Sherifa A. Hamed et al..

Cranial and Peripheral Neuropathy in Rheumatoid Arthritis with Special Emphasis to II, V, VII, VIII and XI Cranial Nerves Sherifa A. Hamed1, Eman A. Hamed2, Amal M. Elattar3, Mohamed S. Abdel Rahman4, Nabila F. Amine5 Departments of Neurology1, Rheumatology & Rehabilitation2, Audiology Unit3, Ophthalmology4, Internal Medicine5, Assiut University

ABSTRACT Background: Reports about cranial nerve involvement in rheumatoid arthritis are insufficient compared to the frequently reported peripheral nerve involvement. Methods: We investigate the occurrence of electrophysiologically evident peripheral and cranial nerve involvement in 55 patients with rheumatoid arthritis (RA) without manifest neuropathy. Results: Patients mean age was 43.1 years and duration of illness was 6.4 years. All patients presented with electrophysiological findings suggestive of peripheral neuropathy. In addition, 69.1% of them had entrapment neuropathies. Carpal tunnel syndrome (CTS) was the commonest entrapment neuropathy (54.6%). Sensorimotor neuropathy with variable severity at sites other than the usual entrapment sites, was diagnosed in 70.9% while bilateral distal sensory neuropathy in lower limbs was identified in 29.1%. Among cranial nerves examined, optic and vestibulocochlear neuropathies were common (29.1% of eyes and 40% of ears examined respectively). Spinal accessory neuropathy was demonstrated in 21.8% of records. Neither facial nor trigeminal nerves were affected. Electrophysiological characteristics of peripheral and cranial neuropathies were indicative of axon loss. Significant association was identified between presence of neuropathy and patients’ ages, duration of the illness, presence of rheumatoid nodules and advanced disease stages. Conclusions: Prolonged immune-mediated vasculitis is the most likely cause of cranial and peripheral neuropathies. However, neurotoxicity from drugs employed in RA treatment, in addition, can not be excluded. (Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2): 545-558).

INTRODUCTION Rheumatoid arthritis (RA) is the most common connective tissue disease, affecting 1% of the population with 3 times more common in females than males. It is mainly a chronic and disabling articular disease1. Based on clinical and immunological observations, it has been well known that nervous system is directly involved in rheumatoid arthritis2. Although involvement of peripheral nervous system (PNS) has been well characterized and frequently reported in RA3,4, the spectrum of cranial nerve involvement in RA remains unclear5. The following cranial neuropathies were rarely reported in rheumatoid arthritis including; trigeminal sensory neuropathy5,

vestibulocochlear neuropathy6,7 and optic 8,9 neuropathy . Peripheral nerve disorders in RA include entrapment neuropathies, multiple mononeuritis, sensorimotor neuropathy and mild sensory neuropathy10. Neuropathies are usually related either to nerve compression by rheumatoid nodules, swollen synovium, aponeurosis or bony exostoses3,4,11 or vasculitis12,13,14. It is generally accepted that immune-vascular mediated mechanisms are responsible for the diverse spectrum of abnormal nerve signs in RA. It is often difficult to diagnose the presence of peripheral neuropathy if slight or early particularly in presence of joint pain and limitations of movement13,14. Standard neurological examination was found to be inadequate for diagnosing suspected early peripheral

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or cranial neuropathy in patients with RA. Electrophysiological testing can be utilized for early diagnosis, defining the extent of peripheral and cranial nerve involvement15,16. Early diagnosis of nerve involvement will help prompt and timely interventions with redirection of management to prevent permanent neurologic sequelae, improve quality of life and chances for long-term survival with less morbidity. The main objectives of this work were to: (1) determine the prevalence and characteristics of cranial nerve involvement (optic, trigeminal, facial, vestibulocochlear and accessory nerves) in patients with RA, in presence or absence of non-entrapment peripheral neuropathy, and (2) correlate cranial and non-entrapment peripheral nerve involvement with different demographic parameters (age, duration of the illness, grades of functional status, disease activity and extra-articular manifestations).

PATIENTS AND METHODS Patients: This study included fifty-five patients (male/female = 10/45) established the revised criteria of American Collage of Rheumatology for rheumatoid arthritis14. All were recruited from the department of Rheumatology over a period of 2 years (2002-2004), Assiut University Hospital, Assiut, Egypt. Excluded from this study were patients with history of manifest central or peripheral nervous system involvement. All patients were specifically asked for symptoms regarding entrapment neuropathies and other neuropathies. During our study, 8 patients with RA were excluded because they had manifest peripheral nervous system involvement. Excluded also were patients with concomitant primary neurologic disease, medical illness as diabetes mellitus or chronic illness that precipitate peripheral nerve involvement, ear or eye problems and usage of drugs (other than for treatment of RA) known to cause neurotoxicity. Sixty sex- and age-matched healthy volunteers served as controls for all neurophysiologic testing. All were selected from hospital paramedical staff and workers. All were specifically asked for symptoms of entrapment neuropathy and neuropathies for general. 546

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This study was accepted by the regional Ethical Committee. Detailed information on the study was given to all patients and control subjects and all gave their written consent to attend this study.

