REVIEW CURRENT OPINION Infectious neuropathies Christian J.M. Sindic Purpose of review Infectious neuropathies are heterogeneous neuropathies with multiple causes. They still represent an important world health burden and some of them have no current available therapy. Recent findings Leprosy incidence has decreased by 50% during the last years, but leprosy-related neuropathies still cause severe disability. The pure neuritic leprosy is a diagnostic challenge that may require nerve biopsy or nerve aspiration cytology. The treatment itself may lead to a ‘reversal reaction’, which further causes injuries to the nerve. HCV-related neuropathies may be related or not to the presence of cryoglobulins. The absence of vasculitis, the most frequent form is a peripheral sensory neuropathy involving small nerve fibers, and more accurately diagnosed by pain-related evoked potentials. HIV-related neuropathy has become the major neurological complication of HIV infection. Both HIV-induced neuropathy and antiretroviral toxic neuropathy are clinically indistinguishable. The existence of an isolated chronic polyneuropathy due to Borrelia burgdorferi remains highly controversial. Lastly, an active infectious ganglioneuritis caused by varicella zoster virus, producing shingles, is the most frequent infectious neuropathy in the world and may cause various neurological complications. Zoster sine herpete remains frequently undiagnosed. Summary Recent data have improved our knowledge and diagnostic tools of infectious neuropathies. Treatment of the injured nerves is not yet available, and prevention and rapid diagnosis remain the main priorities for the clinician. Keywords Borrelia burgdorferi infection, hepatitis C virus, HIV infection, leprosy, peripheral neuropathy, varicella zoster virus INTRODUCTION but the oral mucosa may be a secondary site of Although the endoneural compartment is protected transmission and infection [1]. Worldwide, the by the blood–nerve barrier, some microorganisms detection of new cases is decreasing, from about succeed in producing neuropathies, either by a 515 000 in 2003 to 244 796 in 2009 [2]. In spite of direct invasion of the nerve, or by inducing an this decreasing prevalence, leprosy remains an inflammatory or immune-mediated reaction lead- important health problem in countries such as ing to a nerve injury. In addition, some drugs used India, Brazil, Nepal and central Africa. against the causal infectious agent may also be Leprosy can be classified into three major clinical neurotoxic and induce peripheral neuropathies. subtypes based on the extent of host immune As our therapeutic tools to repair injured nerves response: lepromatous (multibacillar) in the case of are very limited or absent, a rapid diagnosis and a predominant humoral response, tuberculoid an early treatment of these infectious neuropathies (paucibacillar) in the case of a predominant cell- are of the utmost importance to prevent chronic mediated immunity and borderline (in-between). pain, deformities and severe disability. Service de Neurologie et Laboratoire de Neurochimie, Cliniques universitaires Saint-Luc, Faculte´ de Me´decine, Universite´ catholique LEPROSY-RELATED NEUROPATHIES de Louvain, Brussels, Belgium Correspondence to Professor Christian J.M. Sindic, Service de Neuro- Leprosy is a chronic granulomatous infection, logie, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200 principally affecting the skin and peripheral nerves. Brussels, Belgium. Tel: +32 2 764 1082; fax: +32 2 764 3679; e-mail: The infectious agent is an obligatory intracellular [email protected] organism, Mycobacterium leprae. The nasal mucosa is Curr Opin Neurol 2013, 26:510–515 the preferential site of entry and exit of the bacillus, DOI:10.1097/WCO.0b013e328364c036 www.co-neurology.com Volume 26 Number 5 October 2013 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious neuropathies Sindic macrophages. In addition, 28 of 92 AFB-negative KEY POINTS samples had a positive PCR test. The diagnosis of Although the prevalence of leprosy is significantly the remainder group relied on the presence of serum decreasing, pure neuritic forms still occur and diagnosis anti-phenolic glycolipid 1 antibodies and a high may require nerve biopsy or fine needle suspicion based on clinical and epidemiological aspiration cytology. dataset. Mononuclear infiltrates and perineurial fibrosis were more frequently observed in AFB-nega- HCV-related neuropathies are not always associated with cryoglobulinemia, and pain-related evoked tive, clinically suspected PNL than in nonleprosy potentials are more sensitive than standard nerve neuropathies. Together, both anomalies correctly conduction velocity