Search

Despite the regenerative capacity of the peripheral nerve system (PNS), functional recovery after mechanical nerve trauma is often incomplete, resulting in motor, sensory, and autonomic deficits. The elucidation of key molecules involved in trauma-induced Wallerian degeneration and the ensuing regeneration processes is a prerequisite for the development of disease modifying drugs. The chemokine (C-X-C motif) receptor 3 (CXCR3) has been implicated in the recruitment of macrophages, the major immune cell population during the process of Wallerian degeneration. In this study, we examined whether deletion of CXCR3 affects macrophage recruitment, the expression of the proinflammatory cytokine tumor necrosis factor (TNF)- α and the CXCR3 agonist interferon gamma-induced protein 10 (CXCL10), and functional recovery in the sciatic nerve crush model. CXCR3 mice displayed significantly reduced macrophage counts preceded by diminished expression of CXCL10 and TNF- α. Furthermore, functional recovery of sciatic nerve motor function was significantly accelerated. In summary, these data indicate that the deletion of CXCR3 leads to a diminished inflammatory response and an accelerated functional recovery following sciatic nerve crush injury. Therefore, CXCR3 may be an interesting target for therapeutic interventions after traumatic nerve lesions.

Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) genetic disorder characterized by profound bilateral loss of central vision due to selective loss of retinal ganglion cells. Most patients with LHON do not have complaints related to the peripheral nervous system. We investigated possible qualitative and quantitative histological changes in the peripheral nerve of a patient with LHON as compared to normal controls., Methods: Brachial plexus specimens were obtained at necropsy from a patient with LHON carrying the 3460/ND1 mtDNA mutation and age-matched controls without known history of neurological disease. The nerves were evaluated by light microscope coupled to a digital camera-based morphometric analysis and electron microscopy., Results: Extensive axonal degeneration of the large heavily myelinated fibers was found in the brachial plexus from the patient with LHON. In LHON nerve fascicles, we counted over 10 times as many degenerated profiles as found in the control nerve fascicles., Conclusions: Microscopic examination of the brachial plexus in the patient with LHON clearly demonstrated a significant pattern of neurodegeneration. Our study suggests that peripheral neuropathy may be a subclinical feature associated with LHON.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. The CMT1A type can be considered the typical phenotype of this disease. Although pain is not considered a relevant symptom in CMT patients by physicians and no study assessed it comprehensively, this symptom is frequently complained by patients. The objective of the present study was to investigate the nociceptive system in a sample of CMT1A patients suffering from pain by laser-evoked potentials (LEPs). Moreover, we also used a pain specific questionnaire in order to obtain patient-oriented data about their painful symptoms, the Neuropathic Pain Diagnostic Questionnaire (DN4). We evaluated 16 patients affected by CMT1A and 14 controls. All subjects underwent a standard LEP recording session (foot, hand, and face stimulation) and filled in the DN4. While the N2/P2 amplitude to foot stimulation was lower in CMT patients than in controls (p=0.003), no difference in LEP amplitude to both hand and face stimulation was found between patients and healthy subjects (p>0.05). This result is probably due to a length-dependent Adelta-fiber loss which involves mostly the longer fibers coming from the lower limb. In our patients, there was a significant association between a reduced N2/P2 amplitude to foot stimulation and a high DN4 score (p=0.03), meaning that patients with highly probable neuropathic pain had also low N2/P2 amplitude values to painful foot stimulation. This suggests that in our CMT1A patients neuropathic pain is probably related to a reduction of the Adelta afferents., (Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: The corpus callosum (CC) has been shown to be susceptible to atrophy in Alzheimer disease (AD) as a correlate of wallerian degeneration or retrogenesis. However, when and where these 2 mechanisms intervene is still unclear., Methods: In 3 memory clinics, we recruited 38 patients with amnestic mild cognitive impairment (MCI), 38 patients with mild AD, and 40 healthy controls (HC). Combining voxel-based morphometry and diffusion tensor imaging, we investigated CC white matter (WM) density and fractional anisotropy (FA), radial diffusivity (DR), and axial diffusivity (DA)., Results: Compared with HC, patients with amnestic MCI showed reduced WM density in the anterior CC subregion; however, FA, DR, and DA did not differ between the 2 groups. Significant changes were found in patients with mild AD compared with HC in the anterior and posterior CC regions. These differences were evident in both voxel-based morphometry and diffusion tensor imaging analyses. Specifically, we found reduced callosal WM density in the genu, posterior body, and splenium; decreased FA and increased DR in the anterior CC subregion; and increased DA, with no difference in the FA, in the posterior CC subregion., Conclusions: Callosal changes are already present in patients with amnestic mild cognitive impairment (MCI) and mild Alzheimer disease (AD). The precocious involvement of the anterior callosal subregion in amnestic MCI extends to posterior regions in mild AD. Two different mechanisms might contribute to the white matter changes in mild AD: wallerian degeneration in posterior subregions of the corpus callosum (suggested by increased axial diffusivity without fractional anisotropy modifications) and a retrogenesis process in the anterior callosal subregions (suggested by increased radial diffusivity without axial diffusivity modifications).