Methods: All patients underwent complete rheumatologic, medical, neurologic, ophthalmologic and audiologic history and examination. The clinical characteristics of the patients were recorded by joint pain assessment using visual analogue scale (VAS)17, morning stiffness, number of tender joints (Richie index)18, number of arthritic joints, presence of rheumatoid nodules, functional capacity assessed according to ACR revised criteria for the classification of global functional status in RA19 and hand grip strength measurements20. Laboratory parameters included: rheumatoid factor (RF) determined by latex agglutination test, RF titre of =1:80 was considered significant21, erythrocytic sedimentation rate (ESR), C-reactive protein (CRP), complete blood count (CBC), blood urea and creatinine and liver function tests. Radiological grading (X-ray) of both hands, wrists, feet and any other affected joints were performed and staged according to Larsen index (0-4)22 where grade 0 is normal and grade 4 is mutilating abnormality. Electrophysiologic tests: Sensory and motor nerve conduction studies of median, ulnar, common peroneal and sural nerves, were tested on all patients and controls using Dantec Keypoint equipment Medtronic Copenhagen, Denmark. Distal latency (DL), nerve action potentials and F wave determination were measured with surface stimulating and recording techniques as described by Stalberg and Falck23 and Falck et al.24. Based on nerve conduction study findings, we pathophysiologically classified nerve abnormalities as previously described into three group: demyelinating, axonal and mixed (both axonal and demyelinating). In general and regardless of the cause of nerve injury, large myelinated axons responded pathologically either by axon loss or focal demyelination. When enough axonal fibers are affected by a pathological process, degenerated axons no longer contribute to the motor or sensory nerve conduction study responses and the amplitudes of the latter are correspondingly decreased. Focal injury of myelinated fibers that is not severe enough to cause wallerian degeneration

Sherifa A. Hamed et al..

can still compromise the physiological properties of the nerve at the lesion site and thereby impair conduction across it. Focal slowing across the lesion site is said to be synchronized or uniform whenever conduction along essentially all large myelinated fibers is slowed, and essentially to the same degree. In these situations, on nerve conduction studies, the latencies and conduction velocities are altered, but not the amplitude and the duration of the responses. The latencies and conduction velocities (CVs), determined by the conduction rate along the fastestconduction slowing is referred to as differential or desynchronized or non-uniform slowing. In some cases, all fibers are affected by focal demyelinating slowing, but some are affected even more than others. This produces a combination of the two processes described earlier: the distal latencies and CVs are slowed, but in addition, the compound motor and sensory action potentials (CMAPs and SNAPs) are dispersed and often low in amplitude25. Although we are not aiming detection of entrapment neuropathies in such patients, but we applied special neurophysiological techniques to determine the presence of common entrapment neuropathies as was reported before15,26,27 and differentiate them from other peripheral neuropathies (e.g. vasculitic and toxic). These include Carpal tunnel syndrome (CTS), ulnar neuropathy at elbow (Cubital tunnel syndrome), posterior interosseous nerve syndrome, peroneal nerve entrapment at knee joint and planter nerves entrapment at the tarsal tunnel. We utilized segmental stimulation (inching technique) of antidromic sensory conduction of the median nerve across the carpal tunnel as described by Kimura28. Conduction time exceeding 0.5 msec/cm than twice that of the other 1cm segment is considered abnormal. Short segmental stimulation method across the elbow using surface recording and stimulating electrodes was utilized to detect ulnar nerve motor nerve conduction across the elbow. Inching technique at 2cm segment with elbow extended were done as described by Kanakamedala et al.29 for localization of lesion in the cubital tunnel. Motor conduction technique utilizing needle stimulating electrode was utilized as described by Flack and Hurme30 to examine the posterior interosseous nerve, CMAP was obtained over the extensor indicis proprius muscle. Short-segment stimulation method for motor nerve conduction of

