus and syphilis with no evidence of acute infection. Six patients were seronegative for human immunodeficiency virus (HIV); an additional 6-year-old patient who had no HIV risk factors was not tested but remained clinically well during 16 years of follow-up and was presumed to be HIV-negative. Lyme disease testing was not performed, as the disease is not endemic in Israel.

Seven patients met inclusion criteria; all but one were hospitalized for evaluation. Patients ranged in age from 6 to 67 years (median 47); two patients were males (28%). One patient had diabetes mellitus and none was immunocompromised. All seven patients had reported close cat contact. Presentations included facial nerve palsy (n = 3; Fig. 1), abducens nerve palsy (n = 2), oculomotor nerve palsy (n = 1) and glossopharyngeal nerve palsy (n = 1). All patients except the latter had unilateral involvement. The laterality of the glossopharyngeal nerve involvement was clinically difficult to assess. Clinical data are presented in Table 1. Diagnosis was confirmed in all seven patients by B. henselae serology, with IgG titers ranging from 100 to ≤ 800; lymph node PCR was performed and found positive in one patient and lymph node histopathology revealed necrotizing granulomatous lymphadenitis in another patient.

Fig. 1.

(a) A six-year-old girl, exposed to a house-hold cat, with right-sided peripheral seventh cranial nerve palsy due to cat scratch disease. Ophthalmologic examination revealed a left-sided neuroretinitis. (b) The same patient, three weeks later, showing complete recovery

Table 1.

CSD patients with cranial nerve neuropathy: characteristics of the current cohort and previously published cases^a

No.	Source	Age and Sex	Lymph-adenopathy (Location)	Fever	Cat contact	Involved Cranial Nerve	Cranial Nerve Manifestations	Other Clinical Findings	CSD diagnosisb	Antibiotic Treatment	Cortico-steroid Treatment	Time to complete recovery (weeks)	Duration of Follow-Up (months)
1	Present study	62 F	Yes (R & L Cervical)	Yes	Yes	7R	Bell’s palsy	None	Serology	None	Yes	Partial recovery after 12 weeks	3
2	Present study	42 M	Yes (L Cervical)	Yes	Yes	7R	Bell’s palsy	Elevated liver enzymes	Serology	None	Yes	4	51
3	Present study	6 F	No	Yes	Yes	7R	Bell’s palsy	Neuroretinitis	Serology	None	Yes	4	188
4	Present study	53 M	Yes (L Axillary)	Yes	Yes	6R	Horizontal diplopia	Encephalitis Neuroretinitis	Serology	DOX	None	12	14
5 c	Present study	47 F	No	Yes	Yes	6 L	Horizontal diplopia	Neuroretinitis	Serology	DOX	Yes	4	46
6	Present study	67 F	No	No	Yes	3R	Diagonal diplopia	None	Serology	None	Yes	8	54
7	Present study	14 F	Yes (L Cervical)	No	Yes	9	Liquid regurgitation, week gag reflex, nasal voice, hoarseness	None	Serology, PCR	RIF	None	2	120
8	Walter et al. Pediatrics 1998	3 M	Yes (L Axillary)	Yes	Yes	7 L	Bell’s palsy	None	Serology	None	Yes	2	ND
9	Thompson et al. J Neuroophthalmol 1999	40 F	No	Yes	Yes	7R	Bell’s palsy	Neuroretinitis	Serology	None	None	4	ND
10	Ganesan et al. Journal of Oral and Maxillofacial Surgery 2005	29 F	Yes (L intraparotis)	Yes	Yes	7 L	Bell’s palsy	Parinaud oculoglandular syndrome, headaches	Serology	None	None	NR	4
11	Nakamura et al. Brain Dev 2018	7 M	Yes (L Cerival and intra-parotis)	Yes	Yes	7 L	Bell’s palsy	None	Serology	AZ	Yes	24	ND
12	Valor et al. BMJ Case Rep 2018	28 M	Yes (R Cerival and pre-auricular)	Yes	Yes	7R	Incomplete Bell’s palsy	Parinaud oculoglandular syndrome, headaches, myalgia	Serology	AZ	Yes	2	ND
13	Mutucumarana et al. Clin Pediatr (Phila) 2020	5 F	No	Yes	Yes	7 L	Bell’s palsy	Hepato-splenic CSD	Serology	AZ & RIF	None	2	ND
14	Rességuier et al. Revue de Medecine Interne 2013	28 M	Yes (L Cervical and pre-auricular)	Yes	Yes	7 L	Bell’s palsy	Hepatomegaly; Elevated liver enzymes	PCR (LN)	DOX & RIF	None	Partial recovery after 8 weeks	ND
15	Sendi et al. Emerg Infect Dis 2017	46 F	Yes (R Axillary)	NR	Yes	7NR	Bell’s palsy	Meningo-encephalitis, transverse myelitis	Serology	DOX	Yes	24	6