Background: Methamphetamine use is a common problem among women of childbearing age, leading to an increasing number of children with prenatal methamphetamine exposure. Whether microstructural brain changes associated with prenatal methamphetamine exposure can be detected with diffusion tensor imaging (DTI) is unknown., Method: Twelve-direction DTI was performed in 29 methamphetamine-exposed and 37 unexposed children ages 3-4 years on a 3-T MRI scanner. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined in the corpus callosum (genu and splenium) and bilaterally in the frontal and parietal white matter (WM), basal ganglia (caudate, putamen, globus pallidus), and thalamus., Results: Children with prenatal methamphetamine exposure had lower ADC in the frontal (right: -2.1%, p = 0.04; left: -2.0%, p = 0.09) and parietal WM (right: -3.9%, p = 0.002; left: -3.3%, p = 0.02) compared to unexposed children. The methamphetamine-exposed children also showed a trend for higher FA in the left frontal WM (+4.9%, p = 0.06) compared to the unexposed children., Conclusion: Since less myelination and higher dendritic or spine density have been reported in animals exposed to methamphetamine, lower diffusion in our children may reflect more compact axons or greater dendritic or spine density associated with prenatal methamphetamine exposure. These findings suggest alterations in white matter maturation in these children exposed to methamphetamine in utero.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Objective: To analyze and compare the extent of remyelination in lesions from patients with multiple sclerosis (MS) who have a short (early MS lesions) or a long (chronic MS lesions) disease duration and to determine the influence of anatomic localization on the extent of remyelination. In early MS lesions, remyelination has been described as a relatively frequent event, in contrast to chronic MS lesions, where remyelination is absent or limited to the lesion border in the majority of lesions. However, no studies have been published that have quantified and compared the extent of remyelination in early and chronic MS lesions., Methods: We analyzed the occurrence of remyelination in 52 biopsies from 51 patients (early MS) and in 174 lesions from 36 autopsy cases (chronic MS) by immunohistochemistry for myelin proteins, and correlated our findings with anatomic localization, sex, age, and disease duration., Results: Significantly more lesions were remyelinated in early than in chronic MS (80.7% vs 60%). In chronic MS, subcortical lesions showed more extensive remyelination than periventricular lesions. The majority of cerebellar lesions were completely demyelinated., Conclusion: In summary, our data demonstrate that remyelination is a frequent event in early multiple sclerosis lesions. Furthermore, the anatomic localization of a lesion might influence the extent of remyelination.

Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P<0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P<0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex.

Objective: To evaluate a novel method to quantify the density of nerve fibers innervating sweat glands in healthy control and diabetic subjects, to compare the results to an unbiased stereologic technique, and to identify the relationship to standardized physical examination and patient-reported symptom scores., Methods: Thirty diabetic and 64 healthy subjects had skin biopsies performed at the distal leg and distal and proximal thigh. Nerve fibers innervating sweat glands, stained with PGP 9.5, were imaged by light microscopy. Sweat gland nerve fiber density (SGNFD) was quantified by manual morphometry. As a gold standard, three additional subjects had biopsies analyzed by confocal microscopy using unbiased stereologic quantification. Severity of neuropathy was measured by standardized instruments including the Neuropathy Impairment Score in the Lower Limb (NIS-LL) while symptoms were measured by the Michigan Neuropathy Screening Instrument., Results: Manual morphometry increased with unbiased stereology (r = 0.93, p < 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p < 0.001), distal thigh (p < 0.01), and proximal thigh (p < 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r = -0.89, p < 0.001) and was concordant with symptoms of reduced sweat production (p < 0.01)., Conclusions: We describe a novel method to quantify the density of nerve fibers innervating sweat glands. The technique differentiates groups of patients with mild diabetic neuropathy from healthy control subjects and correlates with both physical examination scores and symptoms relevant to sudomotor dysfunction. This method provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies.

Background: Neuromyelitis optica (NMO) is associated with destructive inflammatory lesions, resulting in necrosis and axonal injury. Disability from multiple sclerosis (MS) is due to a combination of demyelination and varying axonal involvement. Optical coherence tomography (OCT), by measuring retinal nerve fiber layer (RNFL) as a surrogate of axonal injury, has potential to discriminate between these two conditions., Methods: Included were 22 subjects with NMO or NMO spectrum disorders and 47 with MS. Seventeen subjects with NMO and all with MS had a remote history of optic neuritis (ON) in at least one eye, at least 6 months before OCT. Linear mixed modeling was used to compare the two diagnoses for a given level of vision loss, while controlling for age, disease duration, and number of episodes of ON., Results: After ON, NMO was associated with a thinner mean RNFL compared to MS. This was found when controlling for visual acuity (56.7 vs 66.6 microm, p = 0.01) or for contrast sensitivity (61.2 vs 70.3 microm, p = 0.02). The superior and inferior quadrants were more severely affected in NMO than MS., Conclusions: Optic neuritis (ON) within neuromyelitis optica (NMO) is associated with a thinner overall average retinal nerve fiber layer compared to multiple sclerosis, with particular involvement of the superior and inferior quadrants. This suggests that NMO is associated with more widespread axonal injury in the affected optic nerves. Optical coherence tomography can help distinguish the etiology of these two causes of ON, and may be useful as a surrogate marker of axonal involvement in demyelinating disease.

