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July2005 Vol.42 Issue:      2 Table of Contents
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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



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).




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 neuropathy8,9.

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 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).





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.

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.



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 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 fastest-conduction 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 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 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 250-4000HZ 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<0.05 was set as significant. Hearing loss was calculated for each ear separately as the amount of threshold shift above the standard audiometric zero, and the average hearing loss of both ears was calculated.




This study included fifty-five patients (male/female ratio = 1: 4.5) diagnosed as RA. The demographic, clinical and laboratory data of the studied group of patients were shown in table (1). Except for the presence of subcutaneous rheumatoid nodules in 72.7% (n=40), non of the patients demonstrated obvious extra-articular manifestations related to rheumatoid arthritis on history and clinical assessment. Patients were treated for at least one month, with single or various combination of the following medications: methotrexate (7.5 mg/week), low-dose steroids (mean 9.0mg/d, in range of 5-25mg/d), folic acid (5mg twice daily) and non-steroidal anti-inflammatory drugs (NSAIDs).

Our patients demonstrated one or more of the following patterns of neuropathies on Electrodiagnostic examination (Table 2): 1) entrapment neuropathy in 69.1% (n=38): bilateral CTS was identified in 54.6% (n=30) of our patients. Only three patients had unilateral cubital tunnel syndrome (5.5%) and five patients (9.1%) had unilateral entrapment of the peroneal nerve at the level of the knee. 2) all patients had peripheral neuropathy recorded away from the common entrapment sites, including: a) Unilateral or bilateral sensorimotor neuropathy involving the same or different peripheral nerves with variable severity at sites other than the usual entrapment sites, was diagnosed in 70.9% (n=39) of patients, and b) bilateral distal sensory neuropathy in lower limbs (sural nerve involvement) was identified in 29.1% (n=16) of patients.

Tables (3) and (4) showed that axonl polyneuropathy (amplitude reduction) was frequently reported in different studied nerves followed by mixed demyelinating (prolonged distal latencies) and axonal neuropathy. Among, sural nerve demonstrated significantly reduced nerve conduction velocity studies (Table 4).

All patients had corrected visual acuity of 6/12 or better, unremarkable anterior segment, introcular pressure and fundus examinations. As P100 amplitude distribution in normal individuals is nongaussian, we applied nonparametric statistics in attempts to calculate the normal limits. Visual abnormalities was observed in (n=32 eyes) 29.1% of eyes examined. Unilateral and bilateral abnormalities represented 28.1% (n=9) and 71.9% (n=23) of them respectively. VEP was abnormal in 14.6% (n=16 eyes), visual field defects was observed in 23.6% of eyes examined (n=26 eyes) among which combined field and evoked response abnormalities were reported in 31.25% of them (n=10 eyes). Minimal prolongation of P100 latencies (demyelinating optic neuropathy) represented 12.5% (n=2) of total abnormalities detected by VEP, prolonged latency and reduced P100 amplitudes (mixed demyelinating and axonal optic neuropathy) represented 37.5% (n=6) of all abnormalities, while the majority of VEP abnormalities (n=8 or 50%) were in the form of minimal amplitude reduction (axonal optic neuropathy) (Table 5).

Visual field defects are grouped into central (7.7% or 2/26), centrocecal (19.2% or 5/26), seidle (3.9% or 1/26), arcuate (19.2% or 5/26), nasal step (3.9% or 1/26), peripheral constriction (11.5% or 3/26), generalized heterogeneous or deep depression (34.6% or 9/26), depressed foveal threshold (3.9% or 1/26), and combined field defects (11.5% or 3/26, one with arcuate and central scotoma, one with double arcuate and temporal wedge scotoma and one with upper arcuate and depressed foveal threshold scotoma).

Hearing impairment was identified in 29.1% (32/110 of ears examined) in which sensorineural and conductive hearing impairment represented 87.5% (28/32) (P<0.05) and 12.5% (8/32) (p<0.05) of them respectively. Bilateral sensorineural and conductive hearing impairment was identified in 18.2% (10/55) and 7.3% (4/55) of patients respectively while unilateral sensorineural hearing impairment was identified in 14.6% (8/55). Mild and moderate hearing impairment was identified in 27.3% (15/55) and 9.1% (5/55) of patients respectively. Speech discrimination, acoustic reflex and tympanograms did not show a statistically significant difference between patients and controls.

