Distal Chronic Inflammatory Demyelinating Polyneuropathy Following COVID-19 Vaccination in a Patient with Solitary Plasmacytoma: A Case Report and Literature Review

Abstract

We herein report a rare case of distal chronic inflammatory demyelinating polyneuropathy (CIDP) following coronavirus disease 2019 (COVID-19) vaccination. A 39-year-old woman with a solitary plasmacytoma developed general weakness 7 days after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine, which had progressed for 3 months. A neurological examination revealed limb weakness with areflexia. Serological tests identified the presence of IgG antibodies against anti-GM1 and anti-GM2 gangliosides. Comprehensive evaluations met the criteria of distal CIDP. Intravenous immunoglobulin, intravenous methylprednisolone, oral prednisolone, and plasma exchange were administered, and she gradually improved. Physicians should be aware of CIDP as a rare complication of COVID-19 vaccination.

Introduction

Since late December 2019, the world has faced a serious public health emergency due to the of coronavirus disease 2019 (COVID-19) pandemic. Emerging reports suggest that COVID-19 infection can cause neurological complications (1,2) and exacerbate the condition of patients with preexisting neurological disorders (3). To immunize the populace against COVID-19, COVID-19 vaccines were rapidly developed and have been administered globally. Although the benefits of COVID-19 vaccination outweigh the adverse events, neurological complications after COVID-19 vaccination have been reported (4,5). As acute peripheral nerve complications following COVID-19 vaccination, Guillain-Barré syndrome (GBS), small fiber neuropathy, parsonage-Turner syndrome, and Herpes zoster reactivation have been reported (4).

Although subacute GBS after COVID-19 vaccination, which reached 10 weeks (6), and cases of chronic inflammatory demyelinating polyneuropathy (CIDP) after COVID-19 vaccination (7-11) have rarely been reported, the incidence of CIDP following COVID-19 vaccination remains to be clarified.

We herein report the first case of distal CIDP positive for anti-GM1/GM2 antibodies in a patient with solitary plasmacytoma that worsened continuously for three months after COVID-19 vaccination.

Case Report

A 39-year-old Asian woman with anemia due to hypermenorrhea began to notice leg weakness seven days after receiving the second dose of the Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine. There was no obvious prior infection, and she had no history of insect bites or recent travel. One month after the onset, she developed numbness in her legs and muscle weakness in both hands. The patient visited an orthopedics department of a hospital, but her evaluation was terminated without follow-up.

Two months after the onset, she became unable to walk and was referred to a neurological clinic. Although peripheral neuropathy was suspected, she was followed up without treatment. Three months after the onset, she could no longer stand alone and was referred to our hospital. Her medications included dienogest for hypermenorrhea. Her family history was not significant. She did not have any allergies. Her diet was normal without alcohol abuse. She usually ate bread and meat with very little rice or fish in her diet.

On admission, the general medical condition of the patient was unremarkable. A neurological examination revealed limb weakness with distal lower extremity predominance and positive Lasègue sign, paresthesia and dysesthesia below the knees, general areflexia, and difficulty standing and walking. The cranial nerves were intact. Results of routine hematological and biochemical analyses, including those for the thyroid function, were normal except for the mild elevation of hemoglobin up to 15.5 g/dL (normal range: 12.1-14.5 g/dL). Comprehensive screening for serum ganglioside antibodies identified the presence of antibodies against anti-GM1 and anti-GM2 IgG but not anti-GM3, GD1a, GD1b, GD3, GT1b, GQ1b, or galactocerebroside. Serum antinuclear antibodies, perinuclear antineutrophil cytoplasmic antibody (ANCA), cytoplasmic ANCA, anti-SSA/SSB antibodies, anti-neurofascin 155 antibody, angiotensin-converting enzyme, human T-cell leukemia virus type 1, interleukin (IL)-2 receptor, IgG4, interferon-gamma release assays, cryoglobulin, anti-Borrelia antibody, vitamin B12, folate, human immunodeficiency virus antibody, rapid plasma regain test, and Treponema pallidum particle agglutination assay results were unremarkable. Serum anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were negative using the in-house cell-based assay (12). An analysis of the cerebrospinal fluid (CSF) showed one mononuclear cell/mm³ (normal range: 0-5 cells/mm³), protein levels of 189 mg/dL (normal range: 10-40 mg/dL), myelin basic protein (MBP) 33 pg/mL (＜103 pg/mL), and a negative oligoclonal band.

