Guillain-Barré syndrome following primary cytomegalovirus infection in a patient with liver transplantation

Abstract

We present the case of a man in his 60s with a 5-month medical history of deceased donor liver transplantation, who developed Guillain-Barré syndrome (GBS) secondary to a primary cytomegalovirus (CMV) infection. This was confirmed by molecular tests and serology antibodies that ruled out other frequent aetiologies. Therapy with intravenous immunoglobulin and valganciclovir was started and the patient gradually improved over the weeks. GBS is the most common aetiology of paralysis worldwide, and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Few cases of GBS have been reported in the context of liver transplant recipients, and those related to CMV infection are extremely rare. This case highlights the importance of considering GBS as a possible differential diagnosis in patients with solid organ transplantation, and it contributes to the knowledge of other infrequent aetiologies of this condition.

Background

Guillain-Barré syndrome (GBS) is the most common aetiology of acute flaccid paralysis, accounting for an estimated 100 000 new cases annually worldwide.¹ Although the pathogenesis of GBS continues to be not fully understood, it has been frequently associated with a preceding infection before the development of the disease in 40%–70% of cases.^{1 2} Cytomegalovirus (CMV) infection has been described previously as a risk factor, although only about 4% of GBS cases are specifically attributable to it.^{2 3} Likewise, even though CMV infection is a relevant and frequent complication of solid organ transplant recipients (SOTR) GBS has rarely been reported in this population, especially in the context of orthotopic liver transplantation (OLT), where as far as we have reviewed, there are still no reports of cases in Colombia or Latin America.⁴ Moreover, although some OLT cases had evidence of CMV infection at or before the onset of the disease, GBS could not be ascribable to it due to the available diagnostic tests at that time or the presence of a more likely diagnosis.^5–8

Here, we discuss the case of a GBS associated with primary CMV infection in the context of OLT, with the unique feature of ruling out other possible aetiologies (infectious or immunosuppressive-induced). In addition, we confirm an acute CMV infection through a Polymerase Chain Reaction (PCR), which was not available in previous reports. Furthermore, we reviewed similar cases to provide insight into the clinical and pathological characteristics underlying this infrequent disease presentation.

Case presentation

A man in his 60s with a 5-month medical history of an uncomplicated deceased donor OLT was admitted to the emergency room with progressive ascending limb weakness and foot dysesthesias for the past 8 days. Interestingly, 3 days before the onset of the symptoms, he presented a self-resolved gastrointestinal infection with at least five to eight daily episodes of diarrhoea, without fever or flu-like symptoms. He denied vomiting, vertigo, shortness of breath or diplopia. Through the days, weakness worsened to the point where he was unable to walk. The patient’s medical history was significant for hypertension, diabetes mellitus, coronary artery ectasia, chronic obstructive pulmonary disease and obstructive sleep apnoea. Five months before the onset of symptoms, he had an OLT secondary to non-alcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma with a Child-Turcotte-Pugh score of 5 points and a Model for End-stage Liver Disease (MELD) score of 7 points. The serology status for immunoglobulin G (IgG) against CMV was positive for the donor and negative for the patient. For this reason, the patient received prophylactic treatment with a daily dose of 900 mg of valganciclovir along with a monthly PCR-based viral load monitoring. After 3 months of treatment and a final undetectable viral load, 6 weeks prior to the onset of the limb weakness and foot dysesthesias, valganciclovir was stopped by the hepatology team. There were no complications during the transplant or in the post-transplant course. He was receiving maintenance immunosuppressive therapy with tacrolimus 3 mg two times per day, prednisone 2.5 mg once per day and mycophenolate mofetil 500 mg two times per day.

The patient’s general physical examination and vital signs were normal. Neurological examination showed no abnormalities of the central nervous system. Muscle strength was 3/5 in the upper extremities and 1/5 in both lower limbs. Areflexia was seen in all extremities. Additionally, the patient had dysesthesias in both lower limbs, which were more significant on the right side. Due to his inability to walk, his gait could not be evaluated. With this clinical presentation, a diagnosis of GBS was considered and the patient was admitted to the hospital.