Although mild prolongation of R1 component of the blink reflex was reported in 10.9% records (12/110) (RT; 11.1±1.7 and LT; 10.9±0.8 vs 10.8±0.8 ms for controls) but this prolongation remained within the normal range indicating very minimal 'afferent' or trigeminal nerve defect. No statistically significance difference was between R2 values of patients’ and control groups [(R2i: RT; 36.0±1.9 and LT; 35.7±5.1 vs 33.7±2.6 for controls) and (R2c: RT; 32.4±4.2 and LT; 37.4±6.5 vs 35.2±2.8 for controls)].

Prolonged facial nerve was identified compared to controls (1.8% or 2/110 of records) while minimal amplitude reduction was observed (4.6% or 5/110) (Fig. 1).

Electrophysiological abnormalities of the spinal accessory nerve were demonstrated in 24 records (21.8% or 24/110) (Fig. 2). Prolonged latency of the accessory nerve (demyelinating accessory neuropathy) was observed in one record (0.9% or 1/110), diminished amplitude of the accessory nerve (axonal accessory neuropathy) was observed in 15 records (13.6% or 15/110) (P<0.01), while combined prolonged latency and diminished amplitude (mixed axonal and demyelinating accessory neuropathy) was observed in 7.3% of records (8/110).

Using parametric and non-parametric statistics, significant positive associations were identified between abnormal electrophysiological findings and the following variables: age of the patients (P<0.01), the duration of illness (for all >10 years duration) (r=0.656, P<0.001), stage of the disease (long-lasting RA of third and fourth clinical grades) (r= 0.659, P<0.001) and presence of rheumatoid nodules (r=0.598, P<0.001). While no association was found between abnormal electrophysiological finding and activity of the disease, positive rheumatoid factor, ESR and treatment modality.



Table 1. Demographic, clinical and laboratory data of the studied RA patients.



Age; years

43.1±13.3 years (range 16-74 years)

Sex (M/F)

10/45 (18.2±81.8)

Duration of illness, years:

6.4±5.2 (range 2½-22)

Morning stiffness (minutes)


Number of active joints


Richie articular index (RAI)


Pain scale (VAS)


Functional capacity (range;1-4)


X-ray grading (G0-4)



6 (10.9)


7 (12.7)


26 (47.3)


16 (29.1)

Subcutaneous nodules (SN):

40 (72.7%)

Laboratory findings:


C-reactive protein (CRP):



7 (12.7)


42 (76.4)

Not done

6 (10.9)

Rheumatoid factor (RF):



17 (30.9)


33 (60.0)

Not done

5 (9.1)

Erythrocytic sedimentation rate (ESR):


High ESR1st hour


High ESR2nd hour




Methotrexate (MTX), steroids and NSAIDs

8 (17)

MTX and steroids

5 (10.6)


13 (27.7)


21 (44.7)

# (%): Number of patients and their percentage

Table 2. Patterns of peripheral neuropathy among the studied group of patients.


Pattern of peripheral Neuropathy

Number of patients (%)

1) Entrapment neuropathies:

38 (69.1%)

- Carpal tunnel syndrome

30 (54.6)

- Cubital tunnel syndrome

3 (5.5)

- Peroneal neuropathy at the knee

5 (9.1)

2) Sensorimotor neuropathy

39 (70.9)

3) Distal sensory polyneuropathy

16 (29.1)


Table 3. Pathophysiologic classification of peripheral neuropathy among the studied group of patients.


Peripheral neuropathies [Total # of nerves examined per patient= 110]



Axon al


Mixed demyelinating

& axonal neuropathy

Median nerve





5 (4.6)

12 (10.9)

27 (24.6)


13 (11.8)

11 (10.0)

22 (20.0)

Ulnar nerve





3 (2.7)

28 (25.5)

9 (8.2)


2 (1.8)


15 (13.6)


1 (0.9)

32 (29.1)

5 (4.6)


4 (3.6)

17 (15.5)

24 (21.8)

# (%): Number of nerves affected and their percentage


Table 4. Nerve conduction velocity (NCV) studies of RA patients compared to controls.


NCV study

Right side

Left side


Motor conduction, m/s












Common peroneal nerve




Distal latencies, ms












Common peroneal nerve




Amplitude of CMAPs, mV












Common peroneal nerve




F wave, ms




Median nerve




Ulnar nerve




Tibial nerve




Sensory conduction, m/s
















Distal latencies, ms
















Amplitude of SNAPs, mV

















*p<0.05; **p<0.01; ***p<0.001

Table 5. Visual evoked responses of patients with RA compared to controls.





P100 latencies, m/s



Right eye



Left eye



Amplitudes, mV









* p<0.05




Fig. (1): Facial nerve latency and amplitude (patients vs controls).





Fig. (2): Accessory nerve latency and amplitude (patients vs controls).



Cranial nerve abnormalities have been described in several connective tissue diseases, but relevant data in RA is very insufficient42.

In this study, we reported electrophysiological findings suggestive of entrapment neuropathy in 69% of our patients which is in agreement with many previous studies. Entrapment neuropathy in rheumatoid arthritis is common, among which impingement of the median nerve in the carpal tunnel (CTS) was the most common (54.6%). It has been previously demonstrated that the prevalence of CTS in patients with RA is about twice as high in general population(11), occurring in 23-69% of patients26,43. It is due to median nerve compression in the wrist by tenosynovitis of the flexor tendons of the fingers. Cubital tunnel syndrome or ulnar nerve entrapment just below the elbow was reported in 5.5% of our patients. It is most probably due to compression by the bulging synovium and the taut aponeurosis of origin of the flexor carpi ulnaris which likely occur in presence of joint deformity44. Peroneal nerve entrapment at the knee joint was reported in 9.1% of the patients. It is possibly due to entrapment by a big Baker’s cyst, visually obvious, extending from the knee joint.

In addition to entrapment neuropathies, all our patients demonstrated electophysiological finding suggesting peripheral nerve involvement away from the common sites of nerve entrapment. Immune-mediated vasculitic process is likely suggested as a cause of peripheral neuropathies. In support: 1) presence of electrophysiological evidenced peripheral neuropathy of various types away from common compression sites (unilateral and bilateral sensorimotor neuropathy, distal sensory neuropathy), 2) the neurophysiological typing and criteria (mainly axonal loss) are highly suggestive of vasculitic etiology. Many clinicopathologic studies support the notion of an ischemic mechanism is the most likely cause of axonal peripheral neuropathy in RA. Autoimmune vascular injury due to heightened immune response to basement membrane antigens would be behind the dysfunction of the vasa nervosum of the peripheral and cranial nerves45, 3) positive association was demonstrated between peripheral neuropathy and patients’ age and duration of illness. It was previously demonstrated that inflammation with polymorphnuclear cells of small and medium-sized blood vessels and occur in 50% of patients with rheumatoid vasculitis with an average age of 56 years46.

Sensorimotor neuropathy, mainly asymmetrical and involving two or more different peripheral nerves, was demonstrated in 70.9% of patients. It has been reported that mononeuritis multiplex and mixed sensorimotor neuropathy are present in patients with RA and vasculitis46,47. Symmetrical distal sensory neuropathy was reported in 29% of the patients. It has been suggested that endarteritis of vasa nervosum resulting in ischemia of the nerve is responsible for pathogenesis of these types of neuropathy. The variable clinical expression can be explained by the acuteness of ischemia, the presence of collateral circulation, and the degree of nervous tissue sensitivity to ischemia48. Vasculitic neuropathy in RA can occur without systemic necrotizing vasculitis12,49,50. Vasculitic neuropathy is one of the clinical manifestations of extra-articular rheumatoid arthritis and as this is considered as a major predictor of mortality in patients with RA, hence prompt diagnosis and treatment is essential to improve the outcome13,51.

Although previous studies reported seldom involvement of cranial nerves in rheumatoid arthritis, in contrast, our results indicate that cranial neuropathy in RA is not uncommon. Approximately one third of the records demonstrated either abnormal visual evoked response and/or field defect suggesting optic nerve involvement. Half of the abnormalities were suggestive of nerve axonal loss (reduced amplitudes). RA was known to be a rare cause of optic neuritis. Vasculitis is often discussed as a cause of optic neuritis but remains controversial in its significance. Vasculitic optic neuropathy or retinopathy, if present in RA was said to be secondary to concomitant hypertension or due to some connective tissue disease other than RA52,53. It had been previously reported that rheumatoid pachymeningitis is the cause of compressive optic neuropathy54. Some studies reported that paracentral visual field defects showed fluctuation parallel to methotrexate dose changes55. In this study, we attributed optic neuropathy to be a primary complication of vasculitic RA and/or secondary to drugs used for its management, however we did not identified significant correlation between utilization of methotrexate and optic neuropathy. Although methotrexate (MTX) remains the most commonly used disease modifying antirheumatic drug in RA because of its cost and experience in its use56, but toxic optic neuropathy is rarely seen with MTX. There are some reported cases56,57 and few registered in United States National Registry of Drug Induced Ocular side effects (Dr F Fraunfelder, pers. Comm., 2001) most occurred after long duration low-dose therapy without obvious precipitant. The pathogenesis is thought to be a demyelinating neuropathy due to MTX-associated folate deficiency57. As most of optic neuropathies in our study showed the electrophysiological characteristics of axonal involvement, so MTX seems unlikely to be the cause.

In this study, basic audiological evaluation revealed that both conductive and sensorineural hearing impairment occurs in approximately 1/3 of patients with RA. Both sensorineural and conductive hearing losses, has been reported in patients with RA6. Some investigators suggested that the most of hearing loss in RA is conductive in nature because the incudo-stapedial and incudo-malleolar joints are synovial in type, hence they could be involved in the rheumatoid inflammatory process as any other joints elsewhere in the body altering the ossicular mechanisms in response to static air pressure modifications58. Discontinuity of the ossicles, rather than stiffness and increased laxity of the middle ear transducer mechanism was also suggested to be responsible for the conductive hearing loss6,7. On the other hand, others reported that the significantly greater hearing loss in RA patients was of sensorineural type and not conductive as a result of extra-articular manifestations of the disease when rheumatoid nodular vasculitis producing damage to the inner ear structures and this is consistent with ours59. Direct immunological damage to the cochlea, arthritis of the vasa nervosum of the auditory nerve due to antigen antibody complex is expected to produce retrochochlear type of hearing loss60,61.

We reported high frequency of subclinical involvement of the spinal accessory nerve (21.8% of records). The main bulk of literature on RA attributes brainstem/cranial nerve dysfunction to bone compression caused by destruction in joints, ligaments and bones by synovitis with consequent sublaxations, mostly at the upper cervical spine. The craniocervical junction is the most delicate localization of RA because of the adjoining sensitive neurovascular structures in the spinal canal62. Anterior atlantoaxial sublaxation is by far the most frequently reported complication of rheumatoid cervical spines and hence lower medullary cranial nerves may undergo affection by compression mechanism. Morphological and functional analysis of all anatomically affected structures is required for early diagnosis. However cranial nerve involvement due to vasculitic process (rheumatoid nodular vasculitis) is also highly suggested in our series in support: 1) absence of radiological evidence of upper cervical cord compression (plain X-ray and MRI imaging) (data not shown), 2) significant positive correlation was identified between involvement of different cranial nerves and patients’ age, duration of illness, presence of rheumatoid nodules and advanced disease stages, and 3) presence of electrophysiological evidence of axonal nerve loss is the common finding in all other affected cranial nerves (optic, trigeminal and facial nerves). Vasculitis is the most plausible explanation for cranial neuropathies located away from the common compression sites.

