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Gut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM). Stereological and morphometric analyses revealed that the absence of gut microbiota impairs the development of somatic median nerves, resulting in smaller diameter and hypermyelinated axons, as well as in smaller unmyelinated fibers. Accordingly, DRG and sciatic nerve transcriptomic analyses highlighted a panel of differentially expressed developmental and myelination genes. Interestingly, the type III isoform of Neuregulin1 (NRG1), known to be a neuronal signal essential for Schwann cell myelination, was overexpressed in young adult GF mice, with consequent overexpression of the transcription factor Early Growth Response 2 ( Egr2 ), a fundamental gene expressed by Schwann cells at the onset of myelination. Finally, GF status resulted in histologically atrophic skeletal muscles, impaired formation of neuromuscular junctions, and deregulated expression of related genes. In conclusion, we demonstrate for the first time a gut microbiota regulatory impact on proper development of the somatic peripheral nervous system and its functional connection to skeletal muscles, thus suggesting the existence of a novel 'Gut Microbiota-Peripheral Nervous System-axis.'

Tetanus is a deadly but preventable disease caused by a protein neurotoxin produced by Clostridium tetani. Spores of C. tetani may contaminate a necrotic wound and germinate into a vegetative bacterium that releases a toxin, termed tetanus neurotoxin (TeNT). TeNT enters the general circulation, binds to peripheral motor neurons and sensory neurons, and is transported retroaxonally to the spinal cord. It then enters inhibitory interneurons and blocks the release of glycine or GABA causing a spastic paralysis. This review attempts to correlate the metalloprotease activity of TeNT and its trafficking and localization into the vertebrate body to the nature and sequence of appearance of the symptoms of tetanus., (© 2021 International Society for Neurochemistry.)

Identification of Mycobacterium leprae DNA by polymerase chain reaction (PCR) is a reliable and an affordable method to confirm leprosy. DNA from 87 nerve samples (61 from paraffin blocks and 26 fresh samples) was extracted. Mycobacterium leprae DNA was amplified by PCR from 80/87 (92%) specimens. Patients were seen over a period of 11 years (2007-2019), and leprosy was diagnosed based on clinical and characteristic histopathology findings. The clinical diagnostic possibilities were as follows: leprous neuropathy in 73/80 (91.3%), mononeuritis multiplex of unknown etiology in four (5.0%), vasculitic neuropathy in two (2.5%), and distal symmetric sensory motor neuropathy in one (1.3%). The biopsied nerves were as follows: superficial radial = 34 (42.6%), dorsal cutaneous branch of ulnar = 19 (23.8%), sural = 18 (22.5%), and superficial peroneal = 9 (11.3%), and corresponding neurological deficits were recorded in 77 (96.3%) cases. The histopathological diagnoses in total group were as follows: (borderline tuberculoid (BT) = 52, tuberculoid (TT) = 8, borderline lepromatous (BL) = 8, borderline borderline (BB) = 3, nonspecific inflammation = 3, healed/fibrosed = 4, and axonopathy = 2). Acid fast bacilli (AFB) was demonstrated in 11 (13.7%) samples. For comparison, 31 clinically and histopathologically defined non-leprous disease control nerves (inherited neuropathy = 20, vasculitis = 8, and nutritional neuropathy = 3) subjected to PCR were negative for M. leprae DNA. In most instances, there are multiple thickened peripheral nerves in suspected cases of leprosy, but neurological deficits pertaining to the thickened nerve are not as widespread. The current findings emphasize the importance of selecting the most appropriate nerve for biopsy to obtain a positive PCR result. We infer that clinical, histopathological, and PCR tests complement each other to help achieve a definitive diagnosis of leprosy particularly in pure neuritic leprosy and in leprous neuropathy with negative skin smears/biopsy.

Cryptococcus is a cosmopolitan fungus with tropism for the nervous system and a higher prevalence of infection in immunosuppressed patients. Neurological compromise caused by this microorganism mainly debuts as a meningeal syndrome (headache, fever, neck stiffness) with predominant encephalic involvement. In this report we present the rare case of a non-HIV patient with flaccid paralysis and peripheral nerve involvement due to crytpococcal meningitis. This is a 53-years-old woman, with a past-medical history of diabetes, who presented with dysarthria, unilateral peripheral facial paralysis, asymmetric ascending quadriparesis, generalized hyporeflexia and urinary retention. Neuroimaging was initially reported as negative for vascular or demyelinating diseases. Electrophysiological studies were performed, and acute flaccid paralysis of undetermined etiology was defined as a temporal clinical diagnosis. Cerebrospinal fluid molecular analysis confirmed the presence of Cryptococcus neoformans var. gatti; posteriorly, antifungal treatment with amphotericin B and fluconazole was started. Polyneuroradiculopathy symptoms significantly improved over the in-hospital stay. In conclusion, spinal cord and peripheral nerve involvement by Cryptococcus is an infrequent cause of acute flaccid paralysis that should be considered in the differential diagnosis even in HIV-negative patients., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and, ((c) strategies to achieve early diagnosis and prevent neurologic impairment to reduce the large burden of disability among newly identified cases; and among those who endure long-term disability in spite of completing multidrug therapy.)