Background: Juvenile myoclonic epilepsy (JME) is a syndrome of idiopathic generalized epilepsy (IGE) without structural brain abnormalities detectable by MRI or CT., Objective: In the present study, we addressed the question of whether diffusion tensor MRI (DTI) can detect disease-specific white matter (WM) abnormalities in patients with JME., Methods: We performed whole head DTI at 3 T in 10 patients with JME, 8 age-matched patients with cryptogenic partial epilepsy (CPE), and 67 age-matched healthy volunteers. Nerve fiber integrity was compared between the groups on the basis of optimized voxel-by-voxel statistics of fractional anisotropy (FA) maps obtained by DTI (analysis of covariance, categorical factor "group," covariate "age")., Results: FA was reduced in a WM region associated with the anterior thalamus and prefrontal cortex in patients with JME compared to both control subjects and patients with CPE (p < 0.001). The patients with CPE showed normal values in this particular WM region. The FA reductions in the patients with JME correlated with the frequency of generalized tonic-clonic seizures (Spearman R = 0.54, p = 0.05). No significant correlations were found in the JME sample between FA reduction and the duration of antiepileptic medication., Conclusions: The results support the hypothesis that juvenile myoclonic epilepsy is associated with abnormalities of the thalamocortical network that can be detected by diffusion tensor MRI.

Objective: To report the clinical, electrodiagnostic, and pathologic findings in 3 patients who presented with complex regional pain syndrome as their primary manifestation of peripheral nerve vasculitis., Design: Case series., Setting: Outpatient clinic in a tertiary care academic medical center., Patients: Patient 1 was a 39-year-old woman with a 9-year history of non-length-dependent severe burning pain and swelling in her extremities. Patient 2 was a 67-year-old man with a 2-year history of severe burning pain and swelling in an extremity after a fall. Patient 3 was a 74-year-old man with a 6-month history of severe allodynic pain and atrophy of the right hand after a viral illness, Results: In all 3 cases, clinical and electrodiagnostic testing were suggestive of multiple mononeuropathies. Nerve biopsy either confirmed vasculitis (patient 1) or was suggestive of angiopathy (patients 2 and 3). Immunomodulative therapy led to marked clinical improvement in all 3 cases., Conclusions: To our knowledge, this is the first report demonstrating that the inflammatory nerve injury seen with peripheral nerve vasculitis can result in complex regional pain syndrome. Clinical and electrodiagnostic assessments can help in the identification and management of these patients.

Objective: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations., Methods: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined., Results: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations., Conclusion: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Cancer patients treated with antimitotic drugs in the taxane and vinca alkaloid classes sometimes develop a chronic painful peripheral neuropathy whose cause is not understood. In animal models of painful peripheral neuropathy due to nerve trauma or diabetes there is obvious axonal degeneration accompanied by an abnormal incidence of spontaneous discharge in A-fiber and C-fiber nociceptors. But animals with paclitaxel- and vincristine-evoked neuropathic pain do not have axonal degeneration at the level of the peripheral nerve. However, recent data show that they do have a partial degeneration of the primary afferent neurons' terminal arbors in the epidermis. It is not clear as to whether this relatively minor degeneration is accompanied by abnormal spontaneous discharge. We surveyed primary afferent axonal activity in the sural nerve of rats with the paclitaxel- and vincristine-evoked pain syndromes at the time of peak pain severity. Compared to vehicle-injected controls, we find a significant increase in spontaneously discharging A-fibers and C-fibers. Moreover, we show that prophylactic treatment with acetyl-l-carnitine (ALC), which blocks the development of the paclitaxel-evoked pain, causes a significant decrease (ca. 50%) in the incidence of A-fibers and C-fibers with spontaneous discharge. These results suggest that abnormal spontaneous afferent discharge is likely to be a factor in the pathogenesis of chemotherapy-evoked painful peripheral neuropathy, and that the therapeutic effects of ALC may be due to the suppression of this discharge.

Objective: We used voxel-based morphometry (VBM) to assess the pattern of regional gray matter (GM) loss in patients with pediatric multiple sclerosis (MS) and its relation with the Expanded Disability Status Scale (EDSS) score, disease duration, and the extent of T2 lesion load (LL)., Methods: From 28 patients with pediatric relapsing-remitting MS (16 girls; mean age = 14.4 years, range = 7 to 16 years) and 21 matched controls, dual-echo and three-dimensional T1-weighted magnetization prepared rapid acquisition gradient echo sequences were acquired. T2 LL was measured using a local thresholding segmentation technique. Data were analyzed using an optimized VBM analysis and statistical parametric mapping., Results: In pediatric patients with MS, mean brain T2 LL was 7.8 mL +/- 11.3. Intracranial volume did not differ between patients and controls. Compared to controls, patients with pediatric MS had significant GM loss in the thalamus, bilaterally, which was significantly correlated with T2 LL (r = -0.80 for the right thalamus, r = -0.74 for the left thalamus, p < 0.05, corrected for multiple comparisons). No correlation was found between thalamic GM loss, disease duration, and disability., Conclusions: In patients with pediatric multiple sclerosis (MS), differently from what happens in adult-onset MS, gray matter (GM) atrophy seems to involve the thalamus only, with sparing of the cortex and other deep GM nuclei. The correlation found between atrophy and T2 lesion load suggests transsynaptic and Wallerian degenerations as the most likely substrate of tissue loss in the thalamus of these patients.

Background: Leukoencephalopathy with neuroaxonal spheroids is a rare cause of severe, subacute dementia that usually presents in childhood and is inherited in an autosomal dominant pattern. The authors present clinical, radiologic, and pathologic features of adult-onset, sporadic cases mimicking cerebral-type progressive MS., Methods: Five patients referred to an MS subspecialty clinic from 1999 to 2006 suspected of having primary cerebral MS. All patients were reviewed clinically, radiologically, and pathologically at Mayo Clinic Rochester. Diagnostic brain biopsies were examined by two neuropathologists., Results: All patients had severe, progressive cognitive and motor impairment, often with prominently asymmetrical features and diffuse nonenhancing subcortical white matter lesions on brain MRI. Cerebrovascular and spinal cord imaging were normal. CSF showed elevated neuron-specific enolase without elevated oligoclonal bands or IgG index. Extensive evaluations for alternative diagnoses were unrevealing. Pathologic examination confirmed leukodystrophy with neuroaxonal spheroids and pigmented glia on all patients. Therapies initiated did not alter the severe progressive disease course., Conclusions: Leukoencephalopathy with neuroaxonal spheroids occurs sporadically, in adults, and mimics cerebral-type MS or other leukodystrophies. Brain biopsy may be diagnostic in life; however, no treatment is known to be effective. Pathologic diagnosis is important to avoid potentially toxic therapies aimed at CNS inflammatory diseases such as MS.

Background: Pelizaeus-Merzbacher-like disease (PMLD) is a genetically heterogeneous disorder within the group of hypomyelinating leukoencephalopathies. Mutations of the gap junction protein alpha 12 (GJA12) gene are known to cause one autosomal recessive PMLD form. Few patients with GJA12 mutated PMLD have been reported, and to date, the frequency as well as the genotypic and phenotypic spectrum of GJA12 related PMLD is unclear., Methods: We report mutation analysis of the GJA12 gene in a clinical and radiologic well-characterized multiethnic cohort of 193 patients with PMLD from 182 families., Results and Conclusions: Only 16 patients (8.3%) from 14 families (7.7%) carry GJA12 mutations including five families where we detected only one mutated allele. Among those, we identified 11 novel alterations. Thus, GJA12 mutations are a rather rare cause for Pelizaeus-Merzbacher-like disease. The clinical phenotype of patients with a GJA12 mutation was evaluated and is overall comparable to the clinical features seen in mild forms of proteolipid protein 1 (PLP1) related disorder but with better cognition and earlier signs of axonal degeneration.

Background: Cerebral involvement is usually absent in pure adrenomyeloneuropathy (AMN). Recently, nonconventional MR studies have reported brain abnormalities in patients with pure AMN, providing evidence that occult cerebral involvement may occur in this disease. It remains unclear, however, whether these brain abnormalities reflect centripetal extension of spinal cord long-tract axonopathy or can be the expression of a pathologic process largely involving the brain., Methods: Conventional MRI and proton MR spectroscopic imaging (1H-MRSI) data of four patients with pure AMN were compared to those of four men with spinal cord injury (SCI) and 10 age-matched healthy men (HM). Resonance intensity areas of N-acetylaspartate (NAA) and choline were calculated as ratios to creatine (Cr) in voxels located in white matter (WM) regions. Functional MRI (fMRI) data during simple motor task were obtained in a separate session in three patients with AMN and three age-matched HM., Results: Conventional MRI examinations were normal in all patients. On 1H-MRSI, NAA/Cr values were lower in all WM regions of patients with AMN than in those of patients with SCI (p < 0.05) and HM (p < 0.01). In contrast, patients with SCI showed NAA/Cr values lower than HM only in the periventricular WM (p = 0.04). At fMRI, patients with AMN showed a more pronounced activation than HM in all movement-associated cortical regions contralateral to the hand moved and an exclusive voxel activation of the primary motor, somatosensory, and posterior parietal cortices ipsilateral to the hand moved., Conclusions: CNS damage in pure adrenomyeloneuropathy is not confined exclusively to spinal cord and seems to primarily involve the brain.

Background: Although the activation-induced intracellular Ca signal is disrupted by sensory neuron injury, the contribution of specific Ca channel subtypes is unknown., Methods: Transients in dissociated rat dorsal root ganglion neurons were recorded using fura-2 microfluorometry. Neurons from control rats and from neuropathic animals after spinal nerve ligation were activated either by elevated bath K or by field stimulation. Transients were compared before and after application of selective blockers of voltage-activated Ca channel subtypes., Results: Transient amplitude and area were decreased by blockade of the L-type channel, particularly during sustained K stimulation. Significant contributions to the Ca transient are attributable to the N-, P/Q-, and R-type channels, especially in small neurons. Results for T-type blockade varied widely between cells. After injury, transients lost sensitivity to N-type and R-type blockers in axotomized small neurons, whereas adjacent small neurons showed decreased responses to blockers of R-type channels. Axotomized large neurons were less sensitive to blockade of N- and P/Q-type channels. After injury, neurons adjacent to axotomy show decreased sensitivity of K-induced transients to L-type blockade but increased sensitivity during field stimulation., Conclusions: All high-voltage-activated Ca current subtypes contribute to Ca transients in sensory neurons, although the L-type channel contributes predominantly during prolonged activation. Injury shifts the relative contribution of various Ca channel subtypes to the intracellular Ca transient induced by neuronal activation. Because this effect is cell-size specific, selective therapies might potentially be devised to differentially alter excitability of nociceptive and low-threshold sensory neurons.

