Misdiagnosis and diagnostic delay in non-paraneoplastic sensory neuronopathies / Erro e atraso diagnóstico nas neuronopatias sensitivas não paraneoplásicas

ABSTRACT Sensory neuronopathies (SN) are a group of peripheral nerve disorders characterized by multifocal non-length-dependent sensory deficits and sensory ataxia. Its recognition is essential not only for proper management but also to guide the etiological investigation. The uncommon SN clinical picture and its rarity set the conditions for the misdiagnosis and the diagnostic delay, especially in non-paraneoplastic SN. Therefore, our objectives were to characterize the diagnostic odyssey for non-paraneoplastic SN patients, as well as to identify possible associated factors. Methods We consecutively enrolled 48 non-paraneoplastic SN patients followed in a tertiary neuromuscular clinic at the University of Campinas (Brazil). All patients were instructed to retrieve their previous medical records, and we collected the data regarding demographics, disease onset, previous incorrect diagnoses made and the recommended treatments. Results There were 34 women, with a mean age at the diagnosis of 45.9 ± 12.2 years, and 28/48 (58%) of the patients were idiopathic. Negative sensory symptoms were the heralding symptoms in 25/48 (52%); these were asymmetric in 36/48 (75%) and followed a chronic course in 35/48 (73%). On average, it took 5.4 ± 5.3 years for SN to be diagnosed; patients had an average of 3.4 ± 1.5 incorrect diagnoses. A disease onset before the age of 40 was associated to shorter diagnosis delay (3.7 ± 3.4 vs. 7.8 ± 6.7 years, p = 0.01). Conclusions These results suggest that diagnostic delay and misdiagnosis are frequent in non-paraneoplastic SN patients. As in other rare conditions, increased awareness in all the healthcare system levels is paramount to ensure accurate diagnosis and to improve care of these patients.

RESUMO As neuronopatias sensitivas (NS) representam um grupo de doenças caracterizadas por ataxia sensitiva e déficits sensitivos multifocais e não-comprimento dependentes. O seu reconhecimento é fundamental para o tratamento apropriado e para a investigação de doenças associadas. O quadro clínico pouco frequente aliado à baixa prevalência, especialmente das formas não-paraneoplásicas (NSnp), colaboram para o atraso e erro no diagnóstico. Os objetivos desse trabalho são descrever a odisseia diagnóstica dos pacientes com NSnp e tentar identificar possíveis fatores associados. Métodos Foram incluídos consecutivamente 48 pacientes com NSnp acompanhados no ambulatório de doenças neuromusculares da Universidade Estadual de Campinas (Brasil). Dados demográficos e sobre o início da NS (incluindo diagnósticos que lhes foram dados e tratamentos prescritos) foram coletados. Resultados Na coorte descrita havia 34 mulheres e a idade ao diagnóstico era de 45,9 ± 12,2 anos. Os sintomas inaugurais eram sensitivos deficitários em 25/48 (52%) dos pacientes, sendo assimétricos em 36/48 (75%) e de evolução crônica em 35/48 (73%). Para 28/48 (58%) dos pacientes a NS era idiopática. Em média, os pacientes com NSnp tiveram um atraso diagnóstico de 5,4 ± 5,3 anos com uma média de 3,4 ± 1,5 diagnósticos incorretos. Pacientes com início antes dos 40 anos tiveram diagnóstico mais precoce que aqueles com início tardio (3,7 ± 3,4 vs. 7,8 ± 6,7 anos, p = 0,01). Conclusão Os dados ora apresentados sugerem que o erro e o atraso diagnóstico são frequentes e impactam os pacientes com NS. A importância do diagnóstico das NS deve ser constante em todos os níveis do sistema de saúde para o diagnóstico correto e a consequente melhora no cuidado a esses pacientes.

