key: cord-1032157-a4g6e2dd authors: Bagella, Caterina Francesca; Corda, Davide G.; Zara, Pietro; Elia, Antonio Emanuele; Ruiu, Elisa; Sechi, Elia; Solla, Paolo title: Chronic Inflammatory Demyelinating Polyneuropathy after ChAdOx1 nCoV-19 Vaccination date: 2021-12-19 journal: Vaccines (Basel) DOI: 10.3390/vaccines9121502 sha: 6754593e230cbbb3e34a164032697d31af69eb4e doc_id: 1032157 cord_uid: a4g6e2dd Recently several patients, who developed Guillain–Barré syndrome characterized by prominent bifacial weakness after ChAdOx1 nCoV-19 vaccination, were described from different centers. We recently observed a patient who developed a similar syndrome, later in the follow up he showed worsening of the neuropathy two months after the initial presentation. Repeat EMG showed reduced nerve sensory and motor conduction velocities of both upper and lower limbs, and a diagnosis of chronic inflammatory demyelinating polyneuropathy (typical CIDP) was made according to established criteria. Our report expands on the possible outcomes in patients who develop Guillain–Barrè syndrome after COVID-19 vaccinations and suggest that close monitoring after the acute phase is needed in these patients to exclude a chronic evolution of the disease, which has important implications for long-term treatment. Vaccines are the most cost-effective measures available against the COVID-19 pandemic with more than seven billion doses administered worldwide in November 2021 (https://coronavirus.jhu.edu/map.html) (accessed on 11 December 2021), thus monitoring of rare adverse events is of fundamental importance. COVID-19 vaccinations have mostly been associated with adverse events of little clinical significance such as injection site reaction or non-specific systemic symptoms such as fever and muscle aches, which usually resolve within days [1] . However, more severe adverse events have been reported in a minority of cases, including immune-mediated thrombocytopenia [2] , and Guillain-Barrè syndrome, that is a potentially serious complication with a mortality rate of 3-5% despite intensive care treatment [3] . The incidence of GBS is estimated to be around 0.4-4.0 cases per 100,000 personyears [4] . The disease is more common in males especially over the age of 75, and less common among children [5] . GBS is generally classified into various subforms based on the pathophysiological profile and symptomatology (e.g., pharyngeal-cervical weakness syndrome, brachialis and bifacial paralysis with paresthesia) [6] . In some patients GBS can deteriorate again after some weeks from onset and several relapses can occur; in these patients a diagnosis of acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP) should be considered [7] . In GBS an infectious trigger is recognized in >50% of cases while onset following vaccinations is debated [4] . Recently several patients who developed a GBS following CoV-19 vaccinations, were described from different centers [8] [9] [10] [11] [12] . In particular, most patients developed bifacial weakness with or without involvement of other peripheral nerves after ChAdOx1 nCoV-19 vaccination, suggesting this might represent a specific neuropathy phenotype associated with the vaccine. Clinical features of these patients are summarized in Table 1 . We recently observed a patient who developed a similar acute syndrome after the first dose of the ChAdOx1 nCoV-19 vaccine, but with worsening of the neuropathy two months after the initial presentation leading to a final diagnosis of CIDP. The patient was a 49-year-old man who presented asymmetric bilateral facial weakness, and paresthesias in the tongue and face. Sixteen days before symptoms onset he received the first dose of ChAdOx1 nCoV-19 vaccine. He denied infections within the prior month. Neurologic examination showed severe bilateral facial paresis, more prominent on the right side, and lower limbs areflexia. Brain and spinal cord MRI showed enhancement of the facial nerves and of the cauda equina and lower thoracic nerve roots, respectively ( Figure 1 ). Cerebrospinal fluid analysis revealed elevated proteins (110 mg/dL; normal range <45 mg/dL) without pleocytosis, and absence of intrathecal IgG synthesis. Serum search for ganglioside autoantibodies was negative, including anti-GQ1b, anti-GD1b, and anti-GM1 antibodies. Blink reflex test displayed bilateral impairment of the motor efferent pathway, while the remaining nerve conduction studies (NCS) and electromyography (EMG) examination were normal. A microbiological work-up of cerebrospinal fluid has ruled out infection of campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, influenza A virus, and hepatitis A, B, C virus. An initial clinical diagnosis of GBS was made and intravenous immunoglobulins (IVI g; 0.4 g/kg/die for 5 days) were initiated 3 days after symptoms onset with mild improvement of the bifacial paresis and resolution of the hypoesthesia. Two months after presentation, his symptoms worsened with painful paresthesias and progressive lower limbs weakness, more prominent during right foot dorsiflexion (4/5 MRC). He developed mild sensory ataxia with wide based gait and postural instability. Repeated nerve conduction study showed marked slowing of sensory and motor conduction velocities of both upper and lower limbs, prolonged distal latency, conduction blocks and absent F response, leading to a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) according to established criteria [13] . He received a second cycle of IVIg with improvement of paresthesias. Later he was treated with IVIg cycles every six weeks. At last clinical evaluation, six months after presentation, the clinical features were characterized by complete resolution of left facial palsy with persistence of slight weakness in the right upper facial area. Gait ataxia improved but did not resolve completely. Paresthesias on the lower limbs were disabling and thus treatment with pregabalin and alpha lipoic acid was started with benefit. Clinical features and examinations of the patient are summarized in table 1. Acute demyelinating polyneuropathy is a rare, but well recognized complication of COVID-19 vaccines. The disease variant with bifacial weakness has recently been recognized to be more common in patients with adenoviral-vectored (Oxford AstraZeneca, Johnson and Johnson) vs. mRNA-based (Pfizer BioNTech, Moderna) vaccines [14] . In line Two months after presentation, his symptoms worsened with painful paresthesias and progressive lower limbs weakness, more prominent during right foot dorsiflexion (4/5 MRC). He developed mild sensory ataxia with wide based gait and postural instability. Repeated nerve conduction study showed marked slowing of sensory and motor conduction velocities of both upper and lower limbs, prolonged distal latency, conduction blocks and absent F response, leading to a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) according to established criteria [13] . He received a second cycle of IVIg with improvement of paresthesias. Later he was treated with IVIg cycles every six weeks. At last clinical evaluation, six months after presentation, the clinical features were characterized by complete resolution of left facial palsy with persistence of slight weakness in the right upper facial area. Gait ataxia improved but did not resolve completely. Paresthesias on the lower limbs were disabling and thus treatment with pregabalin and alpha lipoic acid was started with benefit. Clinical features and examinations of the patient are summarized in Table 1 . Acute demyelinating polyneuropathy is a rare, but well recognized complication of COVID-19 vaccines. The disease variant with bifacial weakness has recently been recognized to be more common in patients with adenoviral-vectored (Oxford AstraZeneca, Johnson and Johnson) vs. mRNA-based (Pfizer BioNTech, Moderna) vaccines [14] . In line with these findings, our patients developed an acute demyelinating polyneuropathy with bifacial palsy 2 weeks after the ChAdOx1 nCoV-19 vaccine, but subsequent clinical and EMG worsening prompted a diagnostic revision to CIDP with acute onset. To date, only one patient who developed CIDP after COVID-19 vaccination was reported, with typical gradual onset of ascending lower limb weakness and sensory changes without facial involvement [15] . A difference of the previously described cases of bifacial palsy, in which the clinical course is reported favorable or stabilized or which have been described in the acute phase, in our patient is available the most prolonged follow-up, that is of 6 months. This pro-longed clinical observation led to diagnose a chronic form of demyelinating polyneuropathy, which was an unexpected clinical evolution. Therefore, our report expands on the possible outcomes in patients who develop Guillain-Barrè syndrome after COVID-19 vaccinations and suggest that close monitoring after the acute phase is needed in these patients to exclude a chronic evolution of the disease, which has important implications for long-term treatment. Our patient presented a clinical onset of GBS with bifacial weakness with paresthesias phenotype; 8 weeks later he presented a clinical deterioration, thus a diagnosis of CIDP was made, supported by neurophysiological findings. The distinction between GBS with fluctuations after start of treatment and CIDP is difficult but it has been recommended that diagnosis of CIDP should be considered when a patient thought to have GBS deteriorates again after 8 weeks from onset or when deterioration occurs 3 times or more [7] . In GBS, acute motor neuropathy may involve facial nerves in various clinical presentations that include unilateral, bilateral facial palsy, bifacial palsy associated with involvement of other cranial nerves and bifacial palsy associated with limb paresthesia, moreover facial involvement is also possible in patients with classical forms of GBS. Interestingly it has been proposed that Bell's palsy may share similar pathogenic mechanisms with autoimmune neuropathies [16] . The specific clinical phenotype of bifacial weakness with paresthesias is quite uncommon and accounts for about less of 