Is β-APP a marker of axonal damage in short-surviving head injury?

β-Amyloid precursor protein (β-APP), a normal constituent of neurons which is conveyed by fast axonal transport, has been found to be a useful marker for axonal damage in cases of fatal head injury. Immunocytochemistry for β-APP is a more sensitive technique for identifying axonal injury than conventional silver impregnation. This study was designed to determine how quickly evidenc of axonal damage and bulb formation appears. Using this method a variety of brain areas were studied from 55 patients who died within 24 h of a head injury. Immunocytochemical evidence of axonal injury was first detected after 2 h survival, axonal bulbs were first identified after 3 h survival, and the amount of axonal damage and axonal bulb formation increased the longer the survival time. Received: 8 February 1996 / Revised, accepted: 13 May 1996     

Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration

Traumatic axonal injury (TAI) arising from diffuse brain injury (DBI) results in focally impaired axonal transport with progressive swelling and delayed disconnection over several hours within brainstem axons. Neocortical DBI-mediated perisomatic axotomy does not result in neuronal death, suggesting that a comparably delayed axotomy progression was responsible for this unanticipated response. To evaluate delayed perisomatic axotomy, the current study was initiated. Rats received intracerebroventricular 10-kDa dextran followed by moderate midline/central fluid percussion injury (FPI) or FPI alone. At 15, 30, 60, and 180 min post-injury, light and transmission electron microscopy identified impaired axonal transport via antibodies targeting amyloid precursor protein (APP), while double-label fluorescent microscopy explored concomitant focal axolemmal alterations via dextran-APP co-localization. At 15 min post-injury, perisomatic TAI was identified with LM within dorsolateral and ventral posterior thalamic nuclei. Using TEM, many sustaining somata and related proximal/distal axonal segments revealed normal ultrastructural detail that was continuous with focal axonal swellings characterized by cytoskeletal and organelle pathology. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 30 min post-injury, perisomatic axotomy predominated. By 60-180 min, somatic, proximal axonal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal axonal segment ultrastructure now revealed the initial stages of Wallerian degeneration. The site of perisomatic axotomy did not internalize dextran, suggesting that its pathogenesis occurred independent of altered axolemmal permeability. Collectively, this DBI-mediated ultrarapid perisomatic axotomy and its sequelae further illustrate the varied axonal responses to trauma.     

Peroneal mononeuropathy: predisposing factors, and clinical and neurophysiological relationships

The most common mononeuropathy in the lower extremity involves the nerve. We retrospectively evaluated the etiological predisposing factors and clinical-neurophysiological features of 36 patients affected by peroneal mononeuropathy (PM). In 30 patients, a clear predisposing factor was identified. PM was more frequently perioperative (11 cases), associated with axonal involvement. Unexpectedly, PM was not only due to surgery close to the peroneal region, but was mostly associated with hip surgery and, rarely, with thoracic-abdominal surgery. A postural predisposing factor of PM was also frequently observed, usually associated with a pure conduction block. Conversely, most patients with bedridden predisposing factor presented axonal involvement, which was rarely associated with conduction block. In 25 of 36 PM cases, a long-term follow-up lead to an improvement (12 cases) or to good recovery (13 cases) of PM. In conclusion, our study shows that: (1) in most PM cases it is possible to identify a predisposing factor; (2) there is a good correlation between predisposing factor and neurophysiological involvement, and (3) PM usually has usually a good prognosis. Received: 10 December 2000 / Accepted in revised form: 31 May 2000     

DWI及SWI序列对弥漫性轴索损伤的诊断价值

目的探讨弥散加权（DWI）和磁敏感加权（SWI）序列在脑弥漫性轴索损伤（DAI）中的诊断价值。方法回顾性分析17例经临床和影像证实的急性DAI患者的MRI资料,包括常规T1WI、T2WI、液体衰减反转恢复（FLAIR）序列以及DWI和SWI序列,分别比较各序列对DAI非出血性和出血性病灶的检出数目,并分析其分布特点和信号特征。结果DAI病灶主要分布在白质、皮髓交界区、基底节、胼胝体、脑干及小脑等区域。DWI对非出血性DAI病灶的检出率最高,与其它序列的差异有统计学意义（P〈0．05）。而SWI对出血性DAI病灶的检出率最高,与其它序列的差异也均有统计学意义（P〈0．05）。结论DWI和SWI序列联合应用大大提高DAI病灶的检出率,为临床早期诊断提供更加可靠的影像学依据,应作为MRI检查DAI的常规和首选序列。     

