Introduction
Sensory ganglionopathy (SG) is a disorder characterised by damage and dysfunction of the sensory neuronal cell bodies lying in the dorsal root ganglion.Reference Sghirlanzoni, Pareyson and Lauria 1 It may be seen in degenerative conditions such as Friedreich’s ataxiaReference Koeppen 2 and is well recognised in the context of paraneoplastic disorders.Reference Graus, Delattre and Antoine 3 We and other authors have also reported SG in the context of autoimmune disorders such as Sjögren’s syndrome and gluten sensitivity.Reference Griffin, Cornblath and Alexander 4 , Reference Hadjivassiliou, Rao, Wharton, Sanders, Grünewald and Davies-Jones 5 Diagnosis can be difficult, and a set of diagnostic criteria, using both clinical and electrophysiological features, has been proposed.Reference Camdessanche, Jousserand and Ferraud 6
The trigeminal ganglion is easily assessed with electrical stimulation of the supraorbital nerve with recording electrodes placed over the orbicularis oculi muscles bilaterally. The recorded responses are termed the Blink Reflex (BR). Responses used most often in clinical practice consist of an initial response ipsilateral to the stimulus, termed R1, followed by a later response seen both ipsilaterally and contralaterally, known as R2. Fibres conducting the R1 synapse within the main trigeminal nucleus in the pons, forming a circuit with the facial nucleus via interneurons that then lead back to the facial muscles. The pathway for the R2 response is polysynaptic, with afferent fibres passing through the spinal trigeminal tract to the spinal trigeminal nucleus. From there, connections exist to ipsilateral and contralateral facial nuclei giving rise to bilateral R2 responses following unilateral stimulation.Reference Esteban 7 Abnormalities of the latencies for R1 and R2 responses are used most frequently in clinical practice.
In the context of sensory ganglionopathy, clinical evidence of sensory involvement of the trigeminal nerve innervated territory is well established in various aetiologies, including Sjögren’s syndrome, paraneoplasia, and acute autonomic and sensory neuropathy.Reference Mori, Iijima and Koike 8 - Reference Koike, Tnaka and Sobue 10 There are, however, few previous reports documenting the electrophysiological features of the BR in association with SG.Reference Auger, Windebank, Lucchinetti, Lucchinietti and Chalk 11 , Reference Malinow, Yannakakis and Glusman 12 In the largest case series, paraneoplastic disorders were not associated with any abnormalities.Reference Auger, Windebank, Lucchinetti, Lucchinietti and Chalk 11 The BR has also been used to delineate subclinical cranial nerve involvement in patients with diabetes mellitus.Reference Trujillo-Hernandez, Huerta, Perez-Vargas, Xochitl and Vasquez 13 , Reference Nazliel, Yetkin, Irteç and Koçer 14 The purpose of the present study was to determine if there was evidence of subclinical involvement of trigeminal fibres in the context of SG diagnoses made in association with a variety of conditions and to characterise any abnormalities present.
Methods
We reviewed the local electromyography database in the Department of Clinical Neurophysiology, Royal Hallamshire Hospital, Sheffield, England, over an 11-year period. We performed a search for patients diagnosed with SG, or possible SG, in whom BR data were available. This resulted in 27 patients being identified. One patient was subsequently excluded because of an interim clinical episode of Miller-Fisher syndrome, which could have accounted for abnormalities in the BR responses. The included cases were scrutinised for the information displayed in Table 1. Based on the information obtained, the diagnostic criteria scoring system for SG proposed by Camdessanche et al was completed for all patients.Reference Camdessanche, Jousserand and Ferraud 6
Table 1 Etiological, clinical, and electrophysiological data used in calculating the diagnostic criteria score for all patients
F=female; M=male; SNAP=sensory nerve action potential; LLN=lower limit of normal.
Electrophysiological examinations were performed using Nicolet EMG machines and Viking select software. Recording technique and normative data were taken from established departmental normative values that are very similar to published reference values.Reference Preston and Shapiro 15 Maximum latency is 13 ms for R1, 41 ms for ipsilateral R2, and 44 ms for contralateral R2. The maximum side-to-side difference in latency is 1.8 ms for R1 and 5.7 ms and 9.4 ms for ipsilateral and contralateral R2, respectively.
Sensory responses were recorded from the median, ulnar, radial, lateral antebrachial, and medial antebrachial nerves in the upper limbs and sural and peroneal nerves in the lower limbs. Motor studies were performed on the median, ulnar, peroneal, and tibial nerves. The number of peripheral nerves examined varied between patients, depending upon how quickly asymmetrical, non-length dependent and/or exclusively sensory involvement could be established. All patients had sensory responses from at least three limbs recorded, with 17 patients having all four limbs examined. Motor responses were recorded from a minimum of two limbs, with 17 patients having more than two limbs examined.
