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Table of Contents    
Year : 2020  |  Volume : 68  |  Issue : 3  |  Page : 630-635

The Multiple Cranial Nerve Palsies: A Prospective Observational Study

1 Department of Neurology, King George's Medical University, Uttar Pradesh, India
2 Department of Pathology, King George's Medical University, Uttar Pradesh, India
3 Department of Pathology, Ram Manohar Lohiya Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Date of Web Publication6-Jul-2020

Correspondence Address:
Dr. Praveen Kumar Sharma
Department of Neurology, King George Medical University, Chowk, Lucknow, Uttar Pradesh - 226003
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.289003

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 » Abstract 

Background: Neurological presentation with isolated multiple cranial nerve palsies is common and its diverse causes include infectious, neoplastic, and inflammatory pathologies. The aetiological spectrum may depend upon geographical regions. We undertook this study to explore clinical spectrum and aetiological profile of multiple cranial nerve palsies.
Methods: This hospital-based prospective observational study was conducted from August 2015 to August 2017. All the consecutive patients of multiple cranial palsies presenting to the neurology department were included in the studies. Primary objectives were to define anatomical syndromes/cranial nerve combinations and to establish aetiology. Secondary objectives were to study associated factors. The multiple cranial nerve palsy was defined as involvement of two or more non-homologous nerves. Patients of neuromuscular junction disorders, anterior horn cell disorders, myopathies, brain stem syndromes were excluded. All patients underwent structured protocol of clinical evaluation, investigations and few specialized investigations in accordance with clinical suspicion to establish the diagnosis.
Results: Fifty-four patients with a mean age of 39.9 ± 14.2 years were included. Commonest cranial nerve involved was the abducens (75.9%) among all nerve combinations. The cavernous sinus syndrome (37%), orbital apex syndrome (22.2%) and jugular foramen syndrome (11.1%) were the most frequent anatomical patterns. Infections (40.7%) were the commonest aetiology followed by neoplastic and idiopathic in four patients.
Conclusion: Cavernous sinus syndrome was the commonest anatomical syndrome of multiple cranial nerve palsies and infections were the commonest cause in this study.

Keywords: Abducens nerve, cavernous sinus syndrome, jugular foramen, multiple cranial neve palsies, orbital apex syndrome
Key Messages: This prospective observational study was conducted to evaluate the association of multiple cranial nerve palsies with anatomical, clinical and etiological diagnoses in Indian population. We found, the cavernous sinus syndrome as the most common anatomical syndrome followed by orbital apex and skull base syndromes. Infections like; Tuberculosis and Fungal, comprise of common etiological diagnosis followed by extra-axial tumors, especially involving the skull base.

How to cite this article:
Mehta MM, Garg RK, Rizvi I, Verma R, Goel MM, Malhotra HS, Malhotra KP, Kumar N, Uniyal R, Pandey S, Sharma PK. The Multiple Cranial Nerve Palsies: A Prospective Observational Study. Neurol India 2020;68:630-5

How to cite this URL:
Mehta MM, Garg RK, Rizvi I, Verma R, Goel MM, Malhotra HS, Malhotra KP, Kumar N, Uniyal R, Pandey S, Sharma PK. The Multiple Cranial Nerve Palsies: A Prospective Observational Study. Neurol India [serial online] 2020 [cited 2020 Oct 22];68:630-5. Available from:

Isolated multiple cranial neuropathies or dysfunction is commonly encountered clinical problem. The evaluation of these patients is often overwhelming due to a wide range of aetiologies as well as the potential for devastating neurologic outcomes. Dysfunction of the cranial nerves can occur due to the lesion anywhere in their course from intrinsic brainstem to their peripheral courses.[1]

The afferent and efferent connections of the cranial nerves traverse through the meninges, subarachnoid space, bony structures of the skull, and superficial soft tissues. The cranial nerve nuclei lie within the brain stem hence intra-axial pathologic process may present initially with only cranial nerve dysfunction too. Therefore, many such pathologic processes are manifested by cranial nerve dysfunction.[2] There may be involvement of homologous nerves on the two sides (i.e., bilateral facial palsy) or different nerves on the same or contra-lateral side. In some conditions, a group of nerves is involved in a discrete anatomic region constituting distinct anatomical syndrome.

