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Stroke Center, Department of Neurology. Fundación Santa Fe de Bogotá, Calle 119 7-75, Bogotá, ColombiaClinical Professor, Universidad De Los Andes, Bogotá, Cra. 1 #18a-12, Colombia
The second largest case series of patients with multiple cranial neuropathies published to date.
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The most frequent etiology of multiple cranial neuropathies in our case series was autoimmune.
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We highlight the need for standardized definitions and inclusion criteria for a better understanding of this entity.
Abstract
Introduction
Multiple cranial neuropathies (MCN) is an entity frequently seen in clinical practice but there is a lack of studies published about this entity, with most of them based on case reports and small case series.
Objective
The aim of this study is to describe the clinical involvement of different cranial nerves, the location within the central or peripheral nervous system and the diagnosis in a group of patients with MCN managed in one hospital in Bogotá-Colombia.
Methodology
A case series study was conducted using the electronic clinical records of a teaching hospital in Bogota-Colombia. Clinical data were collected from patients aged ≥18 with a clinical diagnosis of MCN between 2015 and July 2021.
Results
The cranial nerves most commonly affected were III and VII, with the most prevalent combinations being III-IV, III-VI, and V-VII. Among etiologies, the most frequently found were autoimmune, vascular and neoplastic and most common locations included peripheral nerves, neuromuscular junction, cavernous sinus and lateral medulla.
Conclusions
The differential diagnosis of MCN is broad, but clinical clues may aid in identifying the underlying etiology. According to our results, MG was the most frequent etiology, so it should be considered in any patient with a clinical diagnosis of MCN associated with fatigability.
Multiple cranial neuropathies (MCN) is an entity frequently seen in clinical practice. Even though a universal definition is lacking, it can be defined as a dysfunction of two or more cranial nerves (CN) simultaneously or sequentially (
). Data about prevalence and incidence are unknown and most of the evidence comes from case reports and case series. The largest case series reported to date is Keane's (
The evaluation of these patients is often challenging due to a wide range of etiologies and the potential for unfavorable neurologic outcomes. Dysfunction of the CNs can occur anywhere along its path from the brainstem to their peripheral courses including subcutaneous tissue (
). Different pathogenic mechanisms may produce the dysfunction including infectious, inflammatory, neoplastic, vascular, toxic, traumatic, and bone disorders (
). A systematic approach based on a thorough clinical examination and complementary studies is mandatory for identifying the underlying cause and for initiating treatment promptly.
The aim of this study is to describe the clinical features, anatomical localization, etiologies and ancillary testing of a group of individuals with MCN in Bogotá, Colombia.
2. Methodology
An observational retrospective case series was conducted using the electronic clinical records of a teaching hospital in Bogota-Colombia. Clinical data were collected from patients aged ≥18 years with a clinical diagnosis of MCN between 2015 and July 2021. According to the ethical standards of research lined by The Declaration of Helsinki, the personal information of research subjects was treated according to the principles of confidentiality and privacy.
The diagnosis of MCN was made with the simultaneous or serial involvement of 2 or more different CN. Collected data included demographic characteristics, comorbidities (HIV, diabetes and malignancy), clinical features (specially addressing CN compromise and associated symptoms), topographic and etiologic diagnosis. Information regarding neuroimaging and lumbar puncture results were also included.
The first CN was not examined systematically and therefore not included. We didn't include in the analysis of the results the combination of CN IX and X as they have a common nucleus. Unlike previous case series, we didn't exclude patients with myasthenia gravis (MG), as we approach multiple cranial neuropathy as a clinical condition rather than the physiopathological process.
3. Results
3.1 Demographic and clinical data
From a total of 142 patients, 51% were women. The mean age was 51 years (SD = 19 years). The disease course was acute in 54.92% patients, followed by subacute onset in 16.9% and chronic in 27.46%. Diplopia (18.45%), facial weakness (17.15%), ptosis (12.30%) and dysphagia (11.97%) were the most common associated symptoms (Table 1). Regarding systemic complaints, the most frequent was the presence of headache (45.07%) followed by weight loss (5.63%), periorbital pain (2.11%) and fever (2.11%). Only 1.29% of the patients did not report neurological symptoms associated with MCN and 58.45% of the patients had associated systemic symptoms. Among comorbidities, neoplastic processes were found in 15.49%, diabetes in 7.04% and HIV in 2.11%.