Investigations

Initial blood tests revealed a complete blood count with normocytic hypochromic anaemia and thrombocytopaenia. Liver transaminitis was seen with alanine aminotransferase (ALT) of 299 U/L (4–36 U/L) and aspartate aminotransferase (AST) of 233 U/L (8–33 U/L). Total, direct and indirect bilirubin were normal. Tacrolimus levels were 10.10 ng/mL (5.00–20.00 ng/mL). Molecular studies showed an acute CMV infection with a positive PCR viral load of 106 000 copies in Logarithm 5. No specific serological assays, including IgM, IgG or avidity assays, were performed for CMV. Serology for Epstein-Barr virus (EBV) and varicella zoster virus (VZV) was negative. Finally, a FilmArray gastrointestinal panel was performed, which showed negative results for Campylobacter jejuni, Clostridium difficile toxin A/B, Salmonella, Vibrio cholerae, Yersinia enterocolitica, adenovirus and rotavirus. Cerebrospinal fluid (CSF) assessment 6 days after admission and 2 weeks after onset showed albuminocytological dissociation (leucocytes 0 mm³ and proteins 78 mg/dL). A CSF FilmArray panel was negative for acute viral infections, including CMV, enterovirus, herpes simplex virus 1 and 2, human herpesvirus 6, human parechovirus and VZV. MRI of the spine revealed no structural lesions or myelopathy signs. Electromyography (EMG) with nerve conduction was performed, which reported an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) with axonal changes. Two electrodiagnostic studies were conducted at admission and 1 month later during the hospital stay. In contrast to the initial assessment, the follow-up nerve conduction studies revealed secondary axonal degeneration (table 1). EMG findings on admission showed reduced recruitment without denervation activity. The subsequent control study demonstrated a notable impairment in recruitment accompanied by denervation activity (table 2). This finding is consistent with axonal involvement and could be related with an unfavourable clinical progression.

Table 1.

Nerve conduction studies

Motor nerve conduction study
	Velocity (m/s)		Amplitude (mV)		Latency (ms)
Nerve	At admission	1 month after admission	At admission	1 month after admission	At admission	1 month after admission
R median—APB
Wrist	NR	NR	1.5 (n>5)	0.6	7.19 (n<4)	11.82
Elbow	37 (n>50)	11	1.0 (n>5)	0.1	13.13 (n<4)	34.06
R cubital—ADM
Wrist	NR	NR	3.5 (n>5)	1.0	3.33 (n<4)	8.13
Elbow	44 (n>50)	NR	1.7 (n>5)	NR	6.04 (n<4)	NR
L cubital—ADM
Wrist	NR	NR	3.2 (n>5)	0.8	3.85 (n<4)	10.21
Elbow	46 (n>50)	NR	2.5 (n>5)	NR	7.55 (n<4)	NR
R peroneal—EDB
Ankle	NR	NR	2.5 (n>5)	0.1	4.95 (n<5)	9.43
Fibulla head	37 (n>43)	NR	1.0 (n>5)	NR	12.45 (n<5)	NR
L peroneal—EDB
Ankle	NR	NR	1.6 (n>5)	NR	4.58 (n<5)	NR
Fibulla head	38 (n>43)	NR	0.4 (n>5)	NR	13.33 (n<5)	NR
R tibial—AH
Ankle	NR	NR	3.3 (n>10)	0.2	3.91 (n<5)	9.48
Popliteal fossa	35 (n>43)	NR	1.6 (n>10)	NR	15.78 (n<5)	NR
L tibial—AH
Ankle	NR	NR	2.2 (n>10)	0.1	6.56 (n<5)	9.04
Popliteal fossa	45 (n>43)	22	0.9 (n>10)	0.0	15.89 (n<5)	27.08

Sensory nerve conduction study
	Velocity (m/s)		Amplitude (mV)		Latency (ms)
Nerve	At admission	1 month after admission	At admission	1 month after admission	At admission	1 month after admission
R median
Wrist	NR	26 (n<3.5)	NR	3.9 (n>10)	NR	5.73 (n<3.5)
L median
Wrist	–	32 (n<3.5)	–	5.8 (n>10)	–	4.64 (n<3.5)
R cubital
Wrist	NR	NR	NR	NR	NR	NR
L cubital
Wrist	–	59 (n<3.5)	–	2.9 (n>10)	–	2.76 (n<3.5)
R radial
Forearm	–	NR	–	NR	–	NR
L sural
Calf	NR	NR	NR	NR	NR	NR
R sural
Calf	52 (n<3.5)	NR	7.7 (n>5)	NR	3.33 (n<3.5)	NR
R peroneal
Lat leg	–	NR	–	NR	–	NR
L peroneal
Lat leg	–	NR	–	NR	–	NR

ADM, abductor digiti minimi; AH, abductor hallucis; APB, abductor pollicis brevis; EDB, Extensor digitorum brevis; L, left; N, normal ; NR, non-reactive; R, right.

Table 2.