Brain gadolinium-enhanced magnetic resonance imaging (MRI) showed an increased signal of fluid attenuated inversion recovery in the deep white matter without increased diffusion-weighted imaging and enhancement (Fig. 1A, B) and an enhanced mass in the left temporal bone (Fig. 1C). We performed a biopsy of the mass in the left temporal bone, which revealed plasmacytoma. Whole-body enhanced computed tomography showed no significant findings other than a left renal cyst and leiomyoma uteri. Since a serum free light chain analysis and protein electrophoresis of the serum and urine were negative, we diagnosed her with a solitary plasmacytoma.

Figure 1.

(A-B) Brain magnetic resonance imaging (MRI) shows an increased signal of fluid-attenuated inversion recovery in the deep white matter and the left temporal bone. (C) Brain gadolinium-enhanced MRI shows an enhanced mass in the left temporal bone. (D) Lumbar gadolinium-enhanced MRI on admission day 9 revealed an enhanced and swollen cauda equina. (E) Lumbar gadolinium-enhanced MRI on admission day 44 revealed slight improvements in the enhanced and swollen cauda equina. (F-G) Short tau inversion recovery sequence MRI shows an increased signal and hypertrophy in the lumbar nerve root.

Lumbar gadolinium-enhanced MRI revealed a swollen cauda equina with marked enhancement (Fig. 1D). Short tau inversion recovery sequence MRI showed an increased signal and hypertrophy (5.4 mm) in the lumbar nerve root (Fig. 1F, G). Cervico-thoracic MRI findings were unremarkable. Visual evoked potential (VEP) showed a slight delay in latency as right 112 msec (≤106 msec) and left 109 msec. An ophthalmologic examination did not reveal any visual impairment due to anterior segment abnormalities.

Table 1 summarizes the results of the nerve conduction study (NCS) of the compound muscle action potential (CMAP), which revealed a 33.3% (≤50%) delay in the distal latency of the right median nerve. Abnormal temporal dispersion was observed in the right median nerve. A 32.3% (＞30%) reduction in motor conduction velocity was observed in the right median nerve (Fig. 2). A total of 33.1% (≥30%) motor conduction block was observed in the right ulnar nerve. No CMAP was elicitable in the right tibial nerve. The right peroneal nerve was difficult to evaluate because its amplitude was very low. An NCS of the sensory nerve action potential (SNAP) showed a decrease in SNAP amplitude and conduction velocity in the right median and ulnar nerves. No SNAP was evoked in the right sural nerve.

Table 1.

Nerve Conduction Study.

<Motor Nerve Conduction Study>
Rt. Median	Latency	Duration	Amplitude	NCV
Wrist	6.03 (<4.0) ms	6.27 (<7.8) ms	4.76 (>3.95) mV
Elbow	11.19 ms	7.71 (<7.8) ms	4.38 (>3.95) mV	36.8 (54.3-63.9) m/s
Rt. Ulnar	Latency	Duration	Amplitude	NCV
Wrist	3.18 (<3.1) ms	5.79 (<8.5) ms	12.34 (>4.22) mV
Elbow	7.32 ms	7.17 (<8.5) ms	8.26 (>4.22) mV	45.9 (55.5-67.9) m/s
Rt. Tibial	Latency	Duration	Amplitude	NCV
Ankle	UD	UD	UD
Popliteal fossa	UD	UD	UD	UD
Rt. Peroneal	Latency	Duration	Amplitude	NCV
Ankle	UE	UE	UE
Fibular head	UE	UE	UE	UE
<Sensory Nerve Conduction Study>
Rt. Median	Latency	Amplitude	NCV
Wrist	3.76 (<2.9) ms	2.80 (>13.86) µV	31.9 (58.3-71.8) m/s
Elbow	UD	UD	UD
Rt. Ulnar	Latency	Amplitude	NCV
Wrist	2.68 (<2.4) ms	12.2 (>10.77) µV	39.2 (58.9-74.1) m/s
Elbow	6.80 ms	7.3 (>10.77) µV	46.1 (58.9-74.1) m/s
Rt. Sural	UD	UD	UD
<F-waves>	Latency	NCV	Occurrence
Rt. Median	57.05 ms	22.8 (58.4-73.2) m/s	63 (0-100) %
Rt. Ulnar	47.05 ms	27.8 (62.4-71.6) m/s	44 (19-100) %
Rt. Tibial	UD	UD	0 (81-100) %

NCV: nerve conduction velocity, UD: undetectable, UE: unevaluable

Figure 2.

A nerve conduction study of the compound muscle action potential (CMAP) revealed a 33.3% (≤50%) delay in the distal latency of the right median nerve. Abnormal temporal dispersion was observed in the right median nerve. A 32.3% (>30%) reduction in the motor conduction velocity was observed in the right median nerve.

