Parsonage-Turner syndrome following monkeypox infection and vaccination

Abstract

Beginning in May 2022, monkeypox infection and vaccination rates dramatically increased due to a worldwide outbreak. This case highlights magnetic resonance (MR) neurography findings in an individual who developed Parsonage-Turner syndrome (PTS) 5 days after monkeypox symptom onset and 12 days after receiving the JYNNEOS vaccination. MR neurography of the patient’s left suprascapular nerve demonstrated intrinsic hourglass-like constrictions, a characteristic finding of peripheral nerves involved in PTS. Other viral infections and vaccinations are well-documented triggers of PTS, an underrecognized peripheral neuropathy that is thought to be immune-mediated and results in severe upper extremity pain and weakness. The close temporal relationship between monkeypox infection and vaccination, and PTS onset, in this case, suggests a causal relationship and marks the first known report of peripheral neuropathy associated with monkeypox.

Introduction

The recent international rise in cases of monkeypox virus, an orthopoxvirus in the Poxviridae family, began in May 2022, with its peak in July–September 2022. This outbreak marks the first time that large case numbers have been reported concurrently in non-endemic countries across disparate geographical regions [1]. As of November 10, 2022, there were 79,231 confirmed cases of monkeypox associated with this outbreak, including 28,881 cases in the United States [2, 3].

A few small case series have described associations between monkeypox infections and the central nervous system, wherein patients developed encephalitis, seizures, and headaches [4, 5]. To the authors’ knowledge, however, no published reports have described an association between monkeypox infection and peripheral nerve symptoms. Here we report a patient who developed symptoms of Parsonage-Turner syndrome (PTS) (also known as neuralgic amyotrophy) 5 days after monkeypox symptom onset and 12 days after receiving the first dose of the live, non-replicating JYNNEOS vaccine, suggesting a possible association between monkeypox infection and/or vaccination with PTS.

PTS is considered a rare, though underrecognized, peripheral neuropathy that typically manifests with sudden, severe pain in the shoulder and/or upper arm region, followed by severe weakness in the upper extremity or chest wall. While its precise etiology is unknown, PTS is thought to be immune-mediated as its onset is frequently reported following a stressful antecedent event such as infection, vaccination, strenuous activity, surgery, or trauma [6, 7]. Characteristic findings of involved peripheral nerves in PTS include hourglass-like constrictions (HGCs), i.e., focally decreased calibers of the nerve with accompanying pre- and post-constriction dilatation, and with denervation edema pattern of muscles within that nerve distribution [8, 9]. HGCs were first recognized during surgical exploration but have been increasingly detected by both magnetic resonance (MR) neurography and ultrasound [10, 11].

Case report

Informed consent was obtained from the subject described in this report. A 40-year-old transgender man with no known co-morbidities or family history of peripheral neuropathy developed symptoms of monkeypox infection 8 days after exposure via a sexual partner and 7 days after receiving a previously scheduled first dose of the JYNNEOS vaccine, administered in the left arm. The patient’s symptoms included fatigue, night sweats, lymphadenopathy, and formication, and additionally, he developed the characteristic monkeypox rash – macular, pustular, and occasionally ulcerative lesions on the face, neck, arms, torso, thighs, and genital region (Fig. 1) [12, 13]. The diagnosis of monkeypox was confirmed within 72 hours of symptom onset by polymerase chain reaction testing. Five days after symptom onset, the patient awoke suddenly at night with left shoulder spasms and severe bilateral shoulder pain (rated 8/10). The pain was accompanied by significant weakness in the external rotation of the left shoulder. After 28 days of moderate-to-severe bilateral shoulder pain, with some pain relief from gabapentin (300 mg daily), shoulder massage, and icing, the right shoulder pain subsided, and the left shoulder pain decreased in intensity (rated 2/10).

Fig. 1.

Photograph of the left upper shoulder region demonstrates one of many pustules the patient developed as part of the monkeypox rash

Physical exam 6 weeks following symptom onset revealed visible atrophy of the left supraspinatus and infraspinatus muscles and confirmed marked weakness in left shoulder external rotation. Same-day electromyography (EMG) demonstrated a severe left suprascapular neuropathy with denervation of the left infraspinatus and supraspinatus muscles and no motor unit recruitment. Serological tests, including a comprehensive metabolic panel, complete blood count, C-reactive protein, and Lyme IgG and IgM, were all normal.

MR neurography of the left brachial plexus was performed at 3.0 Tesla one week following EMG to confirm the suspicion of PTS, as other more common entities, such as a ganglion cyst compressing the suprascapular nerve at the level of the suprascapular notch, could also result in similar weakness. Acquired MR sequences, per the standard institutional protocol for PTS, comprised 2-dimensional (2-D) axial proton density (3.5 mm slice thickness) and coronal T2-weighted Dixon (4 mm slice thickness), and 3-D 1.0 mm isotropic oblique coronal inversion recovery sequences, the latter performed before and after the intravenous administration of gadolinium. MR neurography demonstrated intrinsic hourglass-like constrictions of the left suprascapular nerve, a characteristic imaging finding in PTS, and denervation edema of the supraspinatus and infraspinatus muscles (Fig. 2) [8]. The “bullseye” sign of the nerve, i.e., peripheral signal hyperintensity and central hypointensity orthogonal to the long axis of the nerve just proximal to the HGC site [14] that has been previously reported in PTS subjects, was not detected in this patient’s suprascapular nerve; this was likely due to the fact that high through-plane 2-D images orthogonal to the longitudinal axis of the nerve were not obtained for this patient’s exam. Additionally, no intrinsic or extrinsic mass, such as a ganglion cyst, was detected along the course of the suprascapular nerve, and the remainder of the brachial plexus and its visualized side and terminal branch nerves appeared normal [12].