Most of the literature regarding aetiologies of multiple cranial neuropathies consists of case reports or case series. The largest reported retrospective series by Keane had 979 cases, collected over 34-year period and multiple cranial nerve palsies was defined as two or more different cranial nerve involvements.[3] There were diverse locations and causes of cranial nerve involvement and tumours were the commonest cause, however, a sizable proportion remained idiopathic.[3] Widespread and sequential involvements of cranial nerves point towards possibility of malignant infiltration of meninges, however, confirmation of diagnosis may not be possible without biopsy or before autopsy.[4]

In Indian subcontinent, where infectious diseases are predominant, tuberculous meningitis is predominant cause of cranial nerve palsies which is seen in almost one-third cases of tuberculous meningitis. The presence of cranial neuropathy is also associated with poor outcome.[5]

Since there is a paucity of Indian studies on the aetiological spectrum of multiple cranial nerve palsy, we decided to undertake this study with the aim to evaluate clinical spectrum and causes of multiple cranial nerve palsies in tertiary healthcare set up in India.

 » Materials and Methods Top

This was a prospective observational study, wherein consecutive patients presenting with cranial nerve dysfunction to the neurology department, King George's Medical University, Lucknow, were enrolled from August 2015 to August 2017 [Supplementary Document 1]. The study was approved by institutional ethical committee. Written informed consent was obtained from every patient or their guardian before being enrolled in the study.

The inclusion criteria were; patient with two or more different cranial nerve palsies or dysfunction. Non-consenting patients, patients with muscular or neuromuscular junction disorder, anterior horn cell disease, intrinsic brainstem lesions with long tract sign or any other neurological involvement apart from cranial nerves were excluded.

Clinical evaluation

All subjects underwent a detailed clinical evaluation according to structured protocol which included; recording of data in terms of onset and evolution of neurological, other constitutional symptoms, comorbid illnesses and clinical examination to confirm involved cranial nerves by an expert neurologist. Ear, nose and throat examination wherever needed was also performed, by an expert in that field.


Complete blood counts, peripheral smear examination, biochemical investigations in like Liver and Renal function tests, were done in all patients. HIV, HBsAg and HCV testing by ELISA method was done in all cases. Specific investigations such as serum anti-nuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), angiotensin converting enzyme (ACE) levels were done in clinically suspected cases. Chest radiograph and ultrasonography of whole abdomen was done in all cases. A contrast enhanced computed tomography (CECT) scan of para-nasal sinuses, base of skull, mastoid, or chest was obtained if specifically indicated.

Forty-four patients underwent cerebrospinal fluid (CSF) examination which was done in left lateral position with 22-gauge spinal needle under strict aseptic conditions. A minimum 10-15 ml of CSF was obtained and sent immediately for examination. CSF examination included protein, sugar, total and differential leukocyte count, gram stain, India ink stain, acid fast bacilli (AFB) stain, cryptococcal antigen test, polymerase chain reaction (PCR) for mycobacterium and analysis of malignant or atypical cells. Virology for herpes, enterovirus, Japanese encephalitis virus, cytomegalo virus, Ebstien bar virus, and varicella zoster virus was also performed on CSF samples.

Gadolinium-enhanced magnetic resonance imaging (MRI) brain was done in all patients. MRI was performed using a Signa Excite 1.5 T machine (General Electric Medical Systems, Milwaukee, WI, USA). The T1-weighted, T2-weighted, FLAIR, GRE, DWI, and ADC sequences were obtained in all cases. The neuroimaging was evaluated by an expert neuro-radiologist, unware of patient details and clinical data. MR angiography or CT angiogram was done in clinically suspected cases.


Multiple cranial nerve palsy was defined as involvement of two or more non-homologous cranial nerve involvement.[3] Anatomical syndrome were classified as per clinical and imaging findings, as cavernous sinus, orbital apex, jugular foramen, cerebello- pontine angle, base of skull and discrete cranial polyneuropathy syndromes. Cavernous sinus syndrome was defined as involvement with two or more of the third, fourth, fifth (V1, V2) or sixth cranial nerves.[6] Orbital apex syndrome was defined as involvement of third, fourth, sixth and fifth (V1), in combination of optic nerve (II) dysfunction. Jugular foramen syndrome was defined as; combination of involvement of ninth/tenth cranial nerve along with either eleventh or twelfth or both cranial nerves. Base of skull syndrome was defined as; involvement of multiple cranial nerves as they exit from the skull and meninges. Cerebello-pontine angle syndrome was defined as; combination of fifth, seventh and eighth cranial nerve palsy. Remaining combinations of cranial nerve involvement were classified as discrete multiple cranial neuropathy. The course of illness was categorised into acute, sub-acute and chronic. Acute onset was defined when the onset of symptoms to presentation was less than seven days. Sub-acute onset was defined when onset of symptoms to presentation 8-30 days. Chronic onset was defined when onset of symptoms to presentation more than 30 days.