Based on the diagnostic criteria of CIDP (13), her symptoms suggested distal CIDP, a CIDP variant. No red flags for distal CIDP, including a family history, autonomic symptoms, pain, or IgM monoclonal gammopathy, were observed. The motor conduction velocity in the right median nerve was more than 30% below the lower limit of normal value, meeting the criteria of weakly supportive demyelination and the possibility of distal CIDP (13). Based on the possibility of distal CIDP and two supportive features of MRI and CSF (13), we finally diagnosed the patient with distal CIDP following COVID-19 vaccination.

After the administration of intravenous methylprednisolone (IVMP) from admission days 2 to 4, the Lasègue sign disappeared. To obtain further improvement, intravenous immunoglobulin (IVIG) was administered, followed by oral prednisolone 20 mg/day on admission day 18. A second administration of IVMP was performed from admission days 34 to 36, and oral prednisolone was stopped on admission day 37. During the course of these treatments, the muscle weakness in the proximal lower legs gradually improved. Consistent with the improvement in clinical symptoms, MRI findings of the cauda equina were slightly reduced on admission day 44 (Fig. 1E). After four plasma exchanges between admission days 70 and 79, the patient was able to walk approximately 30 meters with a walker, and the protein levels in the CSF decreased to 135 mg/dL. She was transferred to the rehabilitation ward on admission day 111.

Discussion

We encountered a case of distal CIDP with anti-GM1 and anti-GM2 antibodies following COVID-19 vaccination, possibly suggesting an atypical form of GBS. Although this case was diagnosed as one of CIDP because of the time course, the pathophysiology appeared similar to that of GBS in terms of the postvaccination onset, monophasic course, and positive anti-ganglioside antibodies. In addition, the symptoms were also atypical of distal CIDP.

Although rare, a proportion of GBS cases with a long course similar to that of CIDP has been reported (14,15), and 10% of CIDP cases were found to be positive for anti-GM1 antibody (16). In a systematic review of GBS after COVID-19 vaccination, 5 of 28 patients (17.9%) were positive for anti-ganglioside antibodies (17). More interestingly, subacute GBS and acute-onset CIDP following COVID-19 have also been reported, but anti-ganglioside antibodies were not detected in these cases (6-9). Table 2 shows the present and previous cases of CIDP following COVID-19 vaccination (7-9). In contrast, in our case, serum anti-GM1 and anti-GM2 antibodies were still positive three months after vaccination, indicating that a significant GBS-like immune response evoked by COVID-19 vaccination might have continued over several months. One possibility is that the distinct immune system in our patient may have resulted in a unique disease process. Although the exact reason why no autoantibodies other than anti-ganglioside antibodies developed in this case is uncertain, one possibility is that other antibodies are unlikely to be produced after COVID-19 vaccination. Indeed, de novo autoimmune diseases (e.g. thrombotic thrombocytopenia, immune thrombocytopenic purpura, autoimmune hepatitis, IgA nephropathy, autoimmune polyarthritis, and rheumatoid arthritis) are known to occur after COVID-19 vaccination but less frequently than GBS (18). The onset of CIDP in this case may have been related to COVID-19 vaccination, but the possibility of this being an incidental case cannot be ruled out. Some studies have suggested that the causal relationship between GBS and COVID-19 vaccination is unclear (19).

Table 2.

Our And Previous Cases Of Cidp Following Covid-19 Vaccination.

Reference	Present case	[7]	[8]	[9]	[10]
Year and sex	39 F	47 F	47 F	44 F	66 F
Comorbidity	Plasmacytoma	Diabetes mellitus, hypertension, and COVID-19 (7 months ago)	NA	Dysmenorrhea, insomnia, palmoplantar pustulosis, operation to umbilical hernia, and allergy to some food	Type 2 diabetes mellitus with neuropathy, hypertension, and hyperlipidemia
Company of vaccine	Pfizer	Astra Zenecea	Astra Zenecea	Pfizer	Moderna
Onset	7 days after a second dose	17 days after a first dose	16 days after a first dose	1 day after a second dose	3 months after a second dose
Duration of progress	3 months	Acute onset and relapses (3 weeks and 8 weeks later)	Acute onset and one relapse (two months later)	2 months	5 months
Feature of CIDP	Distal CIDP	Acute-onset CIDP	Acute-onset and typical CIDP	NA	NA
Antibody	Positive anti-GM1 and anti-GM2 gangliosides antibodies	Elevated COVID-19 antibody IgG and untested for anti-gangliosides antibodies	Negative antibodies including anti-gangliosides antibodies (GM1, GD1b, and GQ1b)	Negative antibodies including anti-gangliosides antibodies	Negative antibodies
CSF	1 cells/mm3 and protein levels of 189 mg/dL	0 cells/mm3 and protein levels of 250 mg/dL	Elevated proteins (110 mg/dL) without pleocytosis, and absence of intrathecal IgG synthesis	1 cells/mm3 and protein levels of 129 mg/dL	2 cells/mm3 and protein levels of 237 mg/dL
Image	・Brain MRI: increased signal of FLAIR in deep white matter ・Lumber MRI: swollen cauda equina with marked enhancement and increased signal of STIR in the lumber nerve root	・MRI: discrete and confluent hyperintensities in white matter in T2-FLAIR ・Lumber MRI: enhancing thickening of cauda equina nerve roots ・non-18-FDG avid lesion in fused PETMRI: frontal and temporal hypometabolism	Brain and spinal cord MRI: enhancement of the facial nerves and of the cauda equina and lower thoracic nerve roots	Normal spinal MRI	Normal brain and spinal MRI
Treatment	IVIG, twice IVMP, oral prednisolone (20 mg/day), and PLEX	IVIG, oral prednisolone (1 mg/kg/day), and azathioprine	Initial IVIG followed by maintaining therapy of IVIG every six months	Twice IVIG followed by maintaining therapy of IVIG	Initial IVIG followed by maintaining therapy of IVIG every 4 weeks
Prognosis	Gradual partial recovery (walking 30 meters with a walker) over 111 days	Near-complete recovery	Complete resolution of left facial palsy with persistence of slight weakness in the right upper facial area and gait ataxia	Partial recovery	Recovery