Consistent with ours, the occurrence of a trigeminal sensory neuropathy in association with connective tissue diseases is rare, but has been generally accepted as a feature of these diseases42 and irrespective to the disease activity. Most have been reported in diffuse or limited systemic sclerosis, mixed connective tissue diseases and in undifferentiated connective tissue disease63. Facial nerve involvement was also rarely reported among patients with patients with systemic sclerosis, systemic lupus erythematosus (SLE) and mixed connective tissue diseases12,64,65.

Although we did not find a significant association between the utilized drug modality and the abnormal neurophysiological findings, however, the possibility of drug neurotoxicity as a concurrent factor can not be excluded56,61,66. In support: 1) diffuse peripheral and/or cranial nerve involvement was common among patients, and 2) mild bilateral neurophysiological abnormalities are more compatible with diffuse drug toxicity rather than focal vasculitis.



To our knowledge, this is the first study that reported high frequency involvement of cranial nerves in RA patients. The higher incidence of vasculitic optic and vestibulococular neuropathies was surprising and specific vulnerability of these nerves to vasculitis over other cranial nerve needs further critical research. The study also can not exclude the uncommon ocular, auditory and peripheral nerve toxicity related to the drugs frequently employed in RA treatment. The ability to identify and classify clinical and subclinical nerve abnormalities in patients with RA using electrophysiological tests can provide a useful test to the clinician for early evaluation and management of neurological RA. The high prevalence of hearing loss supports the value of doing audiometric studies before excluding cranial nerve involvement in this disease. In addition, awareness and early diagnosis of otologic sequelae in patients with RA will help redirection of management and prompt rehabilitation.




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الملخص العربى


دراسة تأثر الأعصاب الدماغية والطرفية فى مرضى الرثيان المفصلى مع التأكيد على  دراسة اصابات

الأعصاب الثانى، الخامس، السابع، الثامن والحادى عشر من الأعصاب الدماغية


أشتملت هذه الدراسة على عدد 55 مريضا بالرثيان المفصلى ممن لا يعانون من تأثر ظاهرى للأعصاب الدماغية أوالطرفية، و66 من الأصحاء ممن لهم عمر وجنس متناسب لمرضى هذه الدراسة كمجموعة ضابطة. وقد تم فحص جميع المرضى والأصحاء فحصا اكلينيكيا كاملا وبالاختبارات المعملية الروتينية وتقييم ودراسة الأعصاب الدماغية والطرفية لهولاء بالطرق المختلفة لدراسات فسيولوجيا الأعصاب.

وتبين من هذه الدراسة أن جميع مرضى الرثيان المفصلى يعانون من تغيرات مرضية بواحد أو أكثر من الأعصاب الطرفية. وكانت اصابة العصب الأوسط فى متلازمة نفق الرسغ هى الأكثر شيوعا (54.6%) بين التغيرات المرضية الناتجة عن شراك الأعصاب. فى حين أظهرت الأعصاب الحسية والحركية تغيرات مرضية مختلفة فى اصابتها، بينما شكلت  اصابات الأعصاب الحسية المتطرفة نسبة (29.1%) فى هؤلاء المرضى.

وقد أوضحت هذه الدراسة أيضا تأثر الأعصاب الدماغية وكانت التغيرات المرضية فى العصب الثانى والثامن هى الأكثر وضوحا وعلى العكس تبين عدم تأثر العصب الخامس والسابع الدماغى بين هذه المجموعة. هذا وقد أظهرت الدراسة وجود علاقة ايجابية ذات دلالة إحصائية بين درجة اصابة هذه الأعصاب وتفدم أعمار هؤلاء المرضى وطول مدة مرض الرثيان المفصلى وايضا مع وجود العقد الروماتودية وكذلك مع زيادة شدة المرض.

ونستنتج من هذه الدراسة أهمية استخدام دراسات فسيولوجيا الأعصاب فى مرضى الرثيان المفصلى حيث تساعد هذه الوسائل على اكتشاف أى تغيرات مرضية مبكرا فى كلا الأعصاب الدماغية والطرفية ومن ثم سرعة علاجها وتلافى الأضرار الناتجة من التأخر فى اكتشاف اصابتها.

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