There are a variety of imaging modalities for evaluation of peripheral nerves. Of these, ultrasonography (US) is often underused. There are several advantages of this imaging modality, including its cost-effectiveness, time-efficient assessment of long segments of peripheral nerves, ability to perform dynamic maneuvers, lack of contraindications, portability, and noninvasiveness. It can provide diagnostic information that cannot be obtained by electrophysiologic or, in some cases, magnetic resonance imaging studies. Ideally, the neurosurgeon can use US as a diagnostic adjunct in the preoperative assessment of a patient with traumatic, neoplastic, infective, or compressive nerve injury. Perhaps its most unique use is in intraoperative surgical planning. In this article, a brief description of normal US nerve anatomy is presented followed by a description of the US appearance of peripheral nerve disease caused by trauma, tumor, infection, and entrapment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mycobacterium leprae, the causative agent of leprosy (Hansen's disease), is a slow growing intracellular acid-fast bacillus that affects the skin, peripheral nerves and respiratory tract. In patients with suppressed cell-mediated immunity, the infiltration of the Bacilli can produce disseminated illness such as leprous neuromyositis. We reported a case of 56-year-old gentleman presenting with pyrexia of unknown origin, asymmetric sensory motor axonal polyneuropathy and was on chronic exogenous steroid therapy. On evaluation, his skin, muscle, nerve and bone marrow biopsy showed numerous globi of acid-fast Bacilli suggestive of leprous neuromyositis, a rare form of disseminated Hansen's disease. We reported this case in view of its rarity, atypical manifestation of a relatively rare disease and literature review on poor electrophysiological correlation in the diagnosis of leprous neuromyositis as compared to the histopathological examination.

The use of ultrasound guidance has revolutionized regional anesthesia practice. Ultrasound equipment disinfection techniques vary between institutions. To date, there are no large data set publications or evidence-based guidelines that describe risk-reduction techniques for infectious complications related to the use of ultrasound guidance for peripheral nerve blockade. We retrospectively reviewed the medical charts of 7476 patients who received ultrasound-guided single-injection peripheral nerve blockade from October 2003 to August 2013 using our institution's low-level disinfection technique in combination with a sterile transparent film barrier dressing to cover the ultrasound transducer. No indications of block-related infection were found. We conclude that using a practical and efficient low-level disinfection technique and sterile barrier dressing results in an extremely low rate of block-related infection following ultrasound-guided single-injection peripheral nerve blockade.

A systematic ultrastructure of peripheral nerves across the spectrum of leprosy was studied with an aim to better understanding the pathogenesis of nerve involvement in leprosy using light and electron microscope. The pathogenesis of nerve destruction varies in leprosy considerably along the spectrum. The study has begun to shed new light on some aspects of the infection of Mycobacterium leprae (M. lepare) and phenomenon has opened new avenue of research and possible mechanism of pathogenesis in TT/BT/BL/LL leprosy. In tuberculoid type (TT) and borderline tuberculoid (BT) leprosy, the degenerative changes of Schwann cells (SCs) and presence of perineural and perivascular cuffing by mononuclear cells. The endoneurial blood vessel (EBV) showed thickening of basement membrane with hypertrophy of EC leading to narrowing or complete occlusion of lumen and causing ischemia. However, borderline lepromatous (BL) and lepromatous leprosy (LL) foamy macrophages and vacuolated SC contain numerous small dense materials, irregular in shape and size was prominent and, considered to be degenerated and fragmented M. Leprae. The dense materials were also found in the cytoplasm of vascular EC. It was revealed that besides SC, the EC of EBV frequently harbor M. leprae in LL. The lumen of the EBV was wide open with enlarged nucleus. In the present study, the ultrastructural characteristics suggest that hypersensitivity mechanisms are possibly responsible for nerve damage in TT/BT leprosy. However, the study indicates that the mechanisms of nerve damage in BL/LL are basically different wherein hypersensitivity appears to play a very limited role.

Objectives: To evaluate the clinical, neurophysiological and histological features of cases of neuropathy developing after completion of anti-leprosy treatment, where biopsy showed inflammatory changes., Patients and Methods: Seven patients were evaluated by a single neurologist. Electro-neuro-myography and peripheral nerve biopsy were performed in all patients., Results: Median age was 50-6 years. Time from release from treatment and onset of symptoms ranged from 1 to 12 years (median of 6.6 years). Sensory symptoms were the most common complaint, including pain (71%) and paresthesiae (71%). Muscle weakness was found in 51% and muscle atrophy in 43% of the subjects. Peripheral nerve thickening was present in all patients. Neurophysiological studies suggested sensory-motor polyneuropathy and multiple mono-neuropathy. Nerve biopsy showed inflammatory processes with fibrosis of endoneurium, perineurium and epineurium and total or partial loss of fibres. No bacilli were detected with Wade staining. Patients treated with corticosteroids had some relief of symptoms., Conclusion: After release from treatment, leprosy patients may insidiously develop progressive peripheral nerve symptoms not fulfilling criteria for relapse or leprosy reactions. Sensory symptoms predominate and peripheral nerve thickening is an important finding. We speculate that these late onset symptoms are secondary to chronic immune-mediated processes in response to antigens of M. leprae.

Our current knowledge on Campylobacter jejuni infections in humans has progressively increased over the past few decades. Infection with C. jejuni is the most common cause of bacterial gastroenteritis, sometimes surpassing other infections due to Salmonella, Shigella, and Escherichia coli. Most infections are acquired due to consumption of raw or undercooked poultry, unpasteurized milk, and contaminated water. After developing the diagnostic methods to detect C. jejuni, the possibility to identify the association of its infection with new diseases has been increased. After the successful isolation of C. jejuni, reports have been published citing the occurrence of GBS following C. jejuni infection. Thus, C. jejuni is now considered as a major triggering agent of GBS. Molecular mimicry between sialylated lipooligosaccharide structures on the cell envelope of these bacteria and ganglioside epitopes on the human nerves that generates cross-reactive immune response results in autoimmune-driven nerve damage. Though C. jejuni is associated with several pathologic forms of GBS, axonal subtypes following C. jejuni infection may be more severe. Ample amount of existing data covers a large spectrum of GBS; however, the studies on C. jejuni-associated GBS are still inconclusive. Therefore, this review provides an update on the C. jejuni infections engaged in the pathogenesis of GBS.