The definite diagnosis was considered after biopsy from intracranial or primary lesion in clinically suspected cases of malignancy, standard criteria for a specific condition like tuberculous meningitis,[7] after angiography for vascular lesion and International Classification of Headache Disorders (ICHD-3) diagnostic criteria for Tolosa Hunt Syndrome (THS).[6] All the other cases were diagnosed as probable based on clinical features, results of the investigations and treatment response. After exhaustive battery of work up, those patients in whom diagnosis could not be established were labelled as Idiopathic.

Statistical analysis

The qualitative or categorical variables were expressed as percentages; the quantitative data were expressed as mean ± standard deviation. The categorical variables were compared using Chi-square test and Fisher's exact test. All P values <0.05 were considered as significant. Statistical analysis was done using SPSS version 16.0 (Chicago, IL, USA).

 » Results Top

Baseline characteristics

Fifty-four patients (26 males and 28 females) of multiple cranial nerve palsies were included in the study. Mean age was 39.93 ± 14.24 years. Demographic profile, baseline clinical characteristics, systemic symptoms, cranial nerve involvement, along with common anatomical combinations and aetiological profile are summarized in [Supplementary Document 2].

Anatomical syndromes

The cavernous sinus syndrome was seen in 20 cases, orbital apex syndrome in 12 cases [Figure 1], and base of skull syndrome in 8 cases. Other anatomical syndromes like jugular foramen syndrome [Figure 2], discrete cranial polyneuropathy syndromes and Cerebellopontine angle and were seen in 6, 4 and 3 cases, respectively [Table 1]. Definite diagnosis was possible in more than 50% cases of cavernous sinus and orbital apex syndromes but the differences from other syndromes were not significant.
Figure 1: Images from a 45-year-old diabetic male who presented with orbital apex syndrome. (a-d) Showing proptosis, chemosis and ophthalmoplegia involving the left eye. (e) Post contrast T1 image showing contrast enhancement of left orbital apex and ethmoid sinus (white arrow). (f) Gomori-methenamine silver staining showing fungal hyphae (black arrow)

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Figure 2: Images from patient presenting with right jugular foramen syndrome. (a and b) T2 images showing well-defined soft tissue lesion involving right jugular foramen and cerebellopontine angle. (c) Post contrast T1 image showing heterogeneous enhancement of the lesion. The lesion was diagnosed as schwanomma following biopsy. (d) Hematoxylin and eosin section from schwanomma showing hypocellular and hypercellular areas with nuclear palisading (40×)

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Table 1: Clinical anatomical syndromes with definite and probable diagnosis

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Infections were the commonest cause, found in 22 cases (40.7%) and among them, fungal and tuberculous aetiologies were equally common, found in eight (14.8%) patients each group. Tuberculous aetiology was confirmed by TB PCR in two patients and remaining six patients were diagnosed as tuberculous meningitis according to clinical, radiological and other ancillary supportive tests and observations. The fungal causes included six cases of mucormycosis and two cases aspergillosis. Four out of eight fungal cases had type 2 diabetes mellitus. Six (11.1%) patients had cavernous sinus thrombosis secondary to bacterial infection of head and neck and were diagnosed after positive blood or pus culture. All of them showed growth of Methicillin Resistant Staphylococcus aureus (MRSA). Second commonest aetiology was cranial nerves palsies secondary to tumour. Eleven (20.3%) patients had a primary CNS tumour with definite diagnosis in seven cases. Among 11 cases, there was only one intra-axial tumour (Glioma) as the cause of cranial neuropathy, but all other were extra-axial including schwanomma (four cases), meningioma (one case), chordoma (two cases), lymphoma (one case), nerve sheath tumour (one case) and epidermoid cyst (one case). Seven (13%) cases had a clinically suspected metastatic involvement of cranial nerves; among them, four cases were definite as per the results from biopsy from the primary site. Two of such patients had multiple metastases (brain, liver, lung, and lymph nodes) with unknown primary. Three (5.6%) patients had a local spread of tumour, invading the skull bone and causing cranial nerve palsies and two of them were carcinoma of nasopharynx invading the skull base and one patient had squamous cell carcinoma of middle ear which spread to the petrous temporal bone of the same side causing ipsilateral cranial nerves V, VI and VII involvements. Carotido-cavernous fistula causing cavernous sinus syndrome was seen in one case. Ten cases were idiopathic, and among them, six (11.1%) were cavernous sinus syndrome fulfilling criteria of diagnosis of Tolosa-Hunt syndrome [Table 2].
Table 2: Aetiological spectrum as per anatomical classification

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The clinical course of cavernous sinus syndrome and orbital apex syndrome was commonly found to be acute; on the other hand, jugular foramen syndrome presented commonly with a chronic course of illness. Diabetes mellitus as a comorbid condition was found in 15% of cavernous sinus syndrome and 15% of orbital apex syndrome. Fungal and bacterial infections commonly presented as cavernous sinus syndrome and of orbital apex syndrome. All the cases of THS presented as a cavernous sinus syndrome.