Abbreviations: CSD, cat scratch disease; No, number;, F, female; M, male; L, left; R, right; DOX, doxycycline; RIF, rifampin; ND, not done; NR, not reported; AZ, azithromycin ; LN, lymph-node

^a Five previously published reports, including 3 of facial nerve palsy, 1 of trigeminal sensory neuropathy, and 1 of bilateral abducens nerve palsy were excluded from the literature review either due to lack of laboratory confirmation of CSD (Premachandra DJ et al. Br J Oral Maxillofac Surg. 1990, Chiu AG at al. Otolaryngology–Head and Neck Surgery 2001 and Roebuck DJ et al. AJNR Am J Neuroradiol. 1998) or because an alternative, more plausible diagnosis was favored (Pham G et al. Am J Ophthalmol Case Rep 2022 and Ameilia A at al. Asian Pac J Trop Dis 2015)

^b Positive diagnostic results

^C This case was reported previously (Levy-Neuman, J Neuroophthalmol, 2022)

Six of the seven patients had additional manifestations, aside from cranial nerve neuropathy, all characteristic of Typical or Atypical CSD. Fever was reported in five patients (71%), including one patient with prolonged fever lasting few weeks and elevated liver enzymes. Notably, fever typically resolved prior to the onset of cranial neuropathy symptoms. Regional lymphadenopathy/lymphadenitis occurred in four patients (57%) and neuroretinitis was diagnosed in three patients (43%), including one with encephalitis, concomitantly with the cranial neuropathy.

Oculomotor nerve palsy presented as diplopia and mild ptosis, abducens nerve palsy as diplopia and inward deviation of the affected eye, and facial nerve palsy presented as peripheral nerve involvement and was often diagnosed as Bell’s palsy. The glossopharyngeal palsy was most strikingly observed in a 14-year-old girl who presented acutely with severe dysphagia, nasal regurgitation, hoarseness, nasal speech, a weak gag reflex, and unilateral cervical lymphadenopathy. PCR testing of a fine needle aspiration of the lymph node confirmed B. henselae infection. Brain imaging was performed in all seven patients. Four patients underwent CT or CT angiography, which was either normal or demonstrated incidental unrelated findings. Three patients underwent brain MRI, two of whom had abnormal findings. One patient with right oculomotor nerve palsy demonstrated contrast enhancement of the right third cranial nerve. A follow-up MRI performed four months later was normal, with resolution of the initial finding. Another patient, who presented with abducens nerve palsy and encephalitis, showed diffuse hyperintensities in the white matter of both cerebral hemispheres. A follow-up MRI was not performed due to the patient’s refusal, likely related to claustrophobia.

Three of the seven patients were treated with appropriate antibiotics and five patients received systemic corticosteroids (Table 1). Six patients fully recovered within a median time of 4 weeks (range: 2–8 weeks) and maintained recovery over a median follow-up period of 52 months (range 13–187), (Table 1). One patient with facial nerve palsy showed marked clinical improvement after 3 months and was subsequently lost to follow-up.

Discussion

Cranial nerve palsies are a rare, yet well-recognized complication of various infectious and non-infectious diseases, though their pathogenesis remains incompletely understood and lacks broad consensus [9]. Here, we described seven cases of CSD-associated cranial nerve neuropathies affecting the 3rd, 6th, 7th, and 9th nerves. Based on our review of the PubMed database, oculomotor and glossopharyngeal neuropathy due to CSD are reported here for the first time. We believe that the centralized diagnosis of all CSD cases in the country, based on clinical information combined with confirmatory laboratory tests previously shown to have high specificity for CSD [6, 7] enabled the identification of these patients over a 28-year period and contributed new information to the existing body of knowledge.

Cranial nerve palsies have been rarely reported in association with CSD. Earlier reports of CSD-associated cranial neuropathies, published prior to the identification of B. henselae as the etiologic agent of CSD in 1992, were either based on a non-standardized skin test no longer in use or lacked microbiological confirmation. For example, Carithers and Margileth [10] described two children with transient facial nerve palsy lasting 4–5 weeks among 1,471 CSD patients diagnosed by skin test and observed between 1975 and 1990. A review of the more recent publications revealed eight reports of CSD associated-facial nerve palsy, all confirmed by serology and in some cases, by PCR from a lymph node or CSD primary skin lesion, for B. henselae. Table 1 presents the seven cases from the current study (patients 1–7), along with eight previously reported cases of facial nerve palsy with valid CSD diagnosis (patients 8–15), totaling 15 patients.