Background: Neuropathic pain is inadequately treated and poorly understood at the cellular level. Because intracellular Ca signaling critically regulates diverse neuronal functions, the authors examined effects of peripheral nerve injury on the Ca transient that follows neuronal activation., Methods: Cytoplasmic Ca levels were recorded by digital microfluorometry from dissociated dorsal root ganglion neurons of hyperalgesic animals after ligation of the fifth lumbar spinal nerve and control animals. Neurons were activated by field stimulation or by K depolarization., Results: Transients in presumptively nociceptive, small, capsaicin-sensitive neurons were diminished after axotomy, whereas transient amplitude increased in axotomized nonnociceptive neurons. Axotomy diminished the upward shift in resting calcium after transient recovery. In contrast, nociceptive neurons adjacent to axotomy acquired increased duration of the transient and greater baseline shift after K activation. Transients of nonnociceptive neurons adjacent to axotomy showed no changes after injury. In nociceptive neurons from injured rats that did not develop hyperalgesia, transient amplitude and baseline offset were large after axotomy, whereas transient duration in the adjacent neurons was shorter compared with neurons excised from hyperalgesic animals, which show normalization of these features., Conclusions: A diminished Ca signal in axotomized neurons may be in part due to loss of Ca influx through voltage-gated Ca channels. The upward shift in resting Ca level after activation, which is diminished after axotomy in presumed nociceptive neurons, is a previously unrecognized aspect of neuronal plasticity. These changes in the critical Ca signal may mediate various injury-related abnormalities in Ca-dependent neuronal.

Background: The pathological hallmarks of the multiple sclerosis (MS) lesion consist of focal demyelination, inflammation, scar formation, and variable axonal destruction. Despite years of classical histopathological study and more recent intensive use of magnetic resonance technology, the MS lesion is incompletely understood. How it is initiated, how it changes over time, how it correlates with clinical symptoms and other markers of disease activity, and how it is impacted by therapeutic intervention are all largely unknown. As the site of disease pathology, the MS lesion remains the target of attack for therapy. Therefore it is essential we better understand MS lesion evolution and its clinical as well as paraclinical correlates., Review Summary: In this review, we focus on what can be learned about MS from detailed pathological analysis. We discuss the literature on both the traditional and more recent changing concepts about MS pathogenesis. We also review the work of the Multiple Sclerosis Lesion Project, an international collaborative effort to study the pathologic, clinical, and radiologic correlates of the MS lesion., Conclusions: The introduction of new technologies has contributed to a better appreciation regarding the complexity of the MS lesion. The discovery of heterogeneity in demyelinating lesions has suggested that different mechanisms may be involved in MS pathogenesis. This observation may be important for future studies on the etiology and therapy of the disease. However the potential to apply these findings to the clinic will rely on the development of technologies that allow the stratification of MS subtypes without being dependent on brain biopsies.

Live-imaging brain slice techniques were utilized to study the acute changes in transected adult mammalian neocortical neuronal processes. Transected distal axons, but not axon segments directly emerging from the cell body or dendrites, undergo rapid morphological changes leading to attempted sprouting within hours after injury. The stereotypical response involved an initial retraction of the severed axon segments, followed by rapid stabilization. Subsequently, the cut-end underwent extensive swelling, forming large singular or multiple bulb-like structures. Two to three hours after transection, sprout-like protuberances emanated from the swollen bulbs. These axonal sprouts were highly dynamic, with many showing increased length over time and a capacity to change direction. These results indicate that damaged mature axons have an intrinsic capacity to react adaptively and attempt regeneration.

In this case-control study, we compared the optic nerves (ONs) by clinical examination and scanning laser ophthalmoscopy (SLO) of 40 patients with Alzheimer disease (AD) and 50 controls. There was a reduction in the number of ON fibers in patients with AD, with a threefold greater odds ratio for a larger optic cup-to-disc ratio in patients with AD.

We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene. One mutation was in the anticodon binding domain and associated with onset in early childhood and predominant involvement of the lower limbs, thus extending the phenotype associated with GARS mutations.

Objective: We investigated if tau, microtubular binding protein, in serum and ventricular CSF (vCSF) in patients with severe traumatic brain injury (TBI) during the initial posttraumatic days correlated to 1-year outcome., Methods: Patients with severe TBI (n = 39, Glasgow Coma Scale score 2,126 pg/mL on days 2 to 3 discriminated between dead and alive (sensitivity of 100% and a specificity of 81%). A vCSF total tau level of >702 pg/mL on days 2 to 3 discriminated between bad (GOSE 1 to 4) and good (GOSE 5 to 8) outcome (sensitivity of 83% and a specificity of 69%). Patients with GOSE 1 (dead) had higher vCSF total tau levels on days 2 to 3 (p < 0.001) vs both surviving patients (GOSE 2 to 8) and those with NPH. Total tau was not detected in serum throughout the study., Conclusion: The increase in ventricular CSF (vCSF) total tau probably reflects axonal damage, known to be a central pathologic mechanism in traumatic brain injury (TBI). These results suggest that vCSF total tau may be an important early biochemical neuromarker for predicting long-term outcome in patients with a severe TBI.