Intra‐axonal protein aggregation in the peripheral nervous system

Intracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra‐axonal abnormal protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra‐axonal ubiquitin aggregates were more numerous in the patients with PD. Intra‐axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated α‐synuclein aggregation was absent in all cases, while intra‐axonal colocalization of 14‐3‐3 β and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14‐3‐3 β. Age did not correlate with the number of tau, ubiquitin, and 14‐3‐3 aggregates. Thus, both ubiquitin and/or abnormal tau intra‐axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport.     

Screening for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsy in archival nerve biopsy samples by direct-double-differential PCR

Chromosomal imbalance of the peripheral myelin protein-22 gene (PMP22) is known to be the most frequent genetic abnormality in Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP). We applied a new quantitative PCR method, the direct-double-differential PCR (dddPCR), to the gene dosage determination of PMP22. The method allows the quantification of the PMP22 gene copy number independently from DNA fragmentation, even in highly degraded DNA from up to 12-year-old sural nerve biopsy samples. Chromosomal imbalance of the PMP22 gene, which had been detected by examination of four microsatellites located directly adjacent to the PMP22 gene, between the CMT1A-repetition (CMT1A-REP) elements was reliably confirmed by the dddPCR. Using this method we unexpectedly identified two cases with PMP22 imbalance, although morphologically the neuropathies were of a neuronal or axonal type and not of a demyelinating type as usual. One sural nerve biopsy was from a 58-year-old male diabetes mellitus patient with a disproportionately severe polyneuropathy showing a heterozygous duplication of PMP22. The second biopsy exhibiting a heterozygous deletion of PMP22 was from a 58-year-old female patient with a more axonal than demyelinating type of neuropathy without typical tomaculous changes seemingly altered by exogenous, possibly traumatic factors other than diabetes mellitus. Thus, the dddPCR provides a fast and reliable diagnostic tool for the screening and identification of CMT1A and HNPP cases, which is fast and may be essential even when nerve biopsies show morphologically atypical changes. Received: 10 April 2000 / Accepted: 7 June 2000     

Incidence of axonal injury in human brain tissue

Diffuse axonal injury (DAI) is considered to be the morphological correlate of traumatic brain injury as seen in acceleration/deceleration trauma and is believed to be the main cause for a poor clinical outcome in the absence of detectable intracranial lesions. To estimate the overall incidence of DAI, and since most changes are only seen microscopically to rule out whether there is a high number of undetected cases, 450 non-selected human brains were examined. Samples from two brain areas (pons and cerebrum) were immunostained for beta-amyloid-precursor-protein (betaAPP), and axonal damage was assessed microscopically. Axonal injury was detected in 12% of all cases, but only one third had a history of traumatic brain injury. The majority of the positive cases were associated with drug intoxication, chiefly due to opiates. betaAPP staining was positive in both pons and cerebrum to a much higher extent in intoxication than in trauma cases; the latter showing axonal damage mainly in the pons area. This may reflect a more generalized pathomechanism in the intoxication group as compared to more biomechanical mechanisms in the trauma group. The findings also show that various causes may produce diffuse axonal injury and suggest that traumatic brain injury is not the only and probably not even the main cause of the observed neuropathological changes. A correlation between axonal damage and age-related processes could not be shown.     

Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage

To characterize the distribution of apoptotic neurons and their relationships with the stage of disease, a history of HIV-dementia, and the degree of productive HIV infection, microglial activation and axonal damage, we examined the brains of 40 patients. Samples of frontal and temporal cortex, basal ganglia and brain stem were taken post-mortem from 20 patients with AIDS (including three with HIV-dementia, and eight with cognitive disorders that did not fulfil the criteria for HIV-dementia), 10 HIV-positive asymptomatic cases and 10 seronegative controls. Neuronal apoptosis was demonstrated by in situ end labelling in 18 AIDS cases and two pre-AIDS cases; a single apoptotic neuron was present in the temporal cortex of a control. Semiquantitative evaluation showed that the severity of neuronal apoptosis in the cerebral cortex correlated with the presence of cerebral atrophy, but not with a history of HIV dementia. There was no global quantitative correlation between neuronal apoptosis and HIV encephalitis or microglial activation. However, there was some topographical correlation between these changes. In the basal ganglia, apoptotic neurons were much more abundant in the vicinity of multinucleated giant cells and/or p24 expressing cells. Microglial activation was constantly present in these areas. Axonal damage was identified using beta-amyloid-precursor protein (betaAPP) immunostaining in 17 AIDS and eight pre-AIDS brains. Although no global quantitative correlation could be established between axonal damage and neuronal apoptosis there was an obvious topographic correlation supporting the view that axonal damage, either secondary to local microglial activation or due to the intervention of systemic factors, may also contribute to neuronal apoptosis.     

Ultrastructural changes in peripheral nerve in hereditary motor and sensory neuropathy-Lom

Ultrastructural observations have been made on nerve biopsy specimens from five cases of hereditary motor and sensory neuropathy-Lom (HMSNL). A number of features that distinguish it from other hereditary demyelinating neuropathies were identified. Teased fibre studies were not feasible but examination of longitudinal sections by electron microscopy demonstrated demyelination/remyelination. Severe progressive axonal loss was a conspicuous feature. There was no indication of axonal atrophy. Hypertrophic onion bulb changes were present in the younger patients which later regressed, probably secondary to axonal loss. Myelin thickness was generally reduced in relation to axon diameter, indicating hypomyelination, and partial ensheathment of axons by Schwann cells was observed. The Schmidt-Lanterman incisures were atypical in extending for long lengths along the internode. Uncompacted myelin with a periodicity greater than that observed in other neuropathies in which it occurs was a feature, as was the accumulation of pleomorphic material in the adaxonal Schwann cell cytoplasm. An unusual finding was the presence of intra-axonal accumulations of irregularly arranged curvilinear profiles. These resemble those that have been described in experimental vitamin E deficiency. The amount of endoneurial collagen was markedly increased and some endoneurial blood vessels showed a non-specific basal laminal reduplication.     

X连锁Charcot-Marie-Tooth病1型六个家系的病理和基因突变特点

目的 报道6个X连锁Charcot-Marie-Tooth病1型(CMTX1)家系的神经病理和基因型改变特点.方法 6个CMTX1家系的先证者均为男性,发病年龄11 ～24岁,出现下肢远端为主的肌无力、腱反射减低和轻度感觉减退.先证者1伴随发作性白质脑病,先证者5伴随小脑性共济失调.12名家系成员也出现周围神经损害症状,另7名存在高弓足或腱反射减低.对6例先证者行腓肠神经活体组织检查,并对6例先证者、8名受累家庭成员和10名无症状家系成员及50名健康女性进行缝隙连接蛋白32( Cx32)基因测序.结果 6例先证者有髓神经纤维出现轻-中度减少伴轴索再生变性,5例出现薄髓鞘神经纤维,其中3例伴洋葱球样结构,2例伴炎细胞浸润.6个家系的Cx32基因存在5种新突变和1种同义突变,即L20T、I127F、D178G、A197V错义突变,403_404T insT插入突变和L10L沉默突变,10名无症状家系成员中有4名女性为携带者,6名男性和健康对照均没有这些基因突变.结论 该组CMTX1患者的周围神经病理改变以慢性轴索损害为主,Cx32基因较多新突变的出现提示我国CMTX1患者具有个体突变特点.     

Morphological findings on peripheral nerve biopsies in 15 patients with human immunodeficiency virus infection

Summary A peripheral nerve biopsy was performed in 15 patients with human immunodeficiency virus (HIV) infection and polyneuropathy. Two cases [1 asymptomatic, 1 AIDS-related complex (ARC)] presented with chronic inflammatory demyelinating polyneuropathy; there was 1 case (asymptomatic) of mononeuropathy multiplex and 12 cases (1 asymptomatic, 1 ARC, 10 AIDS) with distal symmetrical polyneuropathy. Epi- or endoneurial microvasculitis was observed in 6 cases. Electron microscopy showed that nerve fiber lesions were mainly axonal. Severe segmental demyelination was also present in both cases of chronic inflammatory demyelinating polyneuropathy, with characteristic features of active demyelination in one. Numerous plasmacytoid cells were found in the endoneurium in 4 patients. Tubuloreticular inclusions were present in endothelial cells in the 10 cases with AIDS but absent in the other patients. Direct immunopathological examination with anti-immunoglobulin sera was negative in all cases. HIV was evidenced by in situ hybridization in 2 AIDS patients; no Epstein-Barr virus or cytomegalovirus was detected.     