The most well-known and extensively studied cranial nerve palsy is the peripheral seventh nerve neuropathy, often referred to as Bell’s palsy, which is thought to result from herpes simplex virus infection of the facial nerve, accounting for up to 70% of cases [11, 12]. Nevertheless, it is well-recognized that not all cases of Bell’s palsy are attributable to herpesvirus infections. Despite the widely accepted view that Bell’s palsy is a diagnosis of exclusion, with diagnostic certainty achievable only after the resolution of facial paralysis, there is no consensus on the necessity of diagnostic testing or routine serologic evaluation. Some guidelines explicitly recommend against routine serologic investigations in most cases, with few exceptions such as testing for Lyme disease serology in endemic areas [11]. We suggest that cranial nerve neuropathy caused by CSD should be added to these exceptions. As shown in Table 1, it is noteworthy that cranial nerve involvement in CSD, in contrast to Bell’s palsy or other isolated cranial nerve palsies, is consistently accompanied by features characteristic of CSD. Of the 15 reported cases of cranial nerve palsy (Table 1), 11 of which involved the facial nerve, all had a documented history of close contact with cats; 80% presented with fever, which is not typical of Bell’s palsy; 66% had lymphadenopathy or lymphadenitis; and 66% exhibited additional manifestations of Atypical CSD, including encephalitis, neuroretinitis, Parinaud’s oculoglandular syndrome, hepatosplenic involvement, and others.

Challenging current diagnostic paradigms, we recommend testing for B. henselae infection in patients with cranial neuropathies and a history of cat contact, particularly when CSD is clinically suspected,, given the potential benefit of antibiotic therapy. The importance of obtaining a history of cat contact cannot be overemphasized, as demonstrated in our seven patients with cranial neuropathy, where such history prompted diagnostic testing for CSD. Nonetheless, 10–15% of CSD patients may deny such exposure [13]. We also suggest actively screening for regional lymphadenopathy or lymphadenitis, neuroretinitis and other characteristic features of CSD.

In immunocompetent patients, the prognosis for Typical CSD and most of its extra-nodal manifestations is generally favorable. The infection typically follows a self-limiting course, with most patients achieving full recovery within a few weeks or months without lasting sequelae [5]. This study supports the observation that CSD-associated cranial neuropathies follow a benign course, although the effect of antibiotic and corticosteroid therapy remains uncertain.

Conclusion

CSD is a rare cause of cranial neuropathy, and the diagnosis can often be overlooked. Clues to diagnosis include a history of cat exposure and coexisting clinical manifestations such as fever, regional lymphadenopathy or lymphadenitis, neuroretinitis, or encephalitis, features that are not typical of idiopathic Bell’s palsy. The prognosis is generally favorable, with complete recovery expected in most cases.

Abbreviations

CSD

Cat Scratch Disease

PCR

Polymerase Chain Reaction

Ig

Immunoglobulin

IgM

Immunoglobulin M

IgG

Immunoglobulin G

EIA

Enzyme Immunoassay

FUO

Fever of Unknown Origin

CMV

Cytomegalovirus

EBV

Epstein–Barr Virus

WNV

West Nile Virus

HIV

Human Immunodeficiency Virus

CT

Computed Tomography

MRI

Magnetic Resonance Imaging

Author contributions

MY and MG conceived the study. MY collected and analyzed the data and drafted the manuscript. MG supervised the study and contributed to data interpretation. AK, LK, YP, GGS, AG, DY, RBA, JS, OZ, and ME contributed patient data, assisted in clinical interpretation, and provided critical input on the analysis. All authors critically revised the manuscript for important intellectual content, and all authors read and approved the final version.

Funding

The authors declare that no specific grant from any funding agency, commercial, or not-for-profit sectors was received for this research.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethical approval and consent to participate

Ethics approval was granted by the Tel Aviv Sourasky Medical Center Ethics Committee (Helsinki Committee) under protocol number TLV-0147-08. The study was primarily a retrospective data analysis, for which the Ethics Committee waived the requirement for individual inform consents. However, follow-up data were frequently collected prospectively, and in these cases, informed consent was required. Overall, informed consents were obtained for five of the seven patients included in the study.

Consent for publication

Additionally, two patients provided separate written consent for publication of identifying photographs. One of these patients, diagnosed with CSD-associated facial nerve palsy at the age of 6, signed the publication consent form after reaching the age of 18. Copies of the signed consent forms are available for review by the Editor upon request.

Competing interests

The authors declare no competing interests.