Glial activation is known to contribute to pain hypersensitivity following spinal sensory nerve injury. In this study, we investigated mechanisms by which glial cell activation in medullary dorsal horn (MDH) would contribute to tactile hypersensitivity following inferior alveolar nerve and mental nerve transection (IAMNT). Activation of microglia and astrocytes was monitored at 2 h, 1, 3, 7, 14, 28, and 60 days using immunohistochemical analysis with OX-42 and GFAP antibodies, respectively. Tactile hypersensitivity was significantly increased at 1 day, and this lasted for 28 days after IAMNT. Microglial activation, primarily observed in the superficial laminae of MDH, was initiated at 1 day, maximal at 3 days, and maintained until 14 days after IAMNT. Astrocytic activation was delayed compared to that of microglia, being more profound at 7 and 14 days than at 3 days after IAMNT. Both tactile hypersensitivity and glial activation appeared to gradually reduce and then return to the basal level by 60 days after IAMNT. There was no significant loss of trigeminal ganglion neurons by 28 days following IAMNT, suggesting that degenerative changes in central terminals of primary afferents might not contribute to glial activation. Minocycline, an inhibitor of microglial activation, reduced microglial activation, inhibited p38 mitogen-activated protein kinase (MAPK) activation in microglia, and significantly attenuated the development of pain hypersensitivity in this model. These results suggest that glial activation in MDH plays an important role in the development of neuropathic pain and activation of p38 MAPK in hyperactive microglia contributes to pain hypersensitivity in IAMNT model.

Multiple sclerosis is now recognized as more than simply a disease of inflammation and demyelination in the brain and spinal cord. Conventional MRI has been established as the most important paraclinical tool in the diagnostic assessment of patients with suspected MS, and in the monitoring of treatment efficacy in clinical trials, at least in relapsing disease. Magnetization-transfer, diffusion-weighted MRI, 1H-MRS, and fMRI improve our ability to quantify the pathological changes in MS in vivo. Although we have gained some insight into the disease and are starting to uncover some of the structural and physiological substrates for the disability that develops in MS patients, we are far from understanding what causes MS and how to prevent its progression. Imaging can be used as a tool to better understand the pathophysiology of MS and ultimately improve on the treatment of MS.

Objective: To evaluate the performance characteristics of a brief clinical neuropathy screening tool for use in sensory neuropathies complicating HIV infection., Methods: The authors assessed 80 patients using the Brief Peripheral Neuropathy Screen (BPNS). Patients were defined as having neuropathy if they had both symptoms and signs consistent with this diagnosis. All subjects underwent sensory threshold testing and lower limb epidermal nerve fiber quantification using punch skin biopsy as objective measures., Results: Individuals defined as having neuropathy using the BPNS (n = 37) performed less well on sensory threshold testing than other HIV-infected individuals (p < 0.0001 for warming, cooling, and vibration) and also had lower distal calf epidermal nerve fiber densities (p < 0.0001). Individuals who had symptoms but no neuropathic signs (n = 13) did not perform differently on any objective testing compared with neuropathy-free individuals, supporting the decision to require signs as well as symptoms as an operational criterion for the diagnosis of neuropathy. Of the symptoms listed in the screening tool, the presence of numbness had the greatest diagnostic efficiency for identifying those with neuropathy., Conclusion: The Brief Neuropathy Screening Tool (and the chosen definition of neuropathy) accurately detects those HIV-infected individuals with the greatest degree of peripheral nerve dysfunction and pathology. This is a valid neuropathy screening tool for use in the context of HIV infection, and is simple enough to be applicable in resource-limited settings.

Objective: To define the nature and the temporal evolution of neuronal/axonal injury in patients at the earliest clinical stage of multiple sclerosis (MS), using whole brain N-acetylaspartate (WBNAA) proton MR spectroscopy (1H-MRS)., Methods: Thirty-five patients at presentation with clinically isolated syndromes (CIS) and MRI evidence of disease dissemination in space were studied. The following scans of the brain were acquired within 3 months from the onset of the disease and after 12 months: 1) dual-echo; 2) WBNAA 1H-MRS; 3) pre- and postcontrast T1-weighted. The same scans were obtained in 12 age-matched healthy subjects, without contrast administration. In patients, conventional MRI scans were also repeated 3 months after the first scanning session, to assess the presence of early disease dissemination in time (DIT)., Results: Over the study period, 24 patients showed MRI evidence of disease DIT, thus fulfilling the criteria for a diagnosis of MS. The average WBNAA amount was lower in CIS patients than in controls both at baseline (13.7 vs 16.9 mM, p < 0.001) and at 1-year follow-up (12.6 vs 16.2 mM, p < 0.001), but the average yearly percentage change of WBNAA did not differ between the two groups. No MRI or 1H-MRS quantities were significantly associated with the disease DIT over the study period., Conclusion: Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes, but it does not seem to be related with the disease evolution in the subsequent short-term period.