Introduction: Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin and the nerves. Complex regional pain syndrome (CRPS/Sudeck's dystrophy) is a painful and disabling condition--a triad of autonomic, sensory, and motor symptoms disproportionate to the inciting event (inflammatory, infective, or traumatic nerve damage)., Case: A 20-year-old male presented with continuous pain, aggravated by cold and emotions, loss of fine touch and temperature sensation, redness, swelling, along lateral aspect of left hand and forearm with weakness in the grip of 6 months' duration. There was a 5-year history of sensory loss only over left index finger that he ignored. Examination revealed abnormal sensory and autonomic functions along left radial and median nerve distribution that were confirmed by nerve conduction studies suggestive of mononeuritis multiplex. Radial cutaneous nerve biopsy was suggestive of leprosy. Magnetic resonance imaging and ultrasonography showed no compressive etiology; however, MRI showed involvement of brachial plexus. Antileprosy, anti-inflammatory drugs, and steroids were given in view of neuritis because of lepra reaction with supportive measures of physiotherapy, transcutaneous electrical nerve stimulation, to no avail. A surgical median nerve decompression also failed to relieve the pain. Temporary stellate ganglion block improved the pain scale. Thus, excluding all other causes, the final diagnosis was CRPS secondary to leprosy. There is only one reported case of CRPS with leprosy., Conclusion: Leprous neuropathy caused the nerve damage that lead to CRPS type 2. Very rarely leprosy can lead to CRPS. CRPS is a diagnosis of exclusion., (Wiley Periodicals, Inc.)

Leprosy is a chronic infectious disorder caused by Mycobacterium leprae, which mainly affects skin and peripheral nerves. It is classified as either paucibacillary or multibacillary based upon clinical manifestations and slit-skin smear results. It is speculated that leprosy develops after a long latency period following M. leprae infection. However, the actual time of infection and the duration of latency have never been proven in human patients. To date, four cases of spontaneous leprosy have been reported in chimpanzees who were caught in West Africa in infancy and used for medical research in the USA and Japan. One of these chimpanzees was extensively studied in Japan, and single-nucleotide polymorphism analysis for the M. leprae genome was conducted. This analysis revealed that the chimpanzee was infected with M. leprae during infancy in West Africa and the pathognomonic signs of leprosy appeared after at least 30 years of incubation. Analysis of leprosy in chimpanzees can contribute not only to medical research but also to the understanding of the pathoetiology of leprosy.

The perineural spread by fungal cells during the progression of the infection could be an important prognostic factor, especially in mycoses localized in the rhino-orbito-cerebral and pulmonary areas. We present a clinical case of a 73-year-old male, with diabetes and acute myelomonocytic leukaemia that began with tumefaction on the left side of his face, spreading to the sinus with invasion of the soft tissues and fistulae in the oral cavity. Clinical examination showed cerebral involvement. The histopathological sections and the histochemical techniques showed perineural involvement by fungal cells. Although the patient was diagnosed and treated in a short period of time, he died due to the infection. We would like to alert that perineural spread could be a retrograde way of mycoses dissemination, particularly in infections located in areas rich in neural cells., (Copyright 2009 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.)

Multiple signaling pathways play key regulatory roles during the development of peripheral nervous system (PNS) and also in neuroregeneration process following nerve degeneration. Schwann cells, the glial cells of the PNS, by interacting with neuronal (axonal) ligands, mainly neuregulins via receptor tyrosine kinase (RTK) complex, ErbB2/ErbB3, initiate intracellular signaling pathways to drive proliferation and differentiation of Schwann cells, both during development and the process of regeneration and re-myelination after nerve injury. One of the major signaling kinases, extracellular signal-regulated kinase-1/2 (ERK1/2), that is also a downstream signaling pathway of neuregulin-ErbB2/ErbB3 activation, has been identified as a key regulator of Schwann cell proliferation, differentiation, demyelination and nerve regeneration. Recent studies have provided evidence that the bacterium that causes human leprosy, Mycobacterium leprae that has a unique capacity to invade Schwann cells of the adult PNS, utilizes the neuregulin-ErbB2/ErbB3 associated signaling network to the bacterial advantage. M. leprae directly bind to ErbB2 on myelinated Schwann cells and activate the RTK by a novel route that bypasses the classical neuregulin/growth factor-induced ErbB2-ErbB3 heterodimerization, and subsequently induce downstream the canonical Erk1/2 signaling, leading to myelin breakdown and subsequent axonal damage. This initial injury provides a survival advantage for M. leprae as it induces de-differentiation and generates myelin-free cells, which are highly susceptible to M. leprae invasion and promote bacterial survival. Once invaded M. leprae activate Erk1/2 via a non-canonical pathway and subsequently increase the cell proliferation and maintain the infected cells in de-differentiated state, thereby preventing remyelination. Therefore, by subverting major RTKs and signaling pathways in adult Schwann cells M. leprae appear to propagate the bacterial niche and maintain survival within the PNS. These studies may also provide new insights into our understanding of signaling mechanisms involve in both neurodegeneration and neuroregeneration., ((c) 2009 Elsevier Ltd. All rights reserved.)