Electromyography findings

At admission
			Spontaneous				MUAP			Recruitment
Muscle	Nerve	Roots	Insertion activity	Fibrillation	PSW	Fasciculation	Amplitude	Duration	PPP	Pattern
R anterior tibial	Peroneal	L4-L5	N	None	None	None	N	N	N	Reduced
L anterior tibial	Peroneal	L4-L5	N	None	None	None	N	N	N	Reduced

1 month after admission
			Spontaneous				MUAP			Recruitment
Muscle	Nerve	Roots	Insertion Activity	Fibrillation	PSW	Fasciculation	Amplitude	Duration	PPP	Pattern
R brachioradialis	Radial	C5-C6	1+	None	1+	None	N	N	N	Discrete
L brachioradialis	Radial	C5-C6	1+	1+	1+	None	N	N	N	Discrete
R anterior tibial	Peroneal	L4-L5	1+	None	1+	None	N	N	N	No activity
L anterior tibial	Peroneal	L4-L5	1+	None	1+	None	N	N	N	No activity

L, left; MUAP, motor unit action potential; N, normal; PSW, positive sharp waves; PPP, polyphasic potentials; R, right.

Differential diagnosis

This case fulfilled clinical features required for the diagnosis of GBS. Furthermore, EMG, conduction studies and CSF analysis were consistent with this diagnosis. Other possible infectious aetiologies were ruled out through CSF findings and serological and molecular laboratories mentioned above. Also, tacrolimus-related peripheral neuropathy was unlikely since tacrolimus levels were consistently within the therapeutic range.^{8 9} In consequence, by analysing the over-riding viral load and the temporal relationship between the infection and symptom onset, CMV was strongly suggestive as the most probable cause of GBS.

Treatment

A course of human immunoglobulin was started at 0.4 g/kg/day for 5 days together with ganciclovir at a dose of 900 mg every 12 hours. Physical therapy and respiratory monitoring were indicated, treatment with mycophenolate and prednisone was discontinued and the dose of tacrolimus was adjusted to 2 mg two times per day. Initially, the patient presented an improvement in his neurological condition; however, during the course of admission, he developed right facial weakness and decreased maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) for which non-invasive mechanical ventilation cycles were started due to the risk of ventilatory deterioration. Additionally, a second cycle of human immunoglobulin was started 2 weeks after the first dose.

Outcome and follow-up

During hospitalisation, the patient developed a methicillin-resistant Staphylococcus epidermidis bacteraemia that was managed in the ICU with a vancomycin regimen. In the ICU, the patient presented a severe respiratory failure with the following arterial blood gases at 2600 m of altitude: pH, 7.12; PaO₂, 89 mm Hg; PaCO₂, 85 mm Hg; and HCO₃, 27.6 mEq/L. Consequently, a tracheostomy placement was required. After this, the patient began a gradual recovery of strength and neurological symptoms. His last viral load of CMV was negative after treatment, and the patient was discharged home to continue with physical therapy and follow-up.

Discussion

GBS is an acute immune-mediated polyneuropathy that is often secondary to a previous infection, vaccination or a trigger event such as malignancy or bone marrow transplantation.^{1 7 10} Here we present a case of GBS secondary to CMV infection in the context of an uncomplicated deceased donor OLT that was under immunosuppressive therapy. Contradictorily, given the immunological origin of GBS, it should be unusual to observe this pathology in an immunocompromised host.⁷ However, a small number of cases have been described in the context of SOTR. Interestingly, most of these cases have been reported after renal, heart and face transplants, while cases after an OLT have been scarce. To the best of our knowledge, only nine cases have been described to date (table 3).5–8 11–14

Table 3.

Clinical characteristics of nine cases of GBS in the context of OLT

First author (Reference)	Age/sex	Transplant aetiology	CMV status (D/R)	Serum CMV IgG/IgM, serum PCR for CMV	Time until GBS	Most probably aetiology for GBS	Maintenance immunotherapy	IVIg	TPE
El-Sabrout et al, 2001 (case 2)5	39, M	HCV	P/N	NS/NS, NS*	2 months	CMV	Cs+Pdn	Yes	Yes
El-Sabrout et al, 2001 (case 3)5	34, M	Cryptogenic cirrhosis	P/P	+/+, NS	12 months	CMV	Cs+Pdn+ Bxm	Yes	Yes
Colle et al, 20026	64, M	HCV	N/N	−/−, −	2 months	Campylobacter fetus	Tac+Pdn	Yes	No
Kaushik et al, 200511	46, M	HCV	NS/NS	NS/NS, −	6 months	Tacrolimus-induced	Tac	Yes	No
Moon and Souayah, 200612	62, M	Alcoholic cirrhosis	NS/NS	+/−, NS	6 months	Influenza Vaccination	Tac+Pdn	Yes	No
Lo Re et al, 20187	61, F	HCC	NS/NS	NS/NS, +†	3 months	IRIS	Tac	Yes	No
Ramirez-Sanchez et al, 202113	55, F	HCV	NS/NS	NS/NS, NS	7 months	COVID-19 infection	Cs	No	Yes
Ramavath et al, 20218	34, F	Autoimmune hepatitis	NS/NS	NS/NS, −	10 days	VZV	Tac	Yes	No
Hughes et al, 202214	65, M	Cryptogenic cirrhosis	NS/NS	NS/NS, −	8 months	COVID-19 vaccination	Cs	Yes	No