Herpes Zoster DNA Vaccines with IL-7 and IL-33 Molecular Adjuvants Elicit Protective T Cell Immunity

Herpes zoster (HZ), or shingles, is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia when VZV-specific T-cell immunity is decreased because of aging or immunosuppression. In the present study, we developed HZ DNA vaccine candidates encoding VZV proteins and cytokine adjuvants, such as IL-7 and IL-33. We immunized C57BL/6 mice with DNA plasmids encoding VZV glycoprotein E (gE), immediate early (IE) 63, or IE62 proteins and found that robust VZV protein-specific T-cell responses were elicited by HZ DNA vaccination. Co-administration of DNA plasmids encoding IL-7 or IL-33 in HZ DNA vaccination significantly enhanced the magnitude of VZV protein-specific T-cell responses. Protective immunity elicited by HZ DNA vaccination was proven by challenge experiments with a surrogate virus, vaccinia virus expressing gE (VV-gE). A single dose of HZ DNA vaccine strongly boosted gE-specific T-cell responses in mice with a history of previous infection by VV-gE. Thus, HZ DNA vaccines with IL-7 and IL-33 adjuvants strongly elicit protective immunity.

Comprehensive review and update on herpes zoster

Herpes zoster (HZ) is the result of reactivation and multiplication of latent varicella zoster virus that persisted in latent form within the sensory ganglia following an earlier attack of varicella. It occurs most frequently in older adults and immunosuppressed individuals. Classically, the rash presents as painful, erythematous, maculopapular, and vesicular lesions that typically involve single dermatome, and usually do not cross the midline. The diagnosis is mainly made clinically, except in patients with atypical manifestations in which laboratory virologic testing is required. HZ has been associated with several complications, of which postherpetic neuralgia is the most common and debilitating. The treatment of HZ includes the use of antiviral agents, analgesics for control of acute zoster pain, good skin care for healing, and prevention of secondary bacterial infection. Antiviral agents should be started within 72 hours of onset to reduce the severity of the infection, the duration of the eruptive phase, and the intensity of acute pain. The options for treating postherpetic neuralgia include lidocaine patch, high dose capsaicin patch, gabapentin, pregabalin, opioids, and tricyclic antidepressants. A live attenuated zoster vaccine reduces the incidence of by one-half and the incidence of postherpetic neuralgia by two-thirds. We herein review the recent data on the epidemiology, pathophysiology, diagnosis and management of HZ including HZ vaccine.

Evaluation of Histological Changes in Back Muscle Injuries in Rats over Time

STUDY DESIGN: Animal model study. PURPOSE: The purpose of this study was to evaluate the histological variation in the injured muscle and production of calcitonin gene-related peptide in rats over time. OVERVIEW OF LITERATURE: Vertebral surgery has been reported to cause atrophy of the back muscles, which may result in pain. However, few reports have described the time series histological variation in the injured muscle and changes in the dominant nerve. METHODS: We used 30 male, 8-week-old Sprague-Dawley rats. The right and left sides of the paravertebral muscle were considered as the injured and uninjured sides, respectively. A 115 g weight was dropped from a height of 1 m on the right paravertebral muscle. Hematoxylin and eosin (H&E) staining of the muscle was performed 1–3 weeks after injury for histological evaluation. Fluoro-Gold (FG) was injected into the paravertebral muscle. The L2 dorsal root ganglia on both sides were resected 1, 2, and 3 weeks after injury, and immunohistochemical staining for calcitonin gene-related peptide was performed. RESULTS: H&E staining of the paravertebral muscle showed infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side 1 week after injury. Muscle atrophy occurred 3 weeks after injury, but was repaired via spontaneous replacement of muscle cells/fibers. In contrast, compared with the uninjured side, the percentage of cells double-labeled with FG and calcitonin gene-related peptide in FG-positive cells in the dorsal root ganglia of the injured side was significantly increased at each time point throughout the study period. CONCLUSIONS: These results suggest that sensitization of the dominant nerve in the dorsal root ganglia, which may be caused by cicatrix formation, can protract injured muscle pain. This information may be helpful in elucidating the underlying mechanism of persistent pain after back muscle injury.