Objective: To investigate effects of therapeutic usage of corticosteroids on M. leprae killing and clearance, on clearance of granuloma and on nerve damage in multibacillary (MB) leprosy patients., Design: From a cohort of 400 untreated MB patients, a comparable group of 100 each receiving MDT + steroids (group A) vs MDT alone (group B) were assessed at 18 months as compared to month zero with respect to clinical and granuloma regression, M. leprae killing and clearance, and nerve functions. Analysis was performed using SPSS version 10.0. The significance of association was tested using Chi square and Fisher's exact tests., Results: Regression of lesions assessed clinically and by histopathology was seen in 52% and 53% patients in group A and 46% and 63% in B respectively (P not significant). Clearance of bacteria assessed by bacteriological index (BI) in slit skin smears (SSS) and extent and intensity of antigen using anti-BCG staining were also comparable in the two groups. Multiplication of M. leprae in the mouse foot pad (MFP) indicating the presence of viable bacilli was seen in 14% and 16% of SSS positive BL-LLs patients in groups A and B respectively (P not significant). The occurrence of viable M. leprae was higher among patients with repeat reaction (19%) than single (11%). Using clinical tests (nerve palpation, monofilament and voluntary muscle testing), the proportion of sensory and motor nerves showing improvement or deterioration were similar in the two groups. However using nerve conduction studies, the overall proportion of nerves showing deterioration (22%) was significantly higher than improvement (9%) (P < 0.001)., Conclusions: Treatment with MDT + corticosteroids does not adversely affect the clearance of granuloma, M. leprae and/or its antigens and M. leprae killing. However the continued presence of viable bacteria in > 14% of BL-LLs patients indicate that 12 months of MDT may be insufficient for complete bacterial killing. In both groups nerve conduction studies indicated that deterioration of nerves was high suggesting, MDT + corticosteroids was not very efficacious in the prevention or reversal of nerve damage. A better immuno-modulatory drug or a modified corticosteroid regime is needed.

Perineuritis is an unusual cause of direct peripheral nerve injury. We describe the clinicopathologic features of a 56-year-old man with mononeuritis multiplex due to Lyme disease; sural nerve biopsy demonstrated florid perineuritis. Treatment with intravenous ceftriaxone resulted in marked neurologic improvement. This study supports the notion that perineuritis forms part of the pathogenesis in acute Lyme neuroborreliosis.

Peripheral nerve biopsies from 10 Lepromatous leprosy (LL) patients who were on multidrug treatment (MDT) were investigated by light and electron microscopy. Clofazimine (CLF) has been included as an essential component of MDT, which is the standard WHO regimen for treatment of leprosy. The patients receiving continuous MDT for a long period had viable bacilli in Schwann cells (SCs) of peripheral nerves whereas they had disappeared from the skin. Our ultrastructural observations clearly indicated the presence of CLF crystals in SCs. The crystals were in the form of osmiophilic rods of various shapes and sizes. On the other hand, the blood nerve barrier was clearly noticed in endoneurial blood vessels (EBV), and the barrier seems to play an important role for penetration of antileprosy drugs especially CLF., ((c) 2008 Wiley-Liss, Inc.)

We describe a case of sporotrichosis that disseminated to involve multiple nerves after initiation of immunosuppressive therapy and then precipitously worsened after withdrawal of therapy. This case illustrates that multiple mononeuropathies are not always caused by vasculitis, and a correct pathological diagnosis should be established before treatment. Based on clinical and pathological features, the mechanism of neuropathy may have been due to either direct nerve infection or a bystander effect of inflammatory/immune damage or, perhaps more likely, to both mechanisms.

Background: The diagnosis of tuberculoid leprosy is often difficult on hematoxylin and eosin (H&E) due to the absence of demonstrable nerve destruction. This study evaluates the utility of S-100 staining in identifying nerve fragmentation and differentiation of tuberculoid leprosy from other cutaneous granulomatous diseases., Methods: Fifty cases of leprosy including 38 borderline tuberculoid (BT), two tuberculoid (TT), and 10 indeterminate leprosy (IL) were studied. Eleven controls of non-lepromatous cutaneous granulomatous lesions were included. S-100 was used for identifying the following dermal nerve patterns: infiltrated (A), fragmented (B), absent (C), and intact (D) nerves., Results: On H&E, only 18/38 (47.4%) BT cases and 1/2 (50%) TT cases revealed neural inflammation. On S-100 staining of BT cases, 28/38 (73.7%) showed pattern B followed by patterns C and A in 8/38 (21.1%) and 2/38 (5.3%) cases, respectively. Both the TT cases showed pattern B. Only intact nerves (D) were seen in all the control cases. S-100 identified nerve damage in 4/10 (40%) IL cases. The patterns A, B, and C had sensitivity, specificity, and positive and negative predictive values of 100% in diagnosing tuberculoid (BT + TT) leprosy., Conclusions: S-100 is superior to H&E in identifying nerve fragmentation (p < 0.01). It also aids the differential diagnosis of tuberculoid leprosy.

Leprosy is best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses in humans. The second is a peripheral neuropathy that is initiated by the infection and the accompanying immunological events. The infection is curable but not preventable, and leprosy remains a major global health problem, especially in the developing world, publicity to the contrary notwithstanding. Mycobacterium leprae remains noncultivable, and for over a century leprosy has presented major challenges in the fields of microbiology, pathology, immunology, and genetics; it continues to do so today. This review focuses on recent advances in our understanding of M. leprae and the host response to it, especially concerning molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis. Advances in experimental models include studies in gene knockout mice and the development of molecular techniques to explore the armadillo model. In clinical studies, notable progress has been made concerning the immunology and immunopathology of leprosy, the genetics of human resistance, mechanisms of nerve injury, and chemotherapy. In nearly all of these areas, however, leprosy remains poorly understood compared to other major bacterial diseases.