The most common etiology was autoimmune with 28.17% of the patients (Table 2). Within this category (N = 40), most of the patients had MG 55% patients followed by Guillain-Barré syndrome 35% patients. The predominant variants were the pharyngeal-cervical-brachial form, Miller-Fisher syndrome with and without Bickerstaff brainstem encephalitis. Other less common diagnoses were: systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis.
The second most frequent etiology was vascular (25.35%, n = 36), and arterial ischemic stroke was the leading cause in 72.2%. The most common infarct locations were the lateral medulla (50%), the pons (19.23%) and the mesencephalon (11.53%). Among stroke etiologies, arterial dissection was the most frequent. The remaining diagnoses included hemorrhagic stroke at the pons, carotid artery dissection without stroke, venous sinus thrombosis with intracranial hypertension, cavernous malformation, carotid-cavernous fistula, postsurgical after neurovascular decompression and microvascular disease.
The neoplastic etiology was 16.9% of all patients. Carcinomatous infiltration was present in 42.6% (n = 24), more commonly associated with lymphoma, lung adenocarcinoma and breast carcinoma. Metastatic tumors on the skull base and cerebral parenchyma were found in 25% patients, the majority secondary to lymphomas, followed by kidney, lung and breast neoplasms. From primary tumors, schwannomas were the most prevalent, followed by jugulotympanic glomus.
An infectious cause was found in 7.75% patients, with herpes virus being the most common agent. Other etiologies were: Toxoplasmosis, Cryptococcosis, Neurosyphilis and postseptal cellulitis. One patient had the cranial nerve involvement as a postinfectious manifestation.
Of the idiopathic inflammatory conditions, the Tolosa-Hunt syndrome was the most prevalent. A thickening of the dura was found in 1 patient with the diagnosis of hypertrophic pachymeningitis (Fig. 2). Both diagnoses were made after exclusion of other entities. The demyelinating disease of the central nervous system accounted for a total of 5 patients, 4 with multiple sclerosis and 1 with a neuromyelitis optica spectrum disorder.
The etiology was unknown in 6.81% of the patients. Less frequently encountered in our case series were the following diagnosis (Table 2): functional neurological disorder (n = 3), motor neuron disease (n = 3) and the category of miscellaneous (n = 3) due to ophthalmoplegic migraine and multiple mononeuritis.
3.3 Localization
The peripheral nerve was the most frequent site of involvement (22.4%) with the principal etiologies being Guillán Barré syndrome, Herpes virus infections and secondary vasculitis associated with SLE. The second most common location was the neuromuscular junction with 15.49%, all of them being MG including Anti-AChR, Anti-MuSK, seronegative and congenital myasthenia gravis. Brainstem compromise followed, mainly at the lateral medulla (11.97%). Compromise of multiple locations within the brainstem, including diffuse involvement of the medulla, pons, or midbrain, due to metastasis, basal carcinomatosis or encephalitis, occurred in 8.55% of patients. Also common was the compromise of the cavernous sinus in 8.55% of the patients with the etiologies being vascular, idiopathic-inflammatory and neoplastic. With 4 and 5 patients respectively, the following locations in frequency were the cerebellopontine angle and the skull base (Table 3) A full list of locations can be found in the appendix.
Regarding AN involvement we found that the most affected was the III CN (18.02%), followed by the VII CN (15.99%) and V CN (12.18%) (Table 4). The order of CN combinations from the most to the least frequent is as follows: III-IV, III-VI, V-VII, IV-VI and III-VI.
Regarding additional studies, 83.8% of patients underwent neuroimaging, which showed abnormalities in 52.81% of the cases. Examples of neuroimaging findings are shown in Fig. 1. A lumbar puncture was done in 32.39% patients with 20.42% being abnormal.
Fig. 1Etiology of patients with multiple cranial neuropathies.
Fig. 2Panel A. MRI (Coronal T1 with gadolinium) of a 22-years-old man with Tolosa-Hunt syndrome. Thickening and meningeal enhancement at the lateral wall of the cavernous sinus, left tentorium, middle cranial fossa and Meckel's cave. Panel B (Axial T2 FLAIR) and Panel C (Axial T1 with gadolinium) MRI of a 55-years-old woman with SLE and neuromyelitis optica spectrum disorder with positive anti aquaporin 4 antibodies. Round peripheric lesion at the junction between the pons and the middle cerebellar peduncle with gadolinium enhancement. Panel D Fast Imaging Employing Steady-state Acquisition (FIESTA) and Panel E (Coronal T1 with gadolinium) MRI of a 46-years-old woman with a Vestibular schwannoma at the right cerebello-pontine angle. Panel F (Axial diffusion) MRI of an 81-years-old man with a dorsolateral stroke at the right medulla.