measurements. detected 100% of the former, and 0% of the latter. It should be noted that seven nerve samples were Peripheral neuropathy has become the major normal in the PNL group, indicating that the lesions neurological complication of HIV infection. may be focal and segmental [9]. Varicella zoster reactivation (shingles) is the most As nerve biopsy is an invasive procedure and frequent cause of infectious (ganglio)neuritis with a may lead to neural deficit, fine needle aspiration lifetime risk estimated to be 10–20%. ZSH is a cytology of an affected nerve could be a valuable and diagnostic challenge and is likely underdiagnosed. less invasive procedure for the diagnosis of pure neuritic form. Smears from five suspected cases revealed nerve fiber infiltration by chronic inflam- Nerve involvement in leprosy affects sensory, matory cells in all cases, presence of epithelioid cell motor and autonomic fibers. Sensory loss is the granulomas in three cases and AFB in two cases [10]. earliest and most frequent modality. Granuloma- During or after the multidrug treatment (rifam- tous inflammation of peripheral nerves causes picin, dapsone and clofazimine), a so-called ‘reversal palpable enlargement, which is most often painful. reaction’ may occur leading to an acute, painful and Enlarged nerves can be damaged because of entrap- disabling neuritis. This type of reaction is most ment within fibro-osseous tunnels [3,4]. frequent in the multibacillar lepromatous form, The posterior tibial nerve is the most commonly and should be treated early with oral corticosteroids affected, causing anesthesia on the soles of the feet, [3]. Some authors recommend to combine the followed by the ulnar, median, lateral popliteal and multidrug therapy with 60 mg prednisone, with a facial nerves. In a consecutive series of 100 leprosy gradual tapering over 5 months, to prevent further patients, the facial nerve was involved in 17 [5]. neurological damage [11]. Small dermal nerves can be affected leading to loss of sweating and a glove and stocking sensory loss. The effect of the disease on nerves leads to disability HEPATITIS C VIRUS-RELATED and deformity because of loss of motor function and NEUROPATHIES impaired sensation favoring trauma and secondary Chronic infection with hepatitis C virus (HCV) is a infections. growing global health issue affecting an estimated The presence of a skin lesion overlying a major 170 million people [12&&]. This infection is a leading nerve trunk is associated with a significant increase cause of chronic hepatitis, cirrhosis and hepatocel- in risk of impairment in that nerve. However, a pure lular carcinoma, but has been also associated with neuritic leprosy (PNL) does exist and affects peri- numerous extrahepatic manifestations. The most pheral nerve trunks in the absence of cutaneous frequent is cryoglobulinemia, present in up to signs. About 4–10% of patients with leprosy could 50% of HCV-infected patients and inducing symp- have a pure neural involvement [6,7]. In such cases, tomatic diseases in nearly 15% of cases. Cryoglobu- nerve biopsy examination is an important diagnos- lins are cold-precipitable immunoglobulins, which, tic procedure for detecting the presence of acid-fast following vascular deposition, elicit inflammation bacilli (AFB) within the nerve. However, nerves and occlusion of small-sized and medium-sized do not always contain AFB and may only show blood vessels. Up to 95% of type II and type III relatively unspecific morphological alterations. cryoglobulins (called ‘mixed cryoglobulins’) are Antunes et al. [8&] compared 144 nerve biopsies associated with chronic HCV or HIV infections [13]. from leprosy patients with 196 biopsies from In patients with HCV-associated cryoglobulins, patients with nonleprosy peripheral neuropathies. the involvement of the peripheral nerves ranges In the first group, 109 of 144 were AFB negative, and from 26 to 86% in function of the clinical/electro- 71/124 were M. leprae DNA negative by PCR. Thus, physiological protocols for neuropathy ascertain- only 35 PNL cases were unequivocally diagnosed by ment [12&&]. In the case of acute sensorimotor the presence of AFB in either Schwann cells or mononeuropathy multiplex, pathological features 1350-7540 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-neurology.com 511 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Nerve, neuro-muscular junction and motor neuron diseases are indicative of ischaemic nerve changes as a con- mitochondrial dysfunction. The use of these drugs sequence of small-sized or medium-sized vasculitis. has become uncommon in the developed world but Moderate polyneuropathies are characterized by remains in resource-limited