Changes in the numbers of neurons and astrocytes during the postnatal development of the rat inferior olive

In the developing nervous system, cell death is an important component of refining axonal projections. In the developing rat inferior olive, previous studies have demonstrated cell death as temporally incongruent with both initial axon-target interactions and subsequent axon collateral regression. Furthermore, these studies identified a late rise in neuron numbers that is concurrent with climbing fibre regression. As axonal regression has not previously been associated with increasing neuron numbers, and since immature neurons and glia have similar morphological characteristics, it was decided to reassess the timing of cell death within the inferior olive in animals in which neurons and glia had been differentially stained. Glia were identified by the presence of glial cytoskeletal proteins, S100, or glial fibrillary acidic protein, and stereological counts were made of both neurons and glia in the inferior olive from rats of ages 0, 5, 10, 15, and 30 days. The number of inferior olivary neurons was approximately 22,000 between birth and day 10, which decreased to about 17,500 by day 30 (P<0.05). In contrast, the number of glia rose from about 5,000 at birth to approximately 15,000 by day 10 (P<0.001), after which there was no further increase. The changes in neurons and glia caused the neuron-to-glia ratio to fall to approximately 1.5 by the time of functional maturation within the olive. These results confirm that there is neuronal death in the inferior olive but that it is temporally correlated with both climbing fibre regression and functional maturation of the olivocerebellar projection.     

Decreased axonal calibres without axonal loss in optic nerve following chronic alcohol feeding in adult rats: a morphometric study

Summary The effects of chronic ethanol exposure on number and calibres of optic nerve axons (and number of retinal ganglion cells) were investigated in a rat model. Male Sprague-Dawley rats were fed a liquid, ethanol-containing diet for 5, 10 and 17 weeks with littermates given isocaloric amounts of ethanol-free diet serving as controls. After fixation by perfusion, the optic nerves were imbedded in epoxy resin and sectioned for electron microscopy. Systematic random sampling was made from a cross-shaped area over the nerve. Axons within a counting frame were counted and morphometrically categorized with regard to mean diameter and the total number of axons estimated from number per area and the cross-sectional area of the nerve, which was measured using a digitizer table. According to non-parametric statistical analysis, ethanol exposure resulted in a significant reduction in mean cross-sectional area of the optic nerve and in mean axonal calibre but not in total axonal number in the ethanol-treated rats but there was no significant effect of duration of the exposure. The mean cross-sectional area of the nerve was reduced by 9%, 10% and 18% after 5, 10 and 17 weeks of exposure, respectively. The reduction in cross-sectional area appeared to be related to a proportional reduction in axonal and myelin area fractions. The findings indicate that chronic ethanol exposure results in decreased axonal calibres without axonal loss. This also implies that there is no reduction in the number of retinal ganglion cells.Supported by the Bank of Sweden Tercentenary Foundation (Proj. No. 86/80), the Swedish Medical Research Council (Proj. No. 07121) and Swedish Alcohol Monopoly Foundation for Alcohol Research (89/11)     

Hereditary motor and sensory neuropathy with optic atrophy. Ultrastructural and morphometric observations on nerve fibers, mitochondria, and dense-cored vesicles

Nerve biopsy specimens from three cases of hereditary motor and sensory neuropathy with optic atrophy were studied by light and electron microscopy and by morphometry. All cases had a chronic neuropathy of the neuronal/axonal type with little, presumably secondary, demyelination. There was predominant reduction of the large-caliber population of myelinated and unmyelinated nerve fibers. The number of dense-cored vesicles in unmyelinated and small myelinated fibers was increased. Abnormal mitochondria in Schwann cells with paracrystalline inclusions, prominent cristae including paracrystalline material (cases 1 and 2), and axonal mitochondria with presumable hydroxyapatite crystals (case 3) were found. The morphologic results suggest that hereditary motor and sensory neuropathy with optic atrophy should be regarded as a separate entity within the hereditary motor and sensory neuropathy group.     

