Brachial Neuritis After Botulinum Toxin Injections for Cervical Dystonia: A Need for a Reappraisal?

Abstract

Background

Brachial neuritis has previously been described as a rare occurrence in patients receiving botulinum toxin for cervical or writing/focal arm dystonia.

Methods

We report four cases of patients with a long history of cervical dystonia treated with botulinum toxin injections.

Results

All patients developed pain and muscular weakness around the shoulder, with EMG studies suggesting brachial neuritis.

Conclusions

In the context of these observations, we discuss the question of an association between brachial neuritis and botulinum toxin treatment.

Introduction

Brachial neuritis (BN), also known as brachial plexitis, neuralgic amyotrophy, and Parsonage‐Turner syndrome, is a rare idiopathic lesion of peripheral nerves of the shoulder girdle and upper arm that develops abruptly in otherwise healthy individuals.

It usually begins with a neuralgic pain around the shoulder, the neck, or in the axilla, followed by muscular weakness and deterioration in the affected region after several days. The recovery is spontaneous, and depending on the degree of nerve damage, typically takes six to 12 weeks; however, there have been instances where it has taken a year or longer.

The aetiology of most cases of BN remains unclear, but there is evidence suggesting an autoimmune process with various triggers, including vaccinations1 or immunomodulation (IL2‐ and interferon therapy).2, 3

Other causes of brachial plexopathy include trauma, unusual or strenuous exercise, infiltration by a tumor, radiation, viral infection, or intravenous drug use.4, 5

The diagnosis of BN is foremost clinical but can be confirmed by neurophysiological studies that are also useful to rule out various other conditions, such as compressive radiculopathies. BN is believed to be an axonal process, and, therefore, the diagnosis depends on needle electromyography (EMG).6 EMG generally detects signs of acute denervation, such as fibrillation potential, positive sharp waves, and a reduction in the recruitment of motor units in a patchy distribution. Muscles are usually affected according to nerve distribution more than roots. If performed late in the course of the disease, EMG may show chronic neurogenic changes and early re‐innervation in clinically affected muscles. Nerve conduction study (NCS) is usually normal, but may show a reduction in sensory and motor nerves action potential amplitudes. Often, patients with BN have disproportionally little somatosensory abnormalities.

BN has been reported following botulinum toxin (BT) treatment especially in patients with cervical dystonia7, 8, 9, 10 and writing/focal arm dystonia.11 Here, we present four patients with cervical dystonia who developed acute and transient BN after BT injections.

Case One

This 78‐year‐old woman presented at the age of 64 with torticollis to the left, laterocollis to the right, and was diagnosed with primary sporadic cervical dystonia. She had been treated with BT type A injections every three months, with 600 units (U) of BT (Table 1). After 14 years of treatment, without any intercurrent illness or trauma, she developed a sudden onset of pain and weakness of her right arm that began about eight weeks after her latest round of BT injections. The pain was localized in a lateral point of her right shoulder and radiated down the right arm. On examination, 10 weeks after the latest injections, there was a grade 3 muscle weakness of the deltoid, resulting in muscle paresis affecting shoulder abduction. Biceps and the triceps, however, were spared. EMG showed active denervation in the right deltoid and infraspinatus muscles. Signs of chronic neurogenic changes were present in the right deltoid, infraspinatus, triceps, and much less, in the extensor digitorum communis. Motor and sensory NCS were normal.

Table 1.

Comparison of clinical and neurophysiological findings in brachial neuritis after botulinum toxin injections for dystonia