Objective: To identify the important sites of white matter disruption that underpin executive dysfunction in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a genetic model of pure subcortical vascular disease., Methods: The anatomic pattern of correlation between tissue integrity and executive function was explored with diffusion tensor imaging (DTI), which provides quantitative measures of tissue integrity. Eighteen nondemented patients with CADASIL underwent DTI and cognitive assessment. DTI was normalized to a standard template and correlations assessed at every voxel across the brain with Statistical Parametric Mapping with cluster-level correction for multiple comparisons., Results: For executive tasks, correlations were found in a number of discrete regions in the white matter of the frontal lobes. A distinct, nonoverlapping pattern of correlation was seen for verbal memory. Significant independent correlations remained in some regions after co-varying for age and IQ., Conclusions: Different cognitive functions correlate with structural integrity at different sites in the white and subcortical gray matter. The distribution of regions correlating specifically with executive function provides clues to the organization of the relevant cognitive networks and their important white matter projections. The cingulum bundle is one candidate tract that may carry anteroposterior connections important for executive processes.

Diffusion imaging is a quantitative, MR-based technique potentially useful for the study of multiple sclerosis (MS), due to its increased pathologic specificity over conventional MRI and its ability to assess in vivo the presence of tissue damage occurring outside T2-visible lesions, i.e., in the so-called normal-appearing white and gray matter. The present review aims at critically summarizing the state-of-the-art and providing a background for the planning of future diffusion studies of MS. Several pieces of evidence suggest that diffusion-weighted and diffusion tensor MRI are sensitive to MS damage and able to detect its evolution over relatively short periods of time. Although a significant relationship between diffusion-weighted MRI findings and MS clinical disability was not found in the earliest studies, with improved diffusion imaging technology correlations between diffusion abnormalities and MS clinical aspects are now emerging. However, the best acquisition and postprocessing strategies for MS studies remain a matter of debate and the contribution of newer and more sophisticated techniques to diffusion tensor MRI investigations in MS needs to be further evaluated. Although changes in diffusion MRI indices reflect a net loss of structural organization, at present we can only speculate on their possible pathologic substrates in the MS brain. Postmortem studies correlating diffusion findings with histopathology of patients with MS are, therefore, also warranted.

Background: Whereas recent data from imaging studies challenge the prevailing notion that multiple sclerosis (MS) is purely an inflammatory disease, pathologic studies suggest differences in the disease processes between individual patients with MS. The ability to dissect the pathophysiologic disease heterogeneity, if it indeed exists, by methodologies that can be applied in vivo is important both for the development of new therapeutics and for the ability to identify the optimal therapy for an individual patient., Objective: To design a stratification algorithm for patients with MS based on accepted MRI measurements reflective of inflammation and axonal damage/tissue loss and to assess if such MS subgroups retain their intergroup differences long term., Methods: Mathematical modeling was used to select three discriminatory MRI measures for clinical outcome based on the cross-sectional analysis of 71 patients with untreated MS and tested general applicability of the stratification scheme on the independent longitudinal cohort of 71 MS patients., Results: By consecutive employment of MRI measures reflective of inflammation and tissue loss, the authors were able to separate MS patients into four clinically meaningful subgroups. The analysis of the longitudinal confirmatory cohort demonstrated persistence of the intergroup differences in selected MRI measures for 8 years., Conclusions: The inflammatory activity and destructiveness of the multiple sclerosis process are to some degree independent of each other, and the successive evaluation of both of these variables can strengthen prediction of clinical outcome in individual patients.

The clinical diagnosis of Marchiafava-Bignami disease (MBD) can be difficult. Acute demyelination of the corpus callosum is characteristic of the disease. The authors report the use of MR diffusion-weighted imaging (DWI) in six cases of acute MBD. They show that apparent diffusion coefficient restriction of the corpus callosum and cortical lesions were associated with a higher mortality rate and more severe cognitive sequelae.

The authors report a 24-year-old man who developed encephalopathy and rapid quadriplegia following ingestion of a solution containing diethylene glycol (DEG). As quadriparesis evolved, motor response amplitudes were markedly reduced with preserved conduction velocities. Studies during clinical recovery revealed marked motor conduction velocity slowing and prolonged distal latencies. These data indicate that DEG intoxication may cause a primary acute axonal sensorimotor polyneuropathy with demyelinating physiology during recovery.

CNS demyelinating lesions have been reported in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). There are no studies of cord atrophy in CIDP. Ten patients with CIDP underwent brain and spinal cord MRI to investigate CNS demyelination and cord atrophy. No CNS demyelination was found, but the mean cervical cord area was significantly smaller in CIDP patients vs control subjects. Spinal cord atrophy may be related to degeneration secondary to axonal loss.

Disturbances in dopamine neurotransmission contribute to frontal lobe dysfunction after traumatic brain injury. The changes in dopamine neurotransmission may be mediated by alterations in the dopamine transporter, which plays a key role in maintaining dopamine homeostasis. To determine whether the dopamine transporter system is altered after traumatic brain injury, dopamine transporter protein was examined bilaterally in the rat frontal cortex by Western blot at 1, 7, and 28 days after controlled cortical impact or sham injury ( = 6/group). Dopamine transporter protein expression was decreased in the injured (ipsilateral) cortex at 7 days and bilaterally at 28 days in injured sham control rats. The decrease in dopamine transporter protein levels may reflect a traumatic brain-injury-induced down-regulation of dopamine transporter and/or a loss of dopaminergic fibers.