Psoas compartment block for treatment of motor weakness and pain following herpes zoster

Reactivation of the latent varicella zoster virus in the sensory ganglion causes herpes zoster (HZ). Its characteristic symptom is a painful rash in the involved dermatome. HZ-induced motor weakness is rare and is usually resolved within one year of the onset, but some patients permanently experience motor dysfunction. Epidural steroid administration, with antiviral therapy, can be effective in treating pain from HZ and preventing postherpetic neuralgia. But an epidural block is contraindicated in patients receiving thromboprophylaxis. A psoas compartment block (PCB) provides equivalent analgesic efficacy with significantly low incidence of complication, compared to an epidural block. A 68 year old male patient recieving thromboprophylaxis presented with motor weakness following painful rash in his left L4 dermatome. Ten days before presentation, herpetic rash occurred on his left leg. We performed PCB with a steroid and local anesthetic, which successfully and safely alleviated the pain and motor weakness from HZ.

Herpes Zoster and Postherpetic Neuralgia: Practical Consideration for Prevention and Treatment

Herpes zoster (HZ) is a transient disease caused by the reactivation of latent varicella zoster virus (VZV) in spinal or cranial sensory ganglia. It is characterized by a painful rash in the affected dermatome. Postherpetic neuralgia (PHN) is the most troublesome side effect associated with HZ. However, PHN is often resistant to current analgesic treatments such as antidepressants, anticonvulsants, opioids, and topical agents including lidocaine patches and capsaicin cream and can persist for several years. The risk factors for reactivation of HZ include advanced age and compromised cell-mediated immunity (CMI). Early diagnosis and treatment with antiviral agents plus intervention treatments is believed to shorten the duration and severity of acute HZ and reduce the risk of PHN. Prophylactic vaccination against VZV can be the best option to prevent or reduce the incidence of HZ and PHN. This review focuses on the pathophysiology, clinical features, and management of HZ and PHN, as well as the efficacy of the HZ vaccine.

Characterization of a murine neuron-enriched model of primary trigeminal ganglia cultures to study the interferon-ß antiviral effect against Herpes Simplex Virus type 1 / Caracterización de un modelo murino de cultivos primarios de ganglio trigeminal enriquecido en neuronas para el estudio del efecto antiviral del interferón-ß frente al virus Herpes simple tipo 1

Objective: To characterize a neuron-enriched primary TG culture and evaluate interferon- β expression and activity after HSV-1 infection. Materials and methods: The percentage of neurons present in cultures was assessed by neurofilament immunocytochemistry. Cultures were treated with interferon- β and infected with HSV-1, then viral antigen positive cells were counted and interferon- βexpression was assessed by quantitative PCR. Results: The culture contained 15% neurons and 85% non-neuronal cells. A cytopathic effect was observed, associated with high viral spread (72.9% neurons and 48.3% non-neuronal cells were positive for viral antigen). Interferon- β treatment impaired the cytopathic effect and decreased the infected neurons to 16.7% and infected non-neuronal cells to 7.8%. Viral infection at 6 h postinfection significantly increased the interferon- β transcripts by 18.2 fold, while at 18 h postinfection Interferon pre-treatment in infected cultures increased interferon- β transcription by 3.7 fold. Discussion: This culture model contained 15% neurons, which is 10 times higher compared to other reported cultures, and non-neuronal cells comprised 85% of cells in this culture. All types of cells were found to be infected, which is similar to that reported during acute infections in vivo . Additionally, interferon- βdecreased the infected cells, avoiding the cytopathic effect, which is similar to that reported in swine TG cultures. Conclusions: A neuron-enriched primary TG model was characterized. Interferon- β treatment protected cells from cytopathic effects and viral spread, while viral infection up-regulated interferon- β expression. This result means that interferon- β exerts an important antiviral effect against HSV-1 in these cultures.