Age	Sex	BT indication	BT injection	Symptoms	Time from latest injections	Number of prior set of BT injections	Neurophysiology	Main muscle involved	Outcome	Reference
78	F	Cervical dystonia	Type A 250 U left SC + 100 U right SC + 100 U right SCM + 75 U both LS	Pain right shoulder radiating in the arm and weakness in the right D	8 weeks	56 (14 years)	NCS normal EMG acute denervation right D, Is. Chronic denervation right D, Is, T, ED	Right D, Is	Improvement after 10 weeks	Case #1
74	M	Cervical dystonia	Type A 300 U left SC + 600 U right SC	Pain left side neck radiating to left arm and reduce muscle bulk left shoulder	8 weeks	16 (4 years)	NCS mild reduction left radial nerve sensory action potential EMG chronic denervation left muscle innervated by upper‐middle trunk	Left B, T, ED	Spontaneous recover after 6‐8 weeks	Case #2
71	M	Craniocervical dystonia, axial dystonia	Type A 250 U left SC + 150 U left LS + 75 U right SCM + 10 U both levator anguli oris	Difficulty in lifting right arm above the shoulder	6‐8 weeks	8	NCS not performed EMG acute denervation right D, Is.	Right D, Is	Imrpovement after 8‐9 months	Case #3
64	F	Blepharospasm, writer's cramp	Type A 50 U left eye +50 U right eye	Difficulty in lifting right arm above the shoulder	2‐3 weeks	20 (5 years)	NCS normal EMG acute denervation right B	Right B	Complete resolution in 4‐5 months. No recurrence at next injections	Case #4
53	F	Cervical dystonia	Type A 45 U left SCM + 75 U left TR	Pain left arm followed by weakness (subacute) in left D, B, Is, Ss	2 days pain, 6 weeks weakness	0	NCS normal EMG acute denervation left D, B, Is, Ss, R	Left D, B, Is, Ss	Improvement over the next 5 months	Glanzman et al.5
32	F	Cervical dystonia	Type A 100 U right SCM + 100 U both SC + 100 U both TR after 2wks: further 400 U in posterior cervical region	Pain neck and left upper limb after 1° injection, followed by weakness of right upper limb after 2° treatment	15 days	1	NCS normal EMG acute denervation in right D and B	Right Ss, D, B	Great improvement after 6 weeeks	Sampaio et al.6
36	F	Writer's cramp	Type A 40 U right FPL + 40 U right FDP	Weakness of finger extension and mild of wrist extension (pain neck and left upper limb at previous BT injection lasting 3 weeks)	15 days	1	NCS normal sensory, reduce action potential right radial muscle EMG active denervation in radial‐innervated muscles on the right	Right T and intrinsic hand muscles (lower trunk)	3 months later only slight residual strenght reduction	Sheean et al.9
55	F	Writer's cramp	Type A 60 U left FCR + 60 U left FDS + 40 U left PQ + 40 U left FDP	Wrist drop, weakness arm and hand, no pain (pain in left upper arm and shoulder at previous injection lasting 5‐6 weeks)	7 days post‐ injections	7	NCS small left radial nerve sensory action potential EMG acute and cronich denervation in left ECR, FPL, Tma	Left ECR, FPL, Tma, Br, D, Tmi (upper and lower trunk, posterior cord)	After 12 weeks only moderate residual of weakness	Sheean et al.9
55	M	Cervical dystonia	Type A 90 U right SC+ 40 U right LS + 30 U right SCM	Weakness arm elevation, 3/5 weakness of left Ss, Is, D, 4/5 weakness of left B, Br	10 days post‐injection ‐ 3 weeks, 6 weeks mild atrophy	0	NCS normal EMG acude denervation in left D, B, Br	Left Ss, Is, D (controlateral upper trunk)	Improvment in 13 weeks, complete resolution in 7 months. No recurrence at next injections	Tarsy7
65	F	Cervical dystonia	Type A 150 U split in left SCM and right SC	Pain from left shoulder to elbow, followed by weakness of internal rotation and abduction arm	8 days	0	NCS normal EMG acute denervation in left Ss, Is	Left Ss, Is (suprascapular neuropathy)	Complete resolution in 4 months	Alcalay et al.8

Abbreviations: B, biceps; Br, brachioradialis; BT, botulinum toxin; D, deltoid; ECR, extensor carpi radialis; ED, extensor digitorum communis; FCR, flexor carpi radialis; FCU, flexor carpi ulnaris; FDP, flexor digitorum profondis; FDS, flexor digitorum superficialis; FPL, flexor pollicis longus; Is, infraspinatus; LS, levator scapulae; PQ, pronator quadratus; R, rhomboid; SC, splenius capitis; SCM, sternocleidomastoid; Ss, supraspinatus; T, triceps brachii; Tma, teres major; Tmi, teres minor; TR, trapezius.

Overall, the neurophysiological investigation revealed a possible picture of active and chronic C5 and chronic C7 motor radiculopathies on the right, with no evidence of underlying peripheral neuropathy. However, cervical MRI excluded any structural abnormality and compressive radiculopathies. Furthermore, blood testing for infectious causes (HBV, HIV, Treponema, Borrelia burgdorferi) and an autoimmune screen (ANA) were normal, as was CSF analysis, including cytology and oligoclonal bands.