Fig. 2.

Left brachial plexus MR neurography at 3.0 Tesla. Straight coronal fat-suppressed T2-weighted image (A), focused on the left shoulder region, demonstrates the denervation edema pattern of the left supraspinatus and infraspinatus muscles (stars). Oblique coronal curved multiplanar reformatted fat-suppressed T2-weighted image (B) demonstrates diffuse signal hyperintensity and severe hourglass-like intrinsic constrictions (arrows) of the left suprascapular nerve

The patient began a 2-week course of tecovirimat (TPOXX) 6 days after monkeypox symptom onset. Five days later, the patient’s monkeypox symptoms and rash resolved, but PTS symptoms persisted. The patient continued pain management for PTS symptoms with oral gabapentin, acetaminophen, and ibuprofen, and close monitoring was recommended as there is no accepted treatment for this syndrome.

Discussion

Approximately half of PTS cases are associated with an antecedent event within 2 weeks of symptom onset. Infection (viral or bacterial) is the most common antecedent event, comprising 43.5% of such cases [6]. Vaccination is a less common trigger of PTS, comprising only 4.3–15% of cases with an identifiable antecedent event [6, 7]. The pathophysiology of PTS is thought to involve a combination of immune-mediated, environmental, mechanical, and genetic factors, although the precise mechanism is poorly understood [15]. In this case, given the close temporal relationship of vaccination, monkeypox infection, and the onset of PTS symptoms, it is likely that monkeypox infection and/or vaccination served as the triggering event(s). Delineating whether monkeypox infection or vaccination, or a synergistic effect of the two, was the more likely trigger is difficult given that PTS symptoms began 5 days after viral symptom onset and 12 days after vaccination. Of those patients for whom viral infection precedes symptom onset, 75% report PTS symptoms within 7 days of infection [6]. The window for PTS symptom onset following vaccination is variable, but typically occurs 17–28 days following vaccination [16–18].

A myriad of viral infections has been reported to precede the onset of PTS, including herpes simplex virus, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, parvo virus B19, human immunodeficiency virus (HIV), hepatitis B virus, hepatitis E virus, vaccinia virus, Coxsackie B virus, West Nile virus, Dengue virus, and Sars-CoV-2 (COVID-19) [19, 20]. Of these viruses, only the vaccinia virus shares the same genus as monkeypox (orthopoxvirus). Additionally, several vaccinations have been reported to precede the onset of PTS, including vaccines for tetanus, influenza, shingles, human papilloma virus, and COVID-19 [16]. The JYNNEOS vaccine is a live, non-replicating vaccinia virus vaccine that was approved by the Food and Drug Administration (FDA) in 2019 for the prevention of smallpox and monkeypox in high-risk populations [21]. A search of the Vaccine Adverse Event Reporting System (VAERS) on October 3, 2022, generated no reports of peripheral neuropathy or other related conditions in over 800 reported events for the JYNNEOS vaccine [22].

First reported in Central Africa in 1970, human monkeypox is now endemic to Central and Western Africa [3, 5, 13, 23]. Typical monkeypox symptoms include fever, headache, myalgia, and/or lymphadenopathy 5–21 days after infection. This is followed by a painful rash that evolves into pustular lesions, often concentrated on the face and extremities as well as the oral, genital, and anal mucosa [1, 3, 13]. In the current monkeypox outbreak, most cases have no clear association with animal or travel exposures, suggesting rapid human-to-human transmission [1, 3] [1, 8]. The JYNNEOS vaccine, originally developed for smallpox, is about 85% effective in preventing monkeypox [24].

The diagnosis of PTS has historically relied on patient-reported symptoms corroborated by physical exam and subsequent electrodiagnostic testing. However, recognition is poor among patients and providers, as precipitating events and symptoms may vary and overlap with other common conditions (e.g., cervical radiculopathy, rotator cuff tendinosis). Notably, the reported average time to diagnosis from symptom onset was 11 months in 2006 [6]. More recently, the use of MR neurography and ultrasound to detect hourglass-like constrictions (the etiology of which are unknown) of affected nerves or nerve fascicles has helped to confirm the diagnosis [8, 25]. In a study by Ripellino et al., imaging performed in 39 PTS patients within 31 days of symptom onset demonstrated nerve abnormalities in 90% and HGCs in 74%, with HGCs recognized as early as 12 hours post symptom onset [26].

Although there is no treatment consensus for PTS, early administration of oral steroids and/or intravenous immunoglobulin may reduce the severity and duration of symptoms [27, 28]. In recalcitrant cases, microneurolysis surgery can be performed to manually release the hourglass-like constrictions and facilitate recovery [15, 29]. While the prognosis of PTS is traditionally considered favorable (albeit only after 2–3 years), up to two-thirds of patients experience residual pain and functional deficits and 25% are still unable to return to work at >6-year follow-up [6, 15].

As the monkeypox outbreak evolves and vaccinations become increasingly administered, there may be additional cases of PTS and other peripheral neuropathies, such as Guillain-Barré syndrome, that have been reported following viral infection and/or vaccination [30]. MR neurography, in combination with electrodiagnostic testing, is a valuable diagnostic tool for PTS, as early identification and treatment may lead to improved outcomes [27].