The most common etiology was autoimmune, followed by vascular, neoplastic and infectious causes. In contrast, Keane found tumor as the most prevalent cause followed by vascular diseases and trauma (
). Our findings suggest a much higher presence of autoimmune etiologies, especially related to MG that compromise 55% of this category. The other two published series excluded patients with MG from their analysis. We included these patients because the clinical presentation of MG often presents with multiple CN palsies, especially in ocular MG (
). Keane excluded patients with MG but not those with botulism, which also compromise the neuromuscular junction. As stated before, MCN should be approached as a clinical syndrome, regardless of the pathogenesis associated thus ensuring a broad differential diagnosis and prompt identification of the cause in each patient.
The second most frequent etiology was vascular with Wallenberg syndrome being the most common presentation and arterial dissection the predominant cause. From the neoplastic causes, we found meningeal carcinomatosis as the most common etiology (41.7%). In contrast, extra axial central nervous system tumors were more frequent in both Keane and Mehta et al. case series with Schwannomas being the most prevalent. Regarding infectious etiologies, while bacterial infections were the most frequent in both Mehta et al. and Keane case series, we found that herpes zoster infection was the predominant cause. Among other etiologies, Tolosa Hunt syndrome was found in 5 patients and 4 patients had a functional etiology that exhibited key features distractibility, suggestibility and clinical inconsistency (
Interestingly 9 patients (6.8%) had an unknown etiology, more than the 1% found by Keane but less than the 7.4% reported by Mehta et al. In this category exhaustive workup is made on an individual basis, and it depends on the local resources, the initial hypothesis and in some cases the dilemma of starting empirical therapy or doing a more invasive procedure like a biopsy. These characteristics and the number of patients included, may explain the variability among the articles in this category.
The principal location was the peripheral nerve that differed with the principal anatomical sites (cavernous sinus, brainstem and skull base) reported in other case series where tumors, infections and vascular etiologies predominated (
). There might be some bias as the article by Keane excluded patients with myasthenia gravis and Mehta et al. did not include neuromuscular junction disorders, anterior horn cell disorders, myopathies and brainstem syndromes. The most common cranial nerve involved was the III followed by the VII, which correlates with our most prevalent etiologies being myasthenia gravis, Guillain-Barré syndrome and stroke.
Important clinical features that we found for considering some diagnosis include: an acute onset with a vascular etiology and a chronic curse with a neoplastic cause, fatigability was the hallmark in myasthenia gravis, headache was nonspecific and weight loss was described only in patients with neoplastic and autoimmune etiologies. Most of the patients with neoplastic etiology had a known malignancy, diabetes was common among patients with vascular etiology and was noted in all patients with a metabolic cause and almost one third of patients with infectious etiology had a history of HIV.
Among ancillary testing, having an abnormal CSF was common in autoimmune conditions. An abnormal neuroimaging study was found in vascular and neoplastic causes and a normal neuroimaging was not uncommon in autoimmune etiologies.
5. Conclusion
To date, the understanding of the etiologies for MCN has been limited to case reports and case series where different definitions of the disease have been used. We highlight the need for standardized definitions and inclusion criteria for a better understanding of this entity.
The patient's age, geographic location, progression of the disease, immune competence and associated symptoms are key characteristics for making the diagnosis more accurate. As MG was the most common etiology in our case series, we consider it should be part of the diagnostic approach in these patients.
Fig. 3Panel A. A patient with facial diplegia and paresthesia, a variant of Guillain-Barré syndrome. Panel B. Patient with involvement of the III, IV, VI and VII right CN secondary to idiopathic hypertrophic pachymeningitis.
Habib Moutran Barroso: Writing, editing and design. Hellen Kreinter Rosembaun: Writing, editing and design. María Paula Zafra Sierra: Writing, editing and design. Ericka Ramírez Arquez: Editing and design. Carlos Martínez Rubio: Editing and design.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The Authors declare that there is no conflict of interest.
Acknowledgments
We would like to thank Dr. Saúl Reyes for his help and support.
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