In conclusion, the clinical and electrophysiological features were in favor of a diagnosis of BN, and causes of secondary brachial plexopathy were excluded. She was treated with amitriptyline 20 mg and physiotherapy, improving after 10 weeks regarding the range of movements of the arm.

Case Two

A 74‐year‐old man affected by idiopathic cervical dystonia at age 46 first noted his head turning to the right and neck pain. The most prominent dystonic pattern was a “no–no” tremor that had been treated with BT type A injections eight years after onset (Table 1). Four years after receiving BT injections regularly, and eight weeks after a set of injections, he developed pain in the left side of his neck, radiating to the left arm associated with an abnormal sensation in the left lateral forearm and reduced muscle bulk around the left shoulder. The patient denied any antecedent event like infection, trauma, or unusual physical exercise. Clinical examination revealed wasting around the left shoulder girdle with a reduced muscle bulk of the left biceps, triceps and finger extensor. The left biceps reflex was absent, while the left triceps reflex was present with reinforcement. Reduced pinprick was noticed in the C5 and C6 dermatomes. NCS and a needle EMG study were performed. The left radial sensory nerve action potential (SNAP) was mildly reduced relative to the right, and widespread signs of chronic neurogenic changes mainly affecting the upper and middle trunk innervated muscles were present, including those innervated by C7 root. The widespread and patchy denervation and SNAP findings were consistent with BN. Further BT injections were deferred, and he started to recover spontaneously after six to eight months. The clinical findings were supported by the marked improvement in his NCS/EMG study, more than 12 months later. An MRI scan of the cervical spine and brachial plexus demonstrated a left paracentral compression of the exiting left C6 nerve root, but no other abnormalities. A few years ago, he successfully restarted his BT injections without any recurrence of BN to date.

Case Three

A 71‐year‐old man (previously reported)12 presented at age 42 with axial dystonia, and subsequently developed craniocervical dystonia and sensorineural hearing loss. His treatment comprised trihexyphenidyl, lorazepam, and BT type A injections, repeated every three to four months (Table 1). Two years into his treatment with BT, he developed problems lifting his right arm above the shoulder. These problems started subacutely six‐to‐eight weeks after a set of BT injections, without prior occurrence of any infection, trauma, or unusual physical exercise. On examination, there was wasting of his right deltoid, suprascapular, and interscapular muscles with some fascicular twitches. His triceps, biceps, and the distal muscles were preserved. Needle EMG showed active denervation changes in the right deltoid and infraspinatus. NCS was not performed because of technical limitations due to dystonia. The cervical spine imaging (MRI) showed no corresponding foraminal narrowing and no structural brachial plexus lesion. He received steroid injections in the shoulder, but showed no improvement. After eight‐to‐nine months, he was able to lift the arm above the shoulder. He still had significant wasting around his shoulder muscles, particularly the deltoid, the interscapular, and periclavicular muscles. Therefore, the differential diagnosis comprised BN with a partial lesion of the upper trunk of the brachial plexus, or C5 motor radiculopathy. However, the natural history of the disease and its improvement are highly suggestive of BN.

Case Four

The patient came to our attention at the age of 64, after a 20‐year history of blepharospasm and a recent onset of writing difficulty. She also had a history of bipolar disorder, with three episodes of major depression treated only with Lithium. At the time of examination, she had segmental dystonia with writer's cramp, facial grimacing, and, most disabling, blepharospasm. Treatment with BT type A injections was initiated (Table 1). Five years later, she continued to receive a total dose of 100 units in the orbicularis oculi. However, two‐to‐three weeks after one of these injections, she developed difficulty lifting her right arm above the shoulder. She reported that the symptom had an acute onset and was not preceded by infection, trauma, or unusual physical exercise, and caused some discomfort to the neck and right shoulder. Clinically, there was weakness of shoulder abduction, internal and external rotation, elbow flexion and extension, wrist palmar flexion, and right thumb abduction; throughout, the reflexes were preserved. She had an NCS study that was essentially normal. An EMG study demonstrated signs of active denervation in the right biceps but no other muscles supplied by C5/C6 or the musculocutaneous nerve. CT imaging of the neck demonstrated degenerative changes of the cervical spine and some foraminal narrowing at C4/C5 on the right and bilaterally at C5/C6 and C6/C7. She completely recovered clinically after four to five months, and the BT injections were restarted without any recurrence of BN.

Discussion

We report four cases of BN temporally related to BT injections for dystonia. Similar previously reported cases are summarized in Table 1.7, 8, 9, 10, 11 All these patients, including ours, developed pain around the shoulder and weakness in deltoid and infraspinatus, distant from the injection sites. Similarly, patients treated for writer's cramp developed pain and strength loss in the triceps and proximal arm, which is again different from the site of injection in the forearm.11 The distance between the injection sites and structures affected would exclude traumatic needle injury, but raises the question of association between BN and the BT treatment.

Of course, it could be that BN happened coincidentally in our patients. However, BN is a rare disorder with an incidence rate estimated around 1,64 ‐ 3 per 100,000 person‐years13 or much higher, according to a recent epidemiological study in the Netherlands (about 1 per 1,000 person‐years),14 and a lifetime prevalence estimated around three per 10,000 population.15 Therefore, the observation of four cases in our cohort of 460 patients receiving BT injections over a 10‐year period may indicate a higher prevalence of the disorder among patients treated with BT injections, though the numbers are too small to allow any epidemiological conclusions.

There are different formulations of BT, and all reported patients who developed BN had received BT type A (Table 1). However, this may also be related to the fact that this is considered first‐line therapy for cervical dystonia, whereas BT type B is less frequently used. Moreover, BN was reported only in patients with dystonia, but not in patients who received BT due to other conditions (e.g., hemifacial spasm, spasticity), or for cosmetic reasons where doses may be smaller. The fact that reports of BN after BT use are restricted to patients with dystonia may relate to BT being used most frequently (and possibly at higher doses) in dystonia, or to a propensity to autoimmunity in cervical dystonia.16

Indeed, BT has immunogenic properties, and the main concern in this regard has been the development of neutralizing antibodies by the patient.17 It is thus conceivable that a similar mechanism, akin to BN occurring after vaccinations,1 may occur here. So far, there is no evidence to conclusively link BT injections to BN, and to substantiate a pathophysiological link.

Moreover, it is unclear why such a side effect should occur not after the first injections, but after several years of treatment, or why the latency from the injections in some of our cases was as long as eight weeks. This may either support the notion of an incidental occurrence, but does not exclude a build‐up of autoimmunity, possibly triggered by additional, maybe environmental, factors, especially in some cervical dystonia patients that have a certain HLA type, which might predispose them to autoimmunity.16

By now, three of our four patients have restarted BT injections without any further events of BN. Similarly, the patient reported by Tarsy et al. did not experience a recurrence of BN after restarting the BT injections.9 If BT injections trigger autoimmunity against plexus antigens, how come this lack of an immune response after a new exposure?

If the development of neutralizing antibodies against BT can be considered a paradigm in this regard, some conclusions may be drawn from a study exploring the development and effect of neutralizing antibodies against BT: Sankhla et al. describe seven dystonia patients who developed resistance to BT type A ascribed to neutralizing antibodies.18 All of them reverted to antibody‐negative status, and six of them were re‐injected with BT type A, with initial benefit from the treatment. Three of them, however, lost the benefit with subsequent injections together with re‐emergence of neutralizing antibodies.

This may indicate different immune responses even within the patient group prone to develop antibodies triggered by BT injections. Moreover, it suggests that the immunologic response to BT can wane with time, and that re‐exposure may or may not reactivate the immune response.

Practically, this observation may indicate that restarting BT injections is not necessarily contraindicated in such cases. Of course, BN is a potentially serious side effect and can be a frightening experience for patients who, after intense pain, suffer weakness and consequent functional impairment of their arm.

Prospective studies with large cohorts, or an international surveillance registry would be needed to determine the prevalence of BN amongst patients treated with BT injections (including type and LOT numbers of BT used) to further investigate this matter.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

I.C.: 1B; 3A

A.L.: 1B, 3A, 3B

B.B.: 1B, 3A, 3B

C.C.: 1B, 3B

K.B.: 1A, 1B, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

We confirm that the approval of an institutional review board and patient consent was not required for this work.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: I.C., A.L., and C.C. report no disclosures. B.B. is supported by the Robert Bosch Foundation. K.P.B. has received grant support from Welcome/MRC, NIHR, Parkinsons's UK and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), Marsden's Book of Movement Disorders (Oxford University Press, 2012), and Case Studies in Movement Disorders–Common and Uncommon Presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz; and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.