 » Discussion Top

Most of the previous literature regarding multiple cranial nerve palsies is either from the western countries or is in the form of case series and case reports.[3],[8] The aetiological spectrum of multiple cranial nerve palsies might be different in a developing country like India. To the best of our knowledge, this is the first study from India reporting the entire spectrum of multiple cranial nerve palsies from a tertiary care setting. Previous studies from India have only reported regarding specific anatomical syndromes like cavernous sinus syndrome or specific aetiologies like tuberculosis.[5],[9]

We found that the abducens (VI) cranial nerve was the most commonly involved cranial nerve. This was followed by oculomotor (III) and trigeminal (V) cranial nerve involvement. Cavernous sinus was the most common anatomical site of involvement; the orbital apex was the second most common site of involvement. The largest series of multiple cranial nerve palsies was published by Keane.[3] In the Keane's series, the most common cranial nerve involved was also the abducens (VI) and the most common site was cavernous sinus. But the study by Keane was retrospective and included patients with neuromuscular junction disorders, brainstem syndromes and cranial nerve palsies as a part of generalized neuropathic processes like Guillain-Barre syndrome.[3] Our study reveals a better picture of multiple cranial nerve palsies as we only included those patients who had purely multiple cranial nerve deficits; patients with stroke, brainstem syndromes, neuromuscular junction disorders, polyradiculoneuropathies and anterior horn cell disorders were specifically excluded.

Infections were the commonest aetiology, found in our study, in contrast to western literature where tumour was reported to be the most common cause multiple cranial neuropathies [Table 3]. This was expected, as prevalence of infections is much higher in developing countries like India, as compared to the developed ones. Similar findings were highlighted by Bhatkar and co-workers.[9] Tuberculous and fungal (14.8% each) infections were the most common infections encountered in our study. Tuberculous meningitis is a common cause of multiple cranial nerve palsy in India. The study by Sharma and co-workers found that cranial nerve involvement was present in 38% cases of tuberculous meningitis, with about 10% having multiple cranial nerve involvement.[5] The fungal infections encountered in our study commonly presented with orbital apex and cavernous syndromes; mucormycosis was the most common fungal infection found in our study. Bhatkar et al. reported 24.6% cases of fungal infection, aspergillosis being the most common cause.[9] Bilateral involvement and rapid onset vision loss were seen more in fungal infection as compared to other aetiologies, also shown by Chua et al.[10] Imaging findings in patients with fungal infection showed para-nasal sinusitis, multiple focal areas of bony destruction, heterogeneous signal intensity and contrast enhancement of orbit, nasal sinuses and cavernous sinus. Numerous studies have been mentioned in the literature regarding radiological findings in CNS fungal infections.[11],[12]
Table 3: Common causes of multiple cranial nerve palsies in our series; a comparative analysis with other large published series

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Tolosa Hunt syndrome, diagnosed by ICHD-III criteria [7] was seen in 11% of our cases. This frequency was lower as compared to the previous case series.[3],[9] Tolosa Hunt syndrome is an important cause of painful ophthalmoplegia, however, the aetiology remained unknown.[13] In our study, all six patients had MRI abnormality, like those reported earlier,[14],[15] strong gadolinium enhancement of cavernous sinus wall with or without focal narrowing of ICA within the cavernous sinus. Two out of six patients had type 2 diabetes mellitus. Such co-existence has been reported in recent case reports.[16] A good response to steroid was seen in all but one, who needed long-term immunosuppressant.

Metastasis followed by schwanomma were the most common tumours (benign/malignant) leading to multiple cranial neuropathies in our study. In the Keane's series,[3] schwanomma was found to be the most common tumour, while in the cavernous sinus syndrome series of Bhatkar et al.,[9] metastasis was more common than primary tumour.

Among the lower cranial nerves, the most common combination was of the IX, X and XII cranial nerves. Out the six cases, three were of tumours (one case each of pontine glioma, jugular schwanomma and nerve sheath tumour extending from craniovertebral junction to C2 vertebra). One case was of tuberculous aetiology and two cases were labelled idiopathic. This highlights that infective aetiology was less common as compared to tumour, when involving the lower cranial nerves. Common causes of lower cranial nerves palsies include vascular, traumatic, neoplastic, iatrogenic and infective.[17] In our study, no traumatic or iatrogenic causes of cranial nerve palsies were found. Also, vasculitis, which is a common group of disorders presenting with multiple cranial neuropathies, were not found in our study. A larger study would substantiate all the various groups of disorders which are reported in literature.

Thus, to conclude, among multiple cranial neuropathies, cavernous sinus syndrome and orbital apex syndrome were the most common anatomical pattern of involvement and infections such as tuberculous and fungal were the commonest causes of cranial nerve palsy in our series. The larger studies with long-term follow-up are needed in India to evaluate the causal association. Despite exhaustive workup an aetiological diagnosis cannot be reached in every case.[18-20]


We are thankful to our institution for granting permission to conduct this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Carroll CG, Campbell WW. Multiple cranial neuropathies. Semin Neurol 2009;29:53-65.  Back to cited text no. 1
Beal MF. Multiple cranial-nerve palsies: A diagnostic challenge. N Engl J Med 1990;322:461-3.  Back to cited text no. 2
Keane JR. Multiple cranial nerve palsies: Analysis of 979 cases. Arch Neurol 2005;62:1714-7.  Back to cited text no. 3
Garg RK, Karak B. Multiple cranial neuropathy: A common diagnostic problem. J Assoc Physicians India 1999;47:1003-7.  Back to cited text no. 4
Sharma P, Garg RK, Verma R, Singh MK, Shukla R. Incidence, predictors and prognostic value of cranial nerve involvement in patients with tuberculous meningitis: A retrospective evaluation. Eur J Intern Med 2011;22:289-95.  Back to cited text no. 5
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd ed.ition (beta version). Cephalalgia 2013;33:629-808.  Back to cited text no. 6
Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK, Prasad K, et al. Tuberculous meningitis: A uniform case definition for use in clinical research. Lancet Infect Dis 2010;10:803-12.  Back to cited text no. 7
Keane JR. Cavernous sinus syndrome. Analysis of 151 cases. Arch Neurol 1996;53:967-71.  Back to cited text no. 8
Bhatkar S, Goyal MK, Takkar A, Mukherjee KK, Singh P, Singh R, et al. Cavernous sinus syndrome: A prospective study of 73 cases at a tertiary care centre in Northern India. Clin Neurol Neurosurg 2017;155:63-9.  Back to cited text no. 9
Chua JL, Cullen JF. Fungal pan-sinusitis with severe visual loss in uncontrolled diabetes. Ann Acad Med Singapore 2008;37:964-7.  Back to cited text no. 10
Mancuso AA, Hanafee WN, Winter J, Ward P. Extensions of paranasal sinus tumors and inflammatory disease as evaluated by CT and pluridirectional tomography. Neuroradiology 1978;16:449-53.  Back to cited text no. 11
Jinkins JR, Siqueira E, Al-Kawi MZ. Cranial manifestations of aspergillosis. Neuroradiology 1987;29:181-5.  Back to cited text no. 12
Kline LB, Hoyt WF. The Tolosa-Hunt syndrome. J Neurol Neurosurg Psychiatry 2001;71:577-82.  Back to cited text no. 13
de Arcaya AA, Cerezal L, Canga A, Polo JM, Berciano J, Pascual J. Neuroimaging diagnosis of Tolosa-Hunt syndrome: MRI contribution. Headache 1999;39:321-5.  Back to cited text no. 14
Pascual J, Cerezal L, Canga A, Alvarez de Arcaya A, Polo JM, Berciano J. Tolosa-Hunt syndrome: Focus on MRI diagnosis. Cephalalgia 1999;19(Suppl 25):36-8.  Back to cited text no. 15
Lasam G, Kapur S. A rare case of Tolosa-Hunt-Like syndrome in a poorly controlled diabetes mellitus. Case Rep Med 2016;2016:9763621.  Back to cited text no. 16
Finsterer J, Grisold W. Disorders of the lower cranial nerves. J Neurosci Rural Pract 2015;6:377-91.  Back to cited text no. 17
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Carey RA, Nathaniel SD, Das S, Sudhakar S. Cavernous sinus syndrome due to skull base metastasis: A rare presentation of hepatocellular carcinoma. Neurol India 2015;63:437-9.  Back to cited text no. 18
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Nadgir DB, Ramdas R, Kulkarni RV, Oak PJ, Shah AB. Cavernous sinus syndrome due to syphilitic pachymeningitis. Neurol India 2003;51:289-90.  Back to cited text no. 19
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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