Objetivo: Caracterizar un cultivo primario de ganglio trigeminal (GT) enriquecido en neuronas y evaluar la expresión de interferón- y su actividad frente a la infección con Herpes simple tipo 1 (HSV-1). Materiales y métodos: El porcentaje de neuronas fue determinado por inmunocitoquímica para neurofilamento. Los cultivos fueron tratados con interferón- β e infectados con HSV-1, y se cuantificaron las células positivas para antígeno viral por inmunocitoquímica y la expresión de interferón- β por PCR cuantitativa. Resultados: El cultivo presentó un 15% de neuronas y 85% de células no neuronales. Se encontró efecto citopático, asociado a una alta diseminación de la infección (72,9% neuronas y 48,3% de células no neuronales positivas para antígeno viral). El interferón- β evitó la aparición de efecto citopático y disminuyó las células infectadas a 16,7% en neuronas y a 7,8% las células no neuronales. La infección viral incrementó la expresión de transcritos de interferón- β 18,2 veces a las 6 h de infección, mientras que a las 18 h post infección el tratamiento con interferón incrementó esta expresión 3,7 veces. Discusión: Los cultivos presentaron un 15% de neuronas, lo cual es 10 veces más que en otros cultivos reportados. Las células no neuronales representan el 85% de las células del cultivo, y se evidenció que todos los tipos de células se infectaron; similar a lo que ha sido reportado durante infecciones agudas in vivo . Adicionalmente, el interferón- β disminuyó el porcentaje de células infectadas y evitó la aparición de efecto citopático, similar a lo que ha sido reportado en cultivos de GT porcino. Conclusiones: Se caracterizó un modelo de cultivo primario de GT enriquecido en neuronas. Interferón- β protegió las células del efecto citopático y la diseminación viral mientras que la infección viral incrementó la expresión de interferón- β. Por lo tanto, el interferón- β ejerció un papel antiviral importante frente al HSV-1 en estos cultivos.

Recurrent Herpes-Stomatitis Mimicking Acute Necrotizing Ulcerative Gingivitis

Five Cases of Atypical Herpes Zoster / 대한피부과학회지

Herpes zoster is characterized by multiple groups of vesicles on an erythematous base located within the distribution of a single spinal or cranial sensory ganglion. Classically, herpes zoster occurs in elderly patients, distributed unilaterally within one dermatomal area. The response to antiviral treatment is usually good, with rare recurrence. Herein we report 5 cases of atypical herpes zoster, which showed non-ordinary clinical features of the onset age, location and distribution, clinical course and treatment response. Moreover, since herpes zoster is a viral disorder in dermatologic clinics, different treatment protocols according to various underlying conditions are crucial. Therefore, we reviewed pertinent remedies under such uncommon circumstances.

Five Cases of Atypical Herpes Zoster / 대한피부과학회지

Herpes zoster is characterized by multiple groups of vesicles on an erythematous base located within the distribution of a single spinal or cranial sensory ganglion. Classically, herpes zoster occurs in elderly patients, distributed unilaterally within one dermatomal area. The response to antiviral treatment is usually good, with rare recurrence. Herein we report 5 cases of atypical herpes zoster, which showed non-ordinary clinical features of the onset age, location and distribution, clinical course and treatment response. Moreover, since herpes zoster is a viral disorder in dermatologic clinics, different treatment protocols according to various underlying conditions are crucial. Therefore, we reviewed pertinent remedies under such uncommon circumstances.

Effects of cadmium on photoreceptors and ganglionic cells of retinal layer in mice embryo--an ultrastructural study.

Cadmium (Cd) is one of the environmental contaminant and because of its non-decomposable character, it can damage nature. In this study, TEM was used in order to assess the ultrastructural effects of Cd on photorececptor and ganglionic cells of mouse retinal layer. Apoptotic nuclei, heterochromatic nuclei, deletion of nucleus membrane, invisible nucleolus, and apoptotic cells with mitochondrial changes were observed in mice embryo (days 15 of gestation) following CdCl2 injection to mothers on day 9 of gestation. Cadmium exposure caused apoptotic changes both in photoreceptors and ganglionic cells.

A long-term study of regeneration of mechanical sensory fibers after free nerve transplantation to the rabbit reconstructed penis / 中华整形外科杂志

<p><b>OBJECTIVE</b>To explore the regeneration of mechanical sensory fibers after free nerve transplantation.</p><p><b>METHOD</b>Neuroelectrophysiological technique (single nerve fiber recording) was used to test the regeneration rate of mechanical sensory fibers, the proportion of rapidly and slowly adapting receptors, the stimulating thresholds of regenerated mechanoreceptors and conduction velocity of regenerated fibers. The regeneration pattern of the mechanoreceptors after free nerve transplantation to the rabbit reconstructed penis was also analyzed.</p><p><b>RESULTS</b>9 months after operation, the number of regenerated mechanical sensory fiber was almost normal. The regenerated rapidly adapting receptors had a higher proportion with higher mature degree than the regenerated slowly adapting receptors. 9 months after nerve transplantation the stimulating thresholds of regenerated mechanoreceptors and conduction velocity of regenerated fibers remained below normal.</p><p><b>CONCLUSION</b>After free nerve transplantation to the rabbit reconstructed penis, the function of both rapidly and slowly adapting sensory nerve fiber partially recovered, but in different extent.</p>

Chronic osteomyelitis on mandible induced by trigeminal zoster

The Varicella zoster virus is responsible for two common infectious diseases: chicken pox(Varicella) and shingles(Herpes zoster). Chicken pox is the primary infection. After the initial infection, the virus remains dormant in sensory ganglia until reactivation may occur decades later. The subsequent reactivation is Herpes zoster. Herpes zoster of the trigeminal nerve distribution manifests as painful, vesicle eruptions of the skin and mucosa innervated by the affected nerve. Oral vesicles usually appear after the skin manifestrations. Reports of osteomyelitis of jaw after trigeminal herpes zoster are extremely rare. We report a case of osteomyelitis on mandible caused by herpes zoster infection which was treated by antiviral drug, curettage. At 1 year post-operatively, mandibular mucosa had healed without recurrent sign. But post-herpetic neuralgia is remained.

Segmental Zoster Paresis Showing Spinal Nerve Roots Involvement on Gadolinium-Enhanced MRI

Segmental zoster paresis is a focal, asymmetric limb weakness caused by a herpes zoster infection. It is a rare complication of herpes zoster and the exact pathogenesis is uncertain. However, the most likely cause is the direct spread of the virus from the sensory ganglia to the anterior horn cells or anterior spinal nerve roots. We experienced two patients with segmental zoster paresis who showed both anterior and posterior root involvement on a gadolinium-enhanced MRI, supporting this hypothesis.

How the carotid body works: Different strategies and preparations to solve different problems

This is a review of the different experimental approaches developed to solve the problems in our progress towards a comprehensive understanding of how arterial chemoreceptors operate. An analysis is performed of the bases, advantages and limits of the following preparations: studies of ventilatory reflexes originated from carotid bodies (CBs) in the entire animal; recordings of CB chemosensory discharges in situ; CB preparations perfused in situ; CB explants in oculo; CB explants in ovo; CB preparations incubated in vitro; CB preparations superfused in vitro; CB preparations perfused and superfused in vitro; CB tissue slices in vitro; cells acutely dissociated from CBs; CB cells in tissue culture; petrosal ganglia superfused in vitro; petrosal ganglion cells in tissue culture; and co-cultures of CB and sensory ganglion cells. A brief historical account is given of the passage from one preparation to the next one. Emphasis is placed on personal experience with the different preparations whenever possible. Examples are given of the importance of selecting the appropriate experimental preparation for solving each particular theoretical problem. In fact, brilliant ideas on how the CB works have been unproductive until finding the adequate experimental approach to explore the validity of such ideas.

Chemical and electric transmission in the carotid body chemoreceptor complex

Carotid body chemoreceptors are complex secondary receptors. There are chemical and electric connections between glomus cells (GC/GC) and between glomus cells and carotid nerve endings (GC/NE). Chemical secretion of glomus cells is accompanied by GC/GC uncoupling. Chemical GC/NE transmission is facilitated by concomitant electric coupling. Chronic hypoxia reduces GC/GC coupling but increases G/NE coupling. Therefore, carotid body chemoreceptors use chemical and electric transmission mechanisms to trigger and change the sensory discharge in the carotid nerve.

A Case of Herpes Zoster Duplex Bilateralis / 대한피부과학회지

Herpes zoster classically occurs unilaterally within the area of skin innervated by a single sensory ganglion. Simultaneous involvement of two noncontiguous dermatomes is very rare and it has been referred to as zoster duplex unilateralis or bilateralis, depending whether one or both halves of the body are involved. A 47-year-old woman presented with painful grouped vesicles on the right chest and the left lower back. The tzanck smear and the skin biopsy were consistent with herpetic infection. She was treated with intavenous acyclovir without any significant complications. We report a rare case of zoster duplex bilateralis.