CIDP: chronic inflammatory demyelinating polyneuropathy, COVID-19: coronavirus disease 2019, NA: not available, CSF: cerebrospinal fluid, MRI: magnetic resonance imaging, FLAIR: fluid attenuated inversion recovery, STIR: short tau inversion recovery, PET: positron emission tomography, FDG: fluorodeoxyglucose, IVIG: intravenous immune globulin, IVMP: intravenous methylprednisolone, PLEX: plasma exchange

Although such a notion seems to be somewhat provocative, solitary plasmacytoma might contribute to prolonged anti-ganglioside antibody production. Generally, the immune response to vaccinations in patients with multiple myeloma (MM) is lower than that in the general population because of the immunosuppression induced by MM. In fact, levels of neutralizing antibodies following COVID-19 vaccination were found to be significantly lower in patients with MM than in a control group (20). As the immunoglobulin values were normal in the present patient, she was not in an immunosuppressive state and might have the ability to produce excessive antibodies. A case of CIDP associated with MM has been reported, possibly associated with preexisting paraproteinemia but not anti-ganglioside antibodies (21). In addition, some cases of GBS after the initiation of bortezomib or transplantation in patients with MM have also been reported (22,23). Other factors might be related to the development of CIDP as well. Since all previous CIDP following COVID-19 vaccination occurred in women, sex might be associated with the risk of developing the disease (7-9). According to preceding infection and vaccination, some diseases, such as diabetes mellitus, hepatitis C, lymphoma, monoclonal gammopathy of undetermined significance, human immunodeficiency virus, organ transplant, and autoimmune disorders, are associated with an increased risk of CIDP (24). Low consumption of rice and fish is also a risk factor for CIDP (25). Although the present patient did not have any of the above-mentioned disorders, her dietary preference or other underlying factors might have been associated with the onset of CIDP.

Regarding cerebral deep white matter lesions, CIDP or other factors may be involved. Indeed, those lesions were also detected in a case of combined central and peripheral demyelination (CCPD) associated with COVID-19 vaccination (26) and a case of acute CIDP associated with COVID-19 vaccination (7). In the present case, CCPD was suspected based on an increased T2 signal in the deep white matter and prolonged VEP (27), but the low MBP value and presence of a plasmacytoma steered us away from a diagnosis of CCPD. Other pathological mechanisms related to CIDP might be associated with deep white matter lesions. Furthermore, other possibilities, including COVID-19-related pathological conditions, such as vasculitis, nonspecific age-related vascular changes, and plasmacytoma, cannot be ruled out (28-32).

Muscle weakness following COVID-19 vaccination should be evaluated and treated as early as possible, as delayed treatment for CIDP is associated with a poor prognosis (33). The present patient had not been treated for two months since her first hospital visit. Clinicians should therefore closely monitor the course of these cases and refer the patients immediately to a hospital where treatment is available.

Conclusion

A case of distal CIDP with anti-GM1 and anti-GM2 antibodies following COVID-19 vaccination in a patient with solitary plasmacytoma was reported. Although the benefits of COVID-19 vaccination outweigh the adverse events, muscle weakness following COVID-19 vaccination should be carefully evaluated and treated as early as possible to avoid residual symptoms.

Informed consent was obtained from the patient with a signed document.

The authors state that they have no Conflict of Interest (COI).