the peroneal nerve across the fibular head was done as described by Kanakamedala and Hong31. Prolongation of conduction time and/or abnormal amplitude reduction more than 3SD (standard deviation from mean of the controls) was used as criterion of abnormality. The motor nerve conduction of the posterior tibial verve across the tarsal tunnel was determined utilizing surface electrode recording and stimulation as described by Flesenthal et al.32. Amplitude decrement of more than 30% across the tarsal tunnel is considered abnormal. We specially emphasizing examination of only optic, vestibulocochlear, facial, trigeminal and spinal accessory cranial nerves and not other cranial nerves based on previous involvement of some of these nerves as rarely or commonly involved in RA and other connective tissue diseases due to vasculitic processes and guided by recent reports5,6,7,8,9. In addition, the feasibility and applicability of examination techniques for these nerves are not time consuming and harmless. Facial and accessory nerve distal latencies and amplitudes were measured according to technique described by Stalberg and Falck23. Facial nerve distal latency (DL) was measured with surface stimulating electrode excited the facial nerve at stylomastoid foramen and recording picking electrode was placed on frontalis muscle. Accessory nerve DL was measured with surface stimulating electrode excited the accessory nerve in the posterior triangle of the neck behind the sternocleidomastoid muscle and recording picking electrode was placed on upper part of the trapezius muscle at the junction of the middle and lateral third of the upper border of the muscle. Blink reflex (BR) was obtained by transcutaneous electrical stimulation of the supraorbital branch of the afferent trigeminal nerve using bipolar surface stimulating electrodes as described in Kimura33. Blink reflex is an established method with which it is possible to evaluate the function of the trigeminal (afferent arc) and facial nerves (efferent arc). It can differentiate between disorders of the trigeminal, efferent facial and central (brainstem) parts of the reflex arc33,34. Elicited BR consists of an early and late polysynaptic ipsilateral (R1 and R2i) and contralateral (R2c) responses. Prolonged latency of R1 and R2i responses suggests a lesion of the

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ipsilateral afferent arc (trigeminal). On the other hand, unilateral delay in the latency or absence of the R1 and R2 response regardless of the side of the stimulation suggests a lesion of the efferent arc, the facial nerve. Due to wide range of variability of R2 latency measurements, a latency measurement of R1 is more useful33.

Eye examination: * Visual evoked potential (VEP): VEP was recorded using pattern-reversing checkerboard uniocular (RT and LT) field with a checker size 16’ using Nihon Kohden (Model 2104) evoked potential equipment. VEP is a sensitive method to detect early abnormalities within the optic pathway. Recording over the mid-occiput pattern-reversal VEP (PRVEP) usually has a negative-positive-negative configuration, the major positive peak occurs at 100 msec (P100) in normal subjects35. Peaks are labeled using the average latency values in normal subjects: N75, P100 and N145. VEP amplitudes are more variable and less specific than latencies. We measured the amplitude as the sum of the peaks from N75 to the N100 and that of P100 to N145. As compared to the controls, prolonged latency of P100 indicates demyelinating optic neuropathy while low amplitude indicates axonal optic neuropathy36,37. * Visual field examination: All patients underwent complete ophthalmic examination including measurement of intraocular pressure using applanation tonometry and assessment of optic disc by direct ophthalmoscopy using red-free filter before subjection to visual field examination and all were normal. The automated perimeter used in this study was the Octopus perimeter 500EZ (Bowel radius: 42.5cm, background luminance 4asb; stimulus size available: Goldmann III)38. Basic audiological evaluation according to Elwany et al.39, included: All patients underwent pure-tone audiometry, speech discrimination, tympanometry, and acoustic reflex for basic audiological testing by a specialist audiologist. Pure tone air and bone conduction audiometry were conducted in sound treated room 548

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using audiometer Madsen OB822, six frequencies were utilized: 250, 500, 1000, 2000, 4000 and 8000 Hz. Air conduction hearing threshold level for octave frequency between 250-8000 Hz and bone conduction threshold for frequencies between 2504000HZ was done. Hearing impairment was defined as the average hearing threshold for the better ear at 500, 1000 and 2000 Hz40. Grading of impairment was adopted according to Northern and Downs41 into: Mild impairment is defined as Average threshold between 25-40 dB, moderate impairment is defined as average threshold between 41-55dB, moderately severe impairment is defined as average threshold between 56-70dB and severe impairment is defined as average threshold between 71-90 dB.

Neuroimaging examination: Patients with spinal accessory nerve involvement underwent magnetic resonance imaging (MRI) of the cervical spine to exclude compression induced neuropathy. Statistical analysis: Data were analyzed using SPSS II computer program, version 10.0. Calculation of the normal limits of electrophysiological data was done utilizing parametric (Pearson’s correlation. Spearman and Mann-Whitney for differences were utilized when the distribution in normal individuals is nongaussian (e.g. amplitude distribution). Chi-square test was applied for binomial data. P