Effects of bicarbonate buffer on acetylcholine-, adenosine 5'triphosphate-, and cyanide-induced responses in the cat petrosal ganglion in vitro

Acetylcholine (ACh), adenosine 5'-triphosphate (ATP) and sodium cyanide (NaCN) activate petrosal ganglion (PG) neurons in vitro, and evoke ventilatory reflexes in situ, which are abolished after bilateral chemosensory denervation. Because in our previous experiments we superfused the isolated PG with solutions free of CO2 /HCO3¯ buffer, we studied its effects on the PG responses evoked in vitro. PGs from adult cats were superfused at a constant pH, with HEPES-supplemented (5 mM) saline with or without CO2 /HCO3¯ (5% / 26.2 mM) buffer, and carotid (sinus) nerve frequency discharge (âCN) recorded. Increases in âCN evoked by ACh, ATP and NaCN in CO2-free saline were significantly reduced (P<0.05, Wilcoxon test) when CO2 / HCO3¯ was present in the superfusion medium. Thus, the presence of CO2 / HCO3¯ buffer appears to reduce PG neurons sensitivity to ACh, ATP and NaCN, an effect that may underlie the lack of ventilatory reflexes after bilateral chemodenervation

Localization of sympathetic and sensory nerves innervating heart in the cat using HRP and WGA-HRP as neuronal tracers / 대한해부학회지

The origin of sympathetic and sensory nerves innervating heart in the cat was investigated using HRP (Horseradish peroxidase) and WGA-HRP (Wheat germ agglutinin-horseradish peroxidase) as neuronal tracers. The neural tracers were injected into subepicardial layer and myocardium of the right atrium, left atrium, right ventricle and left ventricle, respectively. Labeled sympathetic neuronal cell bodies were found in superior cervical ganglia, middle cervical ganglia, stellate ganglia and 4th and 5th thoracic ganglia, mainly in middle cervical ganglia and stellate ganglia. Heavier labeled neuronal cell bodies were found in the middle cervical ganglia and stellate ganglia when the neural tracers were injected into left atrium, right ventricle and left ventricle. Labeled sensory neuronal cell bodies were found in nodose ganglia and T1-T6 spinal ganglia, mainly in T1-T5 spinal ganglia. Heavier labeled neuronal cell bodies were found in the nodose ganglia when the neural tracers were injected into left atrium and right ventricle. These results may provide a neuroanatomical data on origin of sensory nerves innervating the heart of the cat.

A Electrodiagnostic Evalustion of Motor Neuron Involvement in Patients with Herpes Zoster / 대한피부과학회지

BACKGROUND: Traditionally, herpes zoster (HZ) has been known to be a recrudescence of a latent viral infection of sensory ganglia, with the spread of the virus along sensory nerves and a dermatomal cutaneous eruption. However, clinically detectable muscular wenkness often occurs in patients with HZ. Accordingly, segmental or non-segmental motor neuron involvement by HZ may occur in addition to the involvement of sensory ganglion. OBJECTIVE: This study was conducted to estimate the frequency of motor neuron involvement in patients with HZ in Korea. METHODS: Fifty six subjects with HZ were enrolled in this study which used a conventional needle EMG (electromyography) and motor nerve conduction velocity test. Studies were conducted a minimum of 2 weeks after the onset of the rash. EMG was performed on the ipsilateral paravertebral muscles at the dermatomial levels of the eruption and controlateral sides. RESULTS: 1. One or more abnormal EMG findings(fibrillation potential, positive waves, bursts of high frequency discharge, polyphasia, fasciculation) were found in 51.8% of HZ patients. 2. Among the subjects with motor involvement, thoracic dermatome was most frequently involved (58.6%). 3. Ipsilateral motor involvement was more common(72.5%) than controlateral involvement(27.5%) among the patients with abnormal EMG findings. 55.2% of patients showed non-segmental motor involvement and that the altered EMG findings were not confined to the segment invaded by the eruption. 4, There was no association between the presence of postherpetic neuralgia or severity of pain or initial allodynia and EMG changes. CONCLUSION: Segmental or non-segmental motor neuron involvement by HZ may not be uncommon in Korea. HZ seems to cause widespread motor nerve changes, albeit usually subclinical alterations in the motor system, easily identifiable on EMG.