Buruli ulcer is an emerging chronic painless skin disease found in the tropics and caused by Mycobacterium ulcerans; however, it remains unknown why the large and deep ulcers associated with this disease remain painless. To answer this question, we examined the pathology of BALB/c mice inoculated in the footpads with M. ulcerans African strain 97-107. On days 54 to 70 after inoculation, extensive dermal ulcers, subcutaneous edema, and numerous acid-fast bacilli were noted at the inoculate region. Nerve invasion occurred in the perineurium and extended to the endoneurium, and some nerve bundles were swollen and massively invaded by acid-fast bacilli. However, Schwann cell invasion, a characteristic of leprosy, was not observed. Vacuolar degeneration of myelin-forming Schwann cells was noted in some nerves which may be induced by mycolactone, a toxic lipid produced by M. ulcerans. Polymerase chain reaction analysis of microdissected nerve tissue sections showed positive amplification of M. ulcerans-specific genomic sequences but not of Mycobacterium leprae-specific sequences. Behavioral tests showed decrease of pain until edematous stage, but markedly ulcerated animals showed ordinary response against stimulation. Our study suggests that the painlessness of the disease may be partly due to intraneural invasion of bacilli. Further studies of nerve invasion in clinical samples are urgently needed.

We hypothesised that some complex regional pain syndromes (CRPS) may have a postinfectious and/or autoimmune basis. Sera from 92 patients with CRPS and 92 controls were investigated for immunoreactivity to Campylobacter strains and to rodent tissues. Both IgA-antibodies to Campylobacter and tissue-specific reactivity were often present in patients with short disease duration (< or = 1.5 years). Patients with minimal preceding trauma had stronger nervous tissue-specific reactivity than other patients, regardless of disease duration. These results provide preliminary evidence for immune activation early in CRPS and, additionally, that patients with minimal trauma may comprise an autoimmune subgroup.

The histopathological features of skin tissue sections in patients clinically diagnosed as leprosy were correlated with the histopathological features of nerve specimens obtained from the same patients. Fifty untreated leprosy patients attending the Outpatient Department of the Department of Dermatology and Sexually Transmitted Diseases of Smt. Sucheta Kriplani and Kalawati Saran Children's Hospitals, New Delhi, India were included in the study. On correlating the histological features of skin and nerve tissue sections, concordant findings were found in 24 out of the 50 patients (48%) but discordance between the histopathological features of skin and nerve tissue sections were found in 26 out of 50 cases (52%). Of these 26 cases, the nerve tissue histology when compared with the skin histology showed features lower down the disease spectrum in 17 (34%) cases. Seven of the 50 patients (14%) showed histological features of leprosy higher in the disease spectrum in the nerve tissue sections than in the skin biopsy sections. One patient clinically LL leprosy demonstrated histopathological features of Histoid leprosy in the skin sections and LL in the nerve sections. The remaining one patient had features of TT leprosy in the skin tissue sections while the nerve tissue histopathology showed non-specific changes. Histological features of the skin tissue sections were consistent with the clinical diagnosis in 33 out of 50 cases (66%). When the clinical groups were correlated with the histological features of the nerve tissue sections, concordance was found in 30 of the 50 cases (60%). On comparison of the histological features of skin and nerve tissue sections with the clinical diagnosis, concordance was still lower i.e., 19 out of 50 cases (38%). Thus the histological features of the skin tissue sections correlated more frequently with the clinical diagnosis than did those of the nerve sections. The importance of neural histology lies in the fact that it shows a higher BI and a lower histological grading in some cases and if not performed the lapse can result in inadequate treatment, drug resistance and even relapse.

Leprosy, also known as Hansen's disease, is a chronic, infectious disease caused by Mycobacterium leprae. Bacilli localize preferentially in the skin and peripheral nerves and have a propensity to cause nerve damage. The resulting disability has caused great suffering for victims in many countries. Despite recent advances in the immunopathogenesis, epidemiology and prognostic factors of leprosy nerve damage, many aspects of the disease have remained enigmatic. The spectrum of clinical and pathological manifestations of the disease ranges from lepromatous to tuberculoid, depending on the host's T-cell-mediated immune response. Diagnosis is based on three criteria: characteristic skin lesions in association with thickened nerves, demonstration of acid fast bacilli in slit skin smears, and histopathology of skin biopsies. Nerve biopsy is necessary to establish the diagnosis of pure "neural leprosy". In developed countries, the diagnosis is suspected when a patient who has stayed in an endemic area suffers from a peripheral neuropathy of unknown etiology. To facilitate determination of the appropriate antibiotic regimen, patients are classified as either paucibacillary or multibacillary. Some patients may have multibacillary leprosy in nerves and paucibacillary leprosy in skin, which emphasizes the usefulness of nerve biopsy. The course of the disease is often complicated by immune mediated "reactions", which can rapidly lead to further nerve damage, namely reversal reaction and erythema nodosum leprosy. However, nerves are often functionally impaired before developing obvious symptoms such as skin reactions or nevralgia (silent neuropathy). Early recognition and prompt treatment with corticosteroids of leprous reactions and "silent neuropathies" is very important to prevent disability with all its attendant problems. Research progress from clinical trials may improve current methods of prevention and treatment of nerve damage in leprosy.

A 7-year-old female presented with Mycoplasma pneumoniae pneumonitis and a progressive ascending limb paralysis. She developed severe respiratory distress, requiring ventilation, and became apparently unresponsive with fixed dilated pupils. Peripheral nerves were inexcitable in nerve-conduction studies. Magnetic resonance imaging of the brain revealed evidence of extensive demyelination. Anti-GM1 immunoglobulin M antibody titers were raised. She improved after a second course of intravenous immunoglobulin and eventually made a full recovery.