5% of the patients affected with GBS or Miller Fisher spectrum disorders [17] , whereas in those patients who have a fluctuating GBS with treatment related fluctuations, who later may become a CIDP, facial involvement was reported to be very common and it is present in about 63% of the patients [7] . On the other hand, CIDP at onset presents uncommonly with cranial nerve involvement, which is reported in about 11% of typical forms mostly with ophthalmological implications rather than facial palsy [13] . GBS and CIDP are immune-mediated disorders in which the exact mechanism of the immune response linked to the pathogenesis is still not clear. In GBS, the pathogenic events are associated with the immune response usually to a previous infection, which subsequently leads to a cross-reaction with the production of antibodies directed to epitopes of the myelin sheath or to peripheral nerves and roots, thus causing an autoimmune process. Antecedent infections are reported in about two-thirds of patients with GBS [17] , therefore molecular mimicry between microbial proteins and nerve cell surface has been one of the suggested pathophysiologic mechanisms. CIDP is typically an idiopathic disease, in which an immune response targeting myelin components of the peripheral nervous system develops due to an autoimmune process, which mainly involves immune mechanisms mediated by T cells. In CIDP, the finding of an infection that precedes the onset is rare and unlikely [18] . Numerous antibodies are associated with GBS (such as GD1a, GD1b, GM1, GQ1b), while usually no autoantibodies are identified in CIDP patients, even if variants with antibodies directed against myelin or proteins localized to the Ranvier node have been also described (such as neurofascin, gliomedin, and contactin-1), which appear to result in a more severe disease phenotype [18] . Neuropathies after vaccination are rare event and CIDP developing in the postvaccination period is distinctly unusual, accounting for about 1.5% of patients [19] , and poorly described [20] . In our patient, the temporal association between the first dose of ChAdOx1 nCoV-19 vaccine and onset of neuropathy is remarkable so that a triggering role of the vaccine appears to be in causal association. It has been proposed that a postvaccination neurological syndrome could result from the generation of host antibodies that cross-react with proteins present in peripheral myelin [8] . These antibodies may be generated in direct response to the SARS-CoV-2 spike protein, because there is evidence of a cross-reactivity between the SARS-CoV-2 spike protein and peripheral nerve glycolipids [8, 21] . This hypothesis is supported by reports of some patients with GBS with bifacial weakness and paresthesias subtype also among patients affected by GBS post COVID-19 [22] , even if in these series it does not appear to be the most common phenotype [23] . Therefore, an immune response to other components of the vaccine should be considered, such as a response against the chimpanzee adenovirus vector. The optimal management and long-term outcomes of these patients remain to be determined. We treated our patient according to the available recommendation with IVIg administration at earliest convenience [17] , however, he developed treatment related fluctuations as observed in about 6-10% of all patients with GBS [17] . This may be due to the possibility that the treatment effect has worn off while the inflammatory phase of the disease is still ongoing, and thus further treatment with repeating IVIg cycles was administered and nonetheless, the patient developed a form of CIDP. To our knowledge this is the first case, among GBS with bifacial palsy onset post COVID-19 vaccination, that shows this evolution of the disease, on this regard, it would be interesting to have additional details on the clinical and EMG follow-up of the previous reported cases with short follow up [8, 9, 12] . In recent months, several case reports have shown that some variants of GBS can occur after the administration of the ChAdOx1 nCoV-19 vaccine, and in particular the bifacial weakness and paresthesia appears to be the prevalent form. This case report clearly shows the need for close monitoring of patients developing GBS after COVID-19 vaccination after the acute phase. We highlight that adequate long-term clinical follow-up is essential in these cases, as evolution to a chronic form is possible, despite adequate treatment. While an eventual causal relationship between different types of COVID-19 vaccines and autoimmune neuropathies remains to be determined, neurologists should be aware of this possibility as prompt diagnosis and treatment is crucial to improve outcomes in patients with GBS or CIDP and other potentially serious neurologic disorders. Informed Consent Statement: Informed consent was obtained from the patient involved in the study. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. The authors declare no conflict of interest. Oxford COVID Vaccine Trial Group. 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