Therapeutic effects of combined treatment with ribavirin and tiazofurin on experimental autoimmune encephalomyelitis development: clinical and histopathological evaluation

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and the helpful tool in preclinical testing of various substances considered for treatment of this human CNS disease. Ribavirin (R) and tiazofurin (T) are purine nucleoside analogues, with the broad spectrum of anti-viral, anti-tumoral and anti-inflammatory properties. We proposed that combined treatment with RT, administrated during the effector phase of EAE, would attenuate disease severity, both clinically and pathologically. Ribavirin was given daily at a dosage of 30 mg/kg and tiazofurin was given at a dosage of 10 mg/kg every other day for 15 days. We detected amelioration of clinical signs and faster recovery in the RT group compared to the control group. Immunohistochemical analyses revealed that RT treatment decrease the number of T cells, macrophages and microglia. In the controls, we detected reactive type of microglia, while in the RT group we noticed ramified/resting form. Demyelination areas and axonal damage were not recorded in the RT group, in contrast to the control group where multiple areas of demyelination zones and axonal loss were found. RT combination treatment suppresses ongoing EAE, prevents demyelination and axonal loss, and therefore may well be the potential therapy for the treatment of MS.     

Carcinomatous neuropathy: clinical and pathologic findings of sural nerve biopsy in 7 cases

Sural nerve biopsy was done 7 cases of cancer patients associated with peripheral neuropathy. There were 3 cases of lung carcinoma and one each of pancreas adenoma, seminoma, sigmoid carcinoma and chondrosarcoma of the femur. The neurological features manifested themselves with sensory pattern of neuropathy associated with ataxia in one case, sensorimotor neuropathy in 3 cases, and idiopathic polyneuropathy, peripheral neuropathy with proximal myopathy and neuropathy with paraneoplastic cerebellar syndrome each in one case, 6 patients showed neuropathy before malignancy was discovered and only one patient had neuropathy after the onset of carcinoma. Sural nerve biopsy studied in all the 7 patients with light and electron microscope revealed no infiltration of carcinomatous cells in the sural nerve fascicles. There was severe loss of myelinated fibers and severely axonal degeneration in one patient. Another patient showed segmental demyelination (5.03 x 10(3)/mm2). There was evidence of both axonal degeneration and demyelination associated with moderate reduction in the number of the myelinated fiber density ranging from 1.02 to 4.35 x 10(3)/mm2. In 6 cases, mononuclear cells were seen in nerve fascicles under the electron microscope. The characteristic pathological findings, their relation with the duration and onset of the cancer and some ideas regarding the pathogenesis are discussed.     

Local and commissural IC neurons make axosomatic inputs on large GABAergic tectothalamic neurons

Large GABAergic (LG) neurons are a distinct type of neuron in the inferior colliculus (IC) identified by their dense vesicular glutamate transporter 2 (VGLUT2)‐containing axosomatic synaptic terminals. Yet the sources of these terminals are unknown. Since IC glutamatergic neurons express VGLUT2, and IC neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on LG neurons come from local axonal collaterals and commissural IC neurons. We injected a recombinant viral tracer into the IC which enabled Golgi‐like green fluorescent protein (GFP) labeling in both dendrites and axons. In all cases, we found terminals positive for both GFP and VGLUT2 (GFP+/VGLUT2+) that made axosomatic contacts on LG neurons. One to six axosomatic contacts were made on a single LG cell body by a single axonal branch. The GFP‐labeled neurons giving rise to the VGLUT2+ terminals on LG neurons were close by. The density of GFP+/VGLUT2+ terminals on the LG neurons was related to the number of nearby GFP‐labeled cells. On the contralateral side, a smaller number of LG neurons received axosomatic contacts from GFP+/VGLUT2+ terminals. In cases with a single GFP‐labeled glutamatergic neuron, the labeled axonal plexus was flat, oriented in parallel to the fibrodendritic laminae, and contacted 9‐30 LG cell bodies within the plexus. Our data demonstrated that within the IC microcircuitry there is a convergence of inputs from local IC excitatory neurons on LG cell bodies. