Globally, an estimated 58 million people are infected with hepatitis C, with an estimated 1.5 million new infections annually [25]. In the absence of treatment, 55% to 85% of acute HCV infections will become chronic. While 95% of infections can be successfully treated with antiviral medications, many patients face barriers to diagnosis and access to treatment. Chronic HCV infection is related to several extrahepatic syndromes, including mixed cryoglobulinemia, renal impairment, polyarthralgia, and sicca syndrome. PN is considered one of the most common neurological complications of chronic HCV, affecting approximately 10% or more [26,27,28].

Up to 50% of chronically infected patients develop mixed cryoglobulinemia [26]. Cryoglobulins represent immunoglobulins that precipitate in vitro at temperatures ≤ 37 °C, generated by clonal expansion of B cells in the setting of persistent immune stimulation. HCV-related cryoglobulinemia is generally comprised of “mixed” cryoglobulin, consisting of either monoclonal IgM with polyclonal IgG (type II) or polyclonal IgM and IgG (type III). Mixed cryoglobulinemic vasculitis affects small- to medium-sized arteries.

Low complement levels (C4 and CH50) and rheumatoid factor activity may suggest cryoglobulinemia. False negative lab results for cryoglobulinemia may reflect problems with collection and/or laboratory processing [29]. Treatment of HCV-associated PN focuses on treatment of the infection with direct-acting antivirals [30]. There is, additionally, evidence to suggest that rituximab may be safe and efficacious [31••].

PNS vasculitis is rare in HIV. When identified, it presents early after initial infection or in the setting of severe immunodeficiency, at which time opportunistic infections may be the driving force for the syndrome. Acute or subacute onset of painful asymmetric PN helps distinguish this entity from HIV-DSP.

Vasculitis affecting all vessel types have been reported, with the pathological hallmark being necrotizing thrombosis or inflammatory infiltration of vessels on nerve biopsy. Early in HIV with mild to moderate immunosuppression, vasculitis may be associated with immune complex deposition or infiltrating CD8 T cells. This may reflect a reaction to HIV infection of endothelial cells or neoplasm. Other potential causes that are important to consider include HBV or HCV co-infection, cryoglobulinemia, immune complex disease, and drug-induced vasculitis. Serum autoantibodies (e.g., ANA, RF, ANCA), when present, are nonspecific given the polyclonal B cell activation given abnormal T cell regulation in HIV infection. With severe immunodeficiency, CMV is the classic vasculitis pathogen, and particularly so with a history of CMV infection (i.e., prior or concurrent CMV retinitis, gastroenteritis, or pneumonia). The diagnostic utility of plasma CMV PCR in this setting is unclear, being insensitive and non-specific for nervous system involvement.

Management depends mostly on the severity of prevailing immunodeficiency. Early vasculitis may therefore be treated with CART, whereas in the setting of concomitant/opportunistic infection therapy is directed toward the underlying co-infection. Clinical trial data is limited given the rarity. For those with advanced immunodeficiency and CMV infection, ganciclovir with or without foscarnet is favored, though the toxicity profiles of these medications in the individual circumstances must be considered (e.g., hematopoietic, renal). Immunosuppressive mediations such as steroids may potentially worsen outcomes in severe immune deficiency.

Mycobacterium leprae and Mycobacterium lepromatosis (together referred to as the M. leprae complex) cause chronic mycobacterial infection of skin and nerve. Familiarity with the signs of lepromatous polyneuropathy (Hansen’s disease) is important as early diagnosis and treatment prevents disability. Leprosy remains an important cause of PN and disability worldwide, with approximately 200,000 cases annually [32]. An asymmetrical, non-length dependent MM is the most common pattern though generalized PN may also be seen.

Predominately in tropic and subtropic regions, most cases are currently reported in South-East Asia and Brazil. In the USA, there are pockets of endemism in Texas, Louisiana, Hawaii, and California. Humans are the principal reservoir, though armadillos also serve as reservoirs in the western hemisphere. Transmission occurs primarily via respiratory or nasal droplets; cutaneous transmission can occur if the skin barrier is not intact. A long interval between infection and clinical symptoms, up to decades, is common as M. leprae is slow growing (with a doubling time of almost 2 weeks) [33].

Neuropathy may result from either direct infection of Schwann cells or the immune response to mycobacterial antigens. Sensory symptoms and signs are more common than motor symptoms, with “negative” sensory symptoms predominating. Temperature and pain sensation are disproportionately affected compared to vibratory sensation and joint proprioception [34]. Commonly affected nerves include superficial nerves such as the sural, fibular, posterior tibial, ulnar, and superficial radial sensory nerves as M. leprae preferentially replicates in cooler temperatures. As such, clinical stigmata tend to be found in cooler regions of the body: nose, ears, tips of fingers, and toes. In up to 10%, skin lesions may be absent with PN being the only symptom.

Clinical diagnosis is made by the presence of typical skin lesions (e.g., hypopigmented or reddish skin patch with definite hypesthesia), thickened or enlarged nerves with sensory loss in the distribution of that nerve, and skin smear or biopsy documenting acid-fast bacilli. Clinical and histological features (Table 1) may be used to classify leprosy patients, with the WHO classification being most employed.

The WHO recommendations for treatment for paucibacillary disease are rifampin and dapsone for 12 months while multibacillary disease is treated with rifampin, clofazimine, and dapsone for 24 months. Screening of contacts and chemoprophylaxis with single-dose rifampin is recommended to reduce transmission to household and near contacts of infected individuals.

Host immune responses are felt to play a large role in development of neuropathy, particularly in paucibacillary disease, and continued evolution of nerve injury is common after initiation of treatment [35]. Two basic types of immune responses, or “reactions” are recognized: (1) a type I or “reversal” reaction (RR); and (2) a type II reaction, or “erythema nodosum leprosum” (EHL) reaction. These reactions can occur before, during, or after introduction of multidrug therapy. The RR represents an increase in cell-mediated immunity and presents with erythematous skin lesions coupled with nerve swelling (particularly the ulnar nerve at the elbow and tibial nerve at the tarsal tunnel/medial malleolus). EHL is distinguished from reversal reactions by subcutaneous red nodules (panniculitis), arthralgia or frank arthritis, and fever.

Steroids improve neurologic outcome of reversal reactions, with current recommendations endorsing prednisolone 40 mg daily, generally for about 12 weeks [36]. No conclusive evidence, however, shows steroids can prevent neuropathy [37]. Shorter courses of steroids are generally used for EHL, but with severe and/or recurrent reactions thalidomide may be considered. For further discussion about treatment options, the interested reader may refer to the recent review by Ebenezer and Scollard [38•].

Guillain-Barré syndrome (GBS) consists of a monophasic acute generalized weakness with mild sensory symptoms and hypo/areflexia localizing to the spinal roots and peripheral nerves, which progresses for four weeks and is followed by a plateau phase. Close to a third of the patients develop respiratory failure [39]. GBS is the most common cause of acute neuromuscular paralysis worldwide, with an annual incidence estimated between 0.4 and 4/100,000 [40,41,42,43]. Incidence increases during the rainy season in tropical countries [43, 44]. At least two-thirds report having either a respiratory or gastrointestinal illness in the preceding 6 weeks [41, 45, 46].

Electrophysiologically, GBS has been divided into different subtypes that have different prognoses and pathophysiology, as well as different associations with distinct infections. These electrophysiological variants are acute inflammatory demyelinating inflammatory polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN). GBS pathophysiology is thought to be explained by a post-infectious immune reaction targeting peripheral nervous system antigens [39]. Some of the most commonly associated pathogens are Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, Dengue virus, and Chikungunya virus. In some cases, evidence of co-infection has been found [41]. Interestingly, prospective studies have shown that asymptomatic infections with these pathogens are also associated with GBS [41, 47]. Conversely, a significant proportion of GBS patients with prodromal symptoms does not show serological evidence of infection [47].

Campylobacter jejuni, a gram-negative rod, is an important cause of bacterial gastroenteritis worldwide [41, 48, 49]. Gastroenteritis from C. jejuni consists of fever, abdominal pain, and diarrhea [49]. C. jejuni has been implicated in a third of GBS cases in prospective series [41, 45, 46, 50]. Associations between GBS and asymptomatic C. jejuni infection have also been found [41]. C. jejuni is thought to cause GBS via molecular mimicry between the bacteria lipooligosaccharide and GM1, GM1b, GD1a, and/or GalNac-GD1a gangliosides located in the node of Ranvier of the axolemma [51,52,53]. This leads to IgG deposition and membrane attack complex formation in the node of Ranvier causing paranodal myelin detachment that progresses to axonal degeneration [54]. Consequently, C. jejuni infection is more likely to cause the AMAN variant, which carries a worse prognosis [41, 45, 47, 48].

The most common virus associated with GBS is cytomegalovirus (CMV), followed by hepatitis E virus (HEV) and Epstein-Barr virus (EBV) [41, 45, 50]. CMV IgM targets the GM2 ganglioside, and it is the most common cause of GBS following renal transplant [55]. In HEV-GBS, there is some weak evidence of molecular mimicry with GM1 or GM2 gangliosides [56, 57]. CMV- and EBV-related GBS most commonly cause sensory symptoms and may be associated with a milder form (e.g., slower time to nadir, capable of ambulating at nadir, normal strength at 6 months) [41, 58]. On the other hand, HEV-GBS may portend a worse prognosis [41]. HEV-GBS may also be accompanied by transient transaminase elevation, which likely reflects the down trending phase of the preceding, usually asymptomatic, infection [59]. In some HEV-GBS cases, a positive HEV RNA in CSF has been detected, suggesting a para-infectious or directly infectious pathophysiology [49]. It must be noted that for CMV- and EBV-related GBS, serological diagnosis necessitates not only a positive IgM, but also IgG titers that are not indicative of a prior infection [41]. M. pneumoniae is an atypical bacterium causing respiratory infections. GBS-associated M. pneumoniae is more common in children, and more frequently involves the cranial nerves [41, 45, 60]. Antibodies against Gal-C, a major component of myelin, are found in most of the patients [60].

Arboviruses (Zika virus, Dengue virus, and Chikungunya virus) have been associated with GBS development in the context of epidemic outbreaks. Of these, the strongest association was found for Zika virus [61, 62]. These patients may develop GBS concomitantly with the Zika infection [61]. About half have facial paresis [61, 62]. Subsequent research using strict serological criteria and performed in endemic countries outside of the epidemic outbreaks did not show a strong association of these viruses and GBS, although this could have been due to low statistical power [47]. Contrary to the infectious agents mentioned earlier, molecular mimicry with gangliosides has not been found with arboviruses epitopes [63]. Table 2 summarizes infectious agent, affected ganglioside(s), and clinical features in GBS.

Different population-based studies have failed to find an association between SARS-CoV-2 infection and GBS [42, 64••, 65]. In fact, the incidence of GBS decreased during the first months of the pandemic despite rising numbers of SARS-CoV-2 infection [64••, 65]. This decrease has been attributed to lockdown measures preventing transmission of known GBS triggers.

The HIV seroconversion syndrome, usually presenting with fever, headache, myalgia, arthralgia, rash, or diarrhea, may also present with GBS. It affects 30–50% of patients with acute HIV infection around 3–9 weeks after viral exposure [66]. When GBS accompanies this syndrome, it is otherwise clinically and electrophysiologically indistinguishable from non-HIV-GBS. The differentiating feature that prompts the clinician to consider HIV is the presence of lymphocytic pleocytosis in the CSF, instead of the expected albumino-cytologic dissociation of non-HIV-GBS cases [66]. GBS-phenotype may also be part of the immune reconstitution inflammatory syndrome [67].

Corynebacterium diphtheria is an exotoxin-producing gram-positive bacterium that causes local infection of the upper respiratory tract or skin [68]. It presents as pharyngitis associated with a grayish-while membranous exudate, a “pseudo-membrane” of the posterior pharynx [68]. This may be followed by diphtheritic polyneuropathy (DP) after a latent period of 3–6 weeks. C. diphtheria produces a protein exotoxin which causes segmental demyelination of nerve roots and proximal peripheral nerves. Most pathology is observed at the level of roots and dorsal root ganglia, likely due to fenestrated capillaries at the blood-nerve barrier. DP has two phases, affecting initially the cranial nerves, and evolving 2 weeks later to a generalized demyelinating polyneuropathy, similar to GBS [69, 70]. Autonomic dysfunction is common, usually manifesting as tachycardia, accommodation paresis, and/or urinary retention [71]. CSF analysis may also show albuminocytologic dissociation [69]. The biphasic course of DP helps differentiating it from GBS. Interestingly, the cranial nerve deficits start to recover while the limb deficits are still worsening. Overall, recovery is seen after 2 months on average [69]. Once DP is established, the management is conservative. Thus, treatment with diphtheria antitoxin plus penicillin or macrolides should be started during the acute sore throat phase to prevent complications and patients are isolated until they have two negative throat swab cultures [68].