Results
Analysis of the clinical examinations of all patients revealed that all but three were ataxic. Asymmetrical sensory loss at the time of initial medical assessment was documented in 13 patients. Five individuals had clinical involvement of the lower limbs only, three suffered upper limb involvement only, and the remaining group had both upper and lower limb involvement. No patients reported sensory disturbance to the face or intraorally. Pain in the distal upper limbs was reported by two patients early in the course of the disease, but was otherwise not noted to be a prominent feature. Sjögren’s syndrome was recognised as the most common aetiology for SG (Table 1). No sensory responses were recordable from either the upper or lower limbs during nerve conduction studies in seven patients (Table 1). The SG diagnostic criteria scores, postulated aetiologies, and BR abnormalities are given in Table 2. All but two patients scored higher than 6.5 on the diagnostic criteria score for a diagnosis of SG. The two patients that did not achieve a score higher than 6.5 had clinical involvement of the lower limbs only, with one patient not clearly having clinical asymmetry and one not fulfilling criteria for Sensory Nerve Action Potential abnormality in the upper limbs.
Table 2 Demographic, etiological, diagnostic score and BR data for all patients
Figures in red indicate values outside of normal range. R1 and R2 latency values are in milliseconds. Maximum latency is 13 ms for R1, 41 ms for IR2, and 44 ms for cR2. The maximum side-to-side difference in latency is 1.8 ms for R1 and 5.7 ms and 9.4 ms for ipsilateral and contralateral R2, respectively.
BR=blink reflex; cR2=contralateral R2; iR2=ipsilateral R2; F=female; male=male.
Analysis of the BR recordings revealed abnormal responses in 9 of 26 patients (34.6%). In two patients, isolated abnormality of the R1 response was noted (Table 2). One patient showed abnormality of the R1 and R2. In the remaining six patients, only R2 abnormalities were seen. Four of nine patients with abnormal BR studies had magnetic resonance imaging of the brain performed. No evidence of brainstem pathology was apparent in any of the cases. In one additional patient with an abnormal BR, full-body positron emission tomography scan was normal. Interestingly, the BR was normal in five of seven patients in whom no sensory responses could be recorded from the limbs.
Discussion
In our cohort, six of 26 patients had abnormalities of R2 and three patients had R1 abnormalities. The R1 response is generally regarded as the more robust response in terms of both latency and resistance to modulation from external factors. Our data suggest that subclinical involvement of trigeminal fibres can be seen in patients with SG, with variable involvement of the R1 and R2 responses.
Overall, our most frequent observation was that of disturbance to R2, with abnormalities ranging from mild prolongation of R2 latency to absence of the R2 response. The pathologic correlate of this finding would appear to be either the more selective involvement of cell bodies of fibres conducting the R2 response within the Gasserian ganglion, or in the multisynaptic central pathways responsible for R2 generation. Previous work looking at cranial reflexes in patients with Sjögren’s syndrome and SG postulated that the likely site of pathology was at the level of the Gasserian ganglion.Reference Valls-Sole, Graus, Font, Pou and Tolosa 16 We suspect that the abnormalities seen in our cohort are also more likely to be secondary to involvement of the Gasserian ganglion.
It is interesting to note that five patients had no sensory responses recordable from the limbs, but had a normal BR. This disparity could be explained by the fact that the fibres conducting both R1 and R2 are thought to be of thin- to medium-thickness myelinated fibres,Reference Esteban 7 , Reference Shahani 17 unlike the large A-alpha fibres responsible for sensory nerve action potential generation on examination of the limbs. There is some suggestion that the A-delta fibres in the limbs are relatively spared in patients with SGReference Leis, Kofler and Ross 18 ; this disparity in fibre type could explain why the BR appears relatively preserved or shows modest abnormality in the context of severe involvement of the limbs.
Our finding of R2 abnormality with preservation of the R1 latency in patients with Friedreich’s ataxia is similar to findings from a previous study examining BR and auditory evoked potentials in this group of patients.Reference De Pablos, Berciano and Calleja 19 Intriguingly, an autopsy of a patient with Friedreich’s ataxia demonstrated loss of secondary sensory neurons in the trigeminal nuclei,Reference Jitpimolmard, Small and King 20 an observation that would manifest on the BR as prolongation/absence of the R2 component. We are not aware of any neuropathological studies looking at the Gasserian ganglion in cases of confirmed SG.
An important observation in our study is the finding of abnormal BR responses in paraneoplastic cases. It has previously been reported that the BR is normal in SG seen in association with malignancyReference Auger, Windebank, Lucchinetti, Lucchinietti and Chalk 11 ; however, we found abnormalities in four of five patients. Although such patient numbers are small, this is in clear contrast to the previous report in which no BR abnormalities were reported in 17 cases of paraneoplastic SG. Although some of the patients with a paraneoplastic SG had only mild R2 abnormalities that one might argue are of equivocal significance, two patients had abnormalities of the R1, which is a robust marker of pathology. The disparity between our findings and those of previous studies could relate to the patchy nature of such disease.
In conclusion, we report BR abnormalities in 34.6% of our SG cohort. The most common abnormality was prolongation of the R2 component, although R1 abnormalities were seen in one-third of those with an abnormal BR. The most likely cause of the BR abnormality is pathology at the level of the Gasserian ganglion, although involvement of the central polysynaptic pathways could also potentially cause abnormalities of the R2 response. Finally, BR abnormalities can be seen in SG related to paraneoplasia.
Disclosures
TA, ASEB, JJPA, MH, and DGR do not have anything to disclose.