Axonal injury in multiple sclerosis has attracted considerable interest during the past few years. It has been demonstrated in association with inflammation within active lesions, but it is also present in normal-appearing white matter. Because axonal loss appears to be responsible for persistent neurological deficits in patients with multiple sclerosis, treatment strategies to prevent damage to neurites and restore function are of paramount importance in controlling the disease process. Some of the currently available immunomodulatory therapies may also reduce axonal damage, as demonstrated using improved imaging technologies, but the precise mechanisms that could protect axons during the inflammatory attack are yet to be identified. Factors that are involved in functional impairment of axonal conduction and those elements that are responsible for direct structural damage to the axon are both potential targets for therapeutic interventions.

The use of magnetic resonance imaging as a surrogate outcome measure in clinical trials, or even as a prognosticator in the assessment of the natural evolution, assumes a close relationship between extent and rate of development of magnetic resonance imaging abnormalities with the clinical status and rate of development of disability. While it may seem obvious that patients who develop new lesions are worse off than those without new lesions, the association between clinical findings and radiological extent of involvement is generally poor. In this review, various confounders are discussed, including inappropriate clinical rating, lack of histopathological specificity (especially for axonal loss), neglect of spinal cord involvement, underestimation of damage to the normal appearing brain tissue (both white and gray matter), and masking effects of cortical adaptation. It is concluded that much progression has been made in magnetic resonance techniques so that the clinico-radiological dissociation has indeed proved to be a paradox. Thus, the relevance of normal appearing brain tissue damage, residual brain volume, spinal cord damage and cerebral plasticity had to be reiterated. The increased awareness of the subtle interplay between these dimensions should be kept in mind when magnetic resonance is used as a surrogate outcome measure. This corroborates with conventional wisdom that one should not rely on a single magnetic resonance measure, but take full advantage of the fact that magnetic resonance is able to provide multidimensional information.

Background and Purpose: The goal of this study was to characterize cortical reorganization after stroke and its relation with the site of the stroke-induced lesion and degree of motor recovery using functional MRI (fMRI)., Methods: Fourteen stroke patients with an affected upper limb were studied longitudinally. Three fMRI sessions were performed over a period of 1 to 6 months after stroke. Upper limb recovery, Wallerian degeneration of the pyramidal tract, and responses to transcranial magnetic stimulation were assessed., Results: Two main patterns of cortical reorganization were found. Pattern 1 was focusing, in which, after initial recruitment of additional ipsilateral and contralateral areas, activation gradually developed toward a pattern of activation restricted to the contralateral sensorimotor cortex in 9 patients. Five patients were found to have pattern 2, persistent recruitment, in which there was an initial and sustained recruitment of ipsilateral activity. Occurrence of recruitment or focusing seemed to depend mainly on whether the primary motor cortex (M1) was lesioned; persistent recruitment was observed in 3 of 4 patients with M1 injury, and focusing was seen in 8 of 10 patients with spared M1. These patterns had no relation to the degree of recovery; in particular, focusing did not imply recovery. However, there was a clear relation between the degree of recovery and the degree of Wallerian degeneration., Conclusions: These results suggest that ipsilateral recruitment after stroke corresponds to a compensatory corticocortical process related to the lesion of the contralateral M1 and that the process of compensatory recruitment will persist if M1 is lesioned; otherwise, it will be transient.

An L5 spinal nerve ligation (SNL) in the rat leads to behavioral signs of mechanical hyperalgesia. Our recent finding that an L5 dorsal root rhizotomy did not alter the mechanical hyperalgesia following an L5 SNL suggests that signals originating from the proximal stump of the injured nerve are not essential. We postulate that Wallerian degeneration of L5 nerve fibers leads to altered properties of adjacent intact nociceptive afferents. To investigate the role of degeneration in sensory versus motor fibers, five injury models were examined concurrently in a blinded fashion. An L5 ganglionectomy produced a selective lesion of sensory fibers. An L5 ventral root rhizotomy produced a selective lesion of motor fibers. The three control lesions included: (1) SNL with L5 dorsal root rhizotomy; (2) L5 dorsal root rhizotomy; and (3) exposure of the L5 roots without transection (sham). Paw withdrawal thresholds to mechanical stimuli were measured at three sites in the rat hindpaw corresponding to the L3, L4, and L5 dermatomes. Both the ganglionectomy and the ventral rhizotomy produced a significant, lasting (>or=20 d) decrease of mechanical withdrawal thresholds that was comparable to that produced by the SNL lesion. The L5 dorsal rhizotomy, by itself, produced a short lasting (

The peripheral nervous system, as opposed to the central nervous system, has the intrinsic capacity to regenerate. It was recognized long ago that this can be achieved only after an extensive clean-up procedure, the so-called Wallerian degeneration, in which myelin debris is removed and a suitable environment for growing axons is generated. Wallerian degeneration and the regeneration process itself both depend on direct cellular interactions as well as on long-range signals between all participating cell types. Elucidating the nature and functional consequences of these signals is a main goal in understanding peripheral nerve repair.

To detect signs of axonal damage in MS, the authors investigated the occurrence in EMG of motor unit action potentials with satellite potentials (SP-MUAP) in the upper limb muscles in 10 consecutive patients with MS with cervical spinal cord demyelinating lesions and 10 control subjects. Subjects' SP-MUAP rate was 0 to 2.5% (median 0%) in the control group, and 0 to 17.5% (median 7.5%) in the MS group (p < 0.01). Motor unit remodeling secondary to axonal transection of spinal motor neurons traversing cervical demyelinating lesions may be hypothesized.