*Tissue CMV invasion was documented through positive gastric biopsy cultures

†Low CMV DNA levels (409 copies/mL) were detected.

Bxm, basiliximab; Cs, cyclosporine; D, donor; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IRIS, immune reconstitution inflammatory syndrome; IVIg, intravenous immunoglobulin; M, male; N, negative; NS, not specified; P, positive; Pdn, prednisone; R, recipient; Tac, tacrolimus; TPE, total plasma exchange; VZV, varicella zoster virus.

Many microorganisms have been associated with GBS, most notably C. jejuni, EBV, CMV, Zika virus, Mycoplasma pneumoniae, HIV and more recently, SARS-CoV-2.¹ Although the relationship between GBS and CMV infection has been previously established, cases are uncommon in patients receiving an OLT. CMV is one of the most common infectious complications following a solid organ transplantation, even in patients who received antiviral prophylaxis.¹⁵ One of the most important risk factors for post-transplant CMV infection is related to the prior ‘mismatch’ serology status of the donor and recipient together with the intensity of immunosuppression.¹⁶ In addition, some studies have shown that the incidence of CMV infection can vary depending on the transplanted organ, with the heart and liver being the most frequent ones.¹⁷ As seen in our patient, CMV-related GBS has been frequently associated with a severe sensorimotor compromise together with facial paralysis and occasionally elevated liver enzymes.¹⁸

In this case, it is important to highlight that the patient experienced a preceding episode of diarrhoea before the onset of symptoms. As it is reported in the literature, this could potentially point towards a previous infection with C. jejuni. Up to 1/3 of GBS cases might be preceded by an infection caused by this microorganism, and the presentation is often accompanied by gastrointestinal symptoms.¹⁰ Nonetheless, it is important to note that CMV infections in SOTR are also associated with gastrointestinal involvement, with diarrhoea being one of the most prevalent manifestations.¹⁹ In a case series of 31 SOTR complicated by CMV disease, as much as 71% of the cases exhibited gastrointestinal symptoms.²⁰ Other studies have revealed that the frequency of CMV-induced diarrhoea in post-liver transplant patients ranges from 2% to 10% of cases.^{21 22} The above suggests that in the context of a SOTR who develops GBS following an episode of diarrhoea, CMV infection may be considered among the potential triggers in the differential diagnosis.

As it was noted, given that CMV is a common post-transplant infection, it was expected that some of the reported cases had evidence of this infection before the onset or at the presentation of the disease (table 3). Nevertheless only in two of the nine cases, CMV was considered the most probable cause and its relationship was established through inconclusive serum antibodies rather than modern molecular methods.⁵ This is important given that antibody tests are not ideal for diagnosis in a transplant setting since CMV infection is highly prevalent in the general population. The clinical value of serology in the diagnosis of CMV illness is further limited by the delay between the original infection and immunoglobulin M antibodies production. Other causes are the persistence of antibodies in certain healthy individuals and the failure of antibody generation in some transplant recipients.^{10 16} Therefore, PCR tests and antigenaemia assays represent the most reliable diagnostic methods for identifying an active CMV infection, displaying a sensitivity ranging between 84% and 100%.^{16 23}

This case might be, as far as we have searched, one of the few reports where GBS occurs after a primary CMV infection in the context of OLT. Contrary to cases reported previously in which modern molecular methods were not available, in this case a PCR test was used to confirm the final diagnosis. Even though CMV is not a common cause of GBS in OLT patients, its early recognition is important to prevent complications and establish a prompt and effective specific treatment.

Learning points.

• Guillain-Barré syndrome (GBS) can be a rare complication after orthotopic liver transplantation (OLT). Although post-transplant immunosuppression is known to increase the likelihood of contracting cytomegalovirus (CMV) opportunistic infections, GBS has not been frequently linked to this condition.

• Careful diagnosis of GBS after primary CMV in OLT recipients is crucial to establish a prompt and effective specific treatment.

• Further studies and reports are required to completely elucidate the mechanism behind the relationship between GBS and CMV infection in patients with OLT.

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