The clinical diagnosis of pure neural leprosy (PNL) remains a public health care problem mainly because skin lesions-the cardinal features of leprosy-are always absent.Moreover, the identification of the leprosy bacillus is not easily achieved even when a nerve biopsy can be performed. In an attempt to reach a reliable PNL diagnosis in patients referred to our Leprosy Outpatient Clinic, this study employed a variety of criteria. The nerve biopsies performed on the 67 individuals whose clinical, neurological, and electrophysiological examination findings strongly suggested peripheral neuropathy were submitted to M. leprae identification via a polymerase chain reaction (PCR). Mononeuropathy multiplex was the most frequent clinical and electrophysiological pattern of nerve dysfunction, while sensory impairment occurred in 89% of all cases and motor dysfunction in 81%. Axonal neuropathy was the predominant electrophysiological finding, while the histopathological nerve study showed epithelioid granuloma in 14% of the patients, acid fast bacilli in 16%, and nonspecific inflammatory infiltrate and/or fibrosis in 39%. PCR for M. leprae was positive in 47% of the nerve biopsy samples (n=23). PCR, in conjunction with clinical and neurological examination results, can be a powerful tool in attempting to identify and confirm a PNL diagnosis.

Objective: To document the cytomorphologic features of leprous neuritis and their correlation with bacterial density., Study Design: A partly retrospective, partly prospective study of the fine needle aspiration cytology of enlarged nerves in leprosy. Cytomorphologic features of nerve aspirates from 28 patients were studied. May-Grünwald-Geimsa and Ziehl-Neelsen staining methods were employed., Results: Five cytomorphologic patterns were observed in smears of nerve aspirates in 19 group I patients with concurrent skin and nerve lesions: (1) inflammation composed of epithelioid cell granulomas (5), bacillary index (BI) = 0; (2) epithelioid cell granulomas with necrosis (5), BI = 0-1+; (3) acellular necrosis (5), BI = 0-4+; (4) macrophage granuloma (3), BI = 5-6+; and (5) granulation tissue (1), BI = 1+. In 9 group II patients with pure neuritic leprosy, 3 patterns were seen: (1) epithelioid cell granulomas (5), BI 0-6+; (2) epithelioid granulomas with necrosis (1), BI = 0; and (3) acellular necrosis (3), BI = 0-6+., Conclusion: The entire spectrum of leprosy is seen in nerve aspirates. Necrosis is often a prominent feature. Recognition of the range of cytomorphologic patterns and their correlation with BI contribute to accurate calibration of the disease in nerves, resulting in appropriate choice of treatment.

Type 1 (reversal) reactions are the most common immunological complications of leprosy. These episodes of delayed hypersensitivity produce severe local immunopathology and ultimately nerve damage. To date, the Mycobacterium leprae antigens associated with type 1 reactions have not been identified. Using monoclonal antibodies to defined protein and carbohydrate M. leprae epitopes (65, 35 and 28 kd and lipoarabinomannan [LAM]) in a two-step immunoperoxidase staining technique, M. leprae antigens were demonstrated in skin and nerve biopsies from patients in reversal reaction. Antigen presence and staining patterns were similar in skin and nerve lesions, implying that the pathological processes are similar in the two sites. Antigens were present both in macrophages and Schwann cells but also as a diffuse extracellular infiltrate associated with the inflammatory infiltrate. The 28-kd antigen was present most strongly and may be a potential candidate antigen for initiating type 1 reactions. LAM also stained strongly and persisted after treatment. The possible roles of LAM and 65 kd in the cellular events of type 1 reactions are discussed.

In leprosy, the causative bacteria, Mycobacterium leprae, will not threaten the lives of the hosts directly because they proliferate only slowly in the Schwann cells of the peripheral nerves. It is the "reactions" which give the patients irreversible morbidity through the inflammatory damages to the peripheral nerves. Physicians should be aware of the possibility of the state of the "reaction" when they examine leprosy patients. They also should be aware of the possibility of leprosy and the state of the "reaction" when they examine patients with cutaneous lesions and/or peripheral nerve disturbances, because it may be the first presenting symptom of the disease. In this review, recent advances on the issue about the reactions are discussed including pathogenesis, immunology, clinical features, pathology, treatment and prevention.

Rhombencephalitis due to Listeria monocytogenes is characterized by progressive cranial nerve palsies and subacute inflammation in the brain stem. In this paper, we report observations made on mice infected with L. monocytogenes. Unilateral inoculation of bacteria into facial muscle, or peripheral parts of a cranial nerve, induced clinical and histological signs of mainly ipsilateral rhombencephalitis. Similarly, unilateral inoculation of bacteria into lower leg muscle or peripheral parts of sciatic nerve was followed by lumbar myelitis. In these animals, intraaxonal bacteria were seen in the sciatic nerve and its corresponding nerve roots ipsilateral to the bacterial application site. Development of myelitis was prevented by transsection of the sciatic nerve proximally to the hindleg inoculation site. Altogether, our results support the hypothesis that Listeria rhombencephalitis is caused by intraaxonal bacterial spread from peripheral sites to the central nervous system.

In conclusion, it may be said that many advances have been made in the diagnosis, treatment and prevention of nerve damage. It is now a well accepted fact that the affinity of M. leprae for Schwann cells and the property of M. leprae to grow in cooler sites of the body have made certain segments of nerve trunks vulnerable. Trauma that supervenes the inflammation and swelling severely aggravates the nerve damage. The reactive phase in all forms of leprosy, the etiology of which is not clearly understood, produces intraneural caseous necrosis in tuberculoid disease and microabscesses in lepromatous disease, causing much irreversible damage to nerves. The steroid treatment that is administered during the reactive phase has helped greatly to stop further damage, although the damage already done to nerves is not always reversible. Preventive measures like detecting the disease before nerve trunks are infected and offering prompt and adequate antileprosy therapy as early as possible have helped to reduce the prevalence of deformities. It is hoped that administering steroids along with antileprosy therapy to prevent active inflammation and or fibrosis of the nerve will reduce the prevalence of nerve damage significantly. Measures which provide rest for the infected nerve to prevent trauma should be explored.

Objective: Invasive zygomycosis is rapidly progressive and is associated with angioinvasion and infarction. Invasive disease requires emergent surgical and medical intervention. Because it is important for surgical pathologists to recognize these fungi and their preferential sites of growth, the objective of this article is to describe the fungal morphology and histopathologic findings in biopsies from patients with zygomycotic disease, with emphasis on preferential sites of fungal growth., Design: Medical record and histologic review identified 20 patients with zygomycosis. Inclusion criteria included the presence of typical ribbonlike hyphae and positive culture, a clinical history of invasive zygomycosis, or both. The histologic features of disease and the fungal morphology were assessed., Results: Fungus ball (15%), rhinocerebral (55%), and pulmonary (30%) disease were the types of disease represented. The inflammatory responses were predominantly neutrophilic (50%), predominantly granulomatous (5%), pyogranulomatous (25%), or absent (20%). Invasive disease was characterized by prominent infarcts (94%), angioinvasion (100%), and, surprisingly, prominent perineural invasion (90%) in biopsies that contained nerves for evaluation. At least rare hyphal septa were always seen (100%), and most branches (95%) varied from 45 degrees to 90 degrees., Conclusions: As known to mycologists, zygomycetes are pauciseptate, rather than aseptate, molds. Therefore, the presence of an occasional septum is expected. Perineural invasion is a common finding in invasive zygomycosis, as are angioinvasion and infarcts. Therefore, prior to excluding the presence of these fungi in biopsies suspected to contain zygomycetes, the perineural space should be carefully examined.

Mycobacterium leprae, the causative organism of leprosy, has a unique predilection for Schwann cells, the glial cells of the peripheral nervous system. M. leprae invasion of Schwann cells leads to the neurological damage that underlies the sensory motor loss and subsequent deformity and disability associated with this disease. Recent studies have begun to elucidate the early events of M. leprae infection of Schwann cells on a molecular level, and the host and bacterial factors that determine the neural predilection of this bacterium. These advances have now provided novel insights into the mechanisms of bacterial interactions with host cells.

The ultrastructural features of Borrelia garinii found in the ear tissues of the vole, Clethrionomys rufocanus, are described. The spirochetes were observed in the interstitium of connective tissue or in contact with fibroblasts and were occasionally situated in the endoneurium of the peripheral nerves. The spirochetes did not injure or enter into the fibroblasts or Schwann cells. The cytotoxicity and migration of the spirochetes are also discussed.

Selective infection of peripheral nerves is a unique property of Mycobacterium leprae that results in serious injury, but its basis is unexplained. Recent evidence from infected armadillos suggests that endothelial cells of peripheral nerve vasculature may be the gatekeepers by which M. leprae infects nerves. The pathogenesis of neuropathy in leprosy may thus entail a dynamic sequence of adhesion, immunologic, and inflammatory processes involving peripheral nerve endothelial cells.

Infection of peripheral nerve by M. leprae, the histopathologic hallmark of leprosy, is a major factor in this disease, but the route and mechanisms by which bacilli localize to peripheral nerve are unknown. Experimentally infected armadillos have recently been recognized as a model of lepromatous neuritis; the major site of early accumulation of M. leprae is epineurial. To determine the epineurial cells involved, 1 cm. segments of 44 nerves from armadillos were screened for acid-fast bacilli (AFB), and thin sections were examined ultrastructurally. Of 596 blocks containing nerve, 36% contained AFB. Overall, M. leprae were found in endothelial cells in 40% of epineurial blood vessels and 75% of lymphatics, and in 25% of endoneurial vessels. Comparison of epineurial and endoneurial findings suggested that colonization of epineurial vessels preceded endoneurial infection. Such colonization of epineurial nutrient vessels may greatly increase the risk of endoneurial M. leprae bacteremia, and also enhance the risk of ischemia following even mild increases in inflammation or mechanical stress. These findings also raise the possibility that early, specific mechanisms in the localization of M. leprae to peripheral nerve may involve adhesion events between M. leprae (or M. leprae-parasitized macrophages) and the endothelial cells of the vasa nervorum.

This study looked for M. leprae in the lymph node, nerve and skin of multibacillary (MB) leprosy patients who become slit skin smear negative after the completion of WHO-MBR. Twenty-five WHO-MBR-treated multibacillary leprosy patients were studied; borderline lepromatous (BL) leprosy (n = 11) and lepromatous (LL) leprosy (n = 14)). Fifteen patients had reaction (erythema nodosum leprosum 11, upgrading reaction 4) either at presentation or during therapy. All patients attained slit skin smear negativity after WHO-MBR (range 24-39 months. Sixteen (64%) patients with multibacillary leprosy showed fragmented bacilli in skin and nerve biopsy or lymph node aspirates after WHO-MBR. Lymph node aspirates alone revealed M. leprae in seven patients, followed by nerve in two and skin in one patient. Four cases showed M. leprae at all sites followed by nerve and skin or lymph node in one case each. A pretreatment bacteriological index (BI) of 4+ or more was significantly associated with the presence of M. leprae at the end of treatment. Also, significantly more lymph node aspirates contained M. leprae in comparison with nerve or skin biopsies. All seven cases in whom treatment was extended beyond 24 months showed M. leprae in tissues even after attaining slit smear negativity. In conclusion, M. leprae persist in tissues after 2 years of WHO-MBR and patients with an initial BI of 4+ or more need to be closely followed up after stopping MDT.

Infection of peripheral nerve by Mycobacterium leprae, the histopathological hallmark of leprosy, is a major factor in this disease, but the route and mechanisms by which bacilli localize to peripheral nerve are unknown. Experimentally infected armadillos have recently been recognized as a model of lepromatous neuritis; the major site of early accumulation of M. leprae is epineurial. To determine the epineurial cells involved, 1-cm segments of 44 nerves from armadillos were screened for acid-fast bacilli and thin sections were examined ultrastructurally. Of 596 blocks containing nerve, 36% contained acid-fast bacilli. Overall, M. leprae were found in endothelial cells in 40% of epineurial blood vessels and 75% of lymphatics, and in 25% of vessels intraneurally. Comparison of epineurial and endoneurial findings suggested that colonization of epineurial vessels preceded endoneurial infection. Such colonization of epineurial nutrient vessels may greatly increase the risk of endoneurial M. leprae bacteremia, and also enhance the risk of ischemia following even mild increases in inflammation or mechanical stress. These findings also raise the possibility that early, specific mechanisms in the localization of M. leprae to peripheral nerve may involve adhesion events between M. leprae (or M. leprae-parasitized macrophages) and the endothelial cells of the vasa nervorum.

Five biopsies of patients with indeterminate leprosy and five with skin lesions of nonspecific chronic inflammation were chosen. Histopathologic changes in the presence of acid-fast bacilli (AFB) in an average number of 145 serial sections from the entire paraffin block from each were evaluated. In all five indeterminate lesions AFB were found in the dermis, but intraneural AFB were present in only two cases. Mainly, lymphocytic infiltrate was present in two and early, poorly formed granulomas were seen in three. It is suggested that nonspecific chronic inflammation of the skin could precede indeterminate disease and that AFB, before they entered the dermal nerves, may be found in other dermal tissues. In most if not all early lesions of indeterminate leprosy Mycobacterium leprae would be found if an adequate number of sections stained for AFB were examined. The histopathologic and immunologic features of indeterminate disease were in favor of it being a primary lesion in leprosy.

As identified by a significant growth in the footpads of immunosuppressed mice, the incidence of viable bacteria in a group of 26 multibacillary (BL-LL) patients released from multidrug (MDT) treatment was found to be two times more in the nerves (46%) as compared to skin (23%). Evidently there was a positive correlation between the overall bacterial load and the incidence of viable organisms. Bacterial growth was also observed in two out of five cases where neither the skin nor the nerve homogenate had shown any presence of acid-fast bacilli. Histopathology of biopsies, skin as well as nerve, including those having viable bacteria did not show any features of active disease.

Nerve biopsy specimens from 53 patients with leprosy and neuropathy were taken from the sural, the dorsal branch of the ulnar, or the superficial radial nerves and processed for light and electron microscopy. There was inflammation in 40 cases (75%), 7 with a granulomatous reaction, various stages of fibrosis in 35 (66%), and endoneurial vascular neoformation in 7. In two cases, small focal infarcts were associated with marked endoneurial inflammation compressing the vessels, in addition to endoneurial lymphocytic vasculitis. Most had an axonal neuropathy of varying degree, some with total fibre loss, others with predominant small myelinated and unmyelinated fibre loss. Signs of demyelination and remyelination were the main findings in 9 cases (17%). Bacilli were present in endothelial, perineurial, Schwann cells and in macrophages. On two occasions, they lost their alcohol acid resistance, were suspected in semithin sections, and confirmed ultrastructurally. The biopsy was decisive for the diagnosis of leprosy in 15 cases (28%), most without skin lesions. We evaluated the effectiveness of the treatment in 20 (37.7%), 12 without and 8 with bacilli, despite negativity in the skin. The diagnosis of leprosy based on skin lesions was confirmed with the nerve biopsy in 9 cases, 6 had an inflammatory neuropathy suggestive of leprosy in the absence of bacilli, and 3 had nonspecific changes in the sural nerve since the neuropathy was in the upper limbs. We conclude that nerve biopsy is indicated for the diagnosis of leprosy in cases without clinically visible skin lesions and to evaluate the effectiveness of the treatment. In these cases the ultrastructural studies are important for recognition of the bacilli. Vascular lesions may play an important role in the progression of the nerve damage, including the occurrence of focal nerve infarcts which, to our knowledge, have not been previously reported in association with leprosy.

Among the lesions caused by mycobacteriosis, peripheral neuropathy has been regarded as the pathognomonic one peculiar to leprosy which is caused only by M. leprae (ML) which can not be cultivated. If that whole sentence is correct, no past report should be in existence concerning the peripheral neuropathy caused by the experimental inoculation of certain cultivated mycobacterium and not of ML. There was, however an exception challenging to that theory which was done by Sasaki et al. in 1985. The author, therefore, tried to reproduce this type of lesion in the nude mice modifying their method to know whether a leproma derived and cultivable mycobaceterium HI 75 (III 75) still have the ability to cause neuropathy as they observed. The mycobacterium utilized in the study was originally separated from a leproma by Skinsnes et al. as M. leprae (ML) III 75 in 1975 and was identified as M scrofulaceum (MS) by Stanford et al. in 1977. The strain was kept on cultivating in his laboratory till 1984 and in our thereafter. The groups of mice served for the present experiments consisted of two. The mice in the first group were infected intravenously and those in the latter group were by subcutaneous injections in the cheeks mixed with hyaluronic acid. The first one was unsuccessful to make remarkable neuropathy, however, the second one showed the marked invasions of the bacilli in peripheral nerves encompassed by numerous macrophages which were heavily loaded with the mycobacteria. The author believes that the present result is helpful to solve the question about the differences of the characteristics of HI-75 before and after causing neuropathy in vivo, the mutual relationship between ML, MS and III 75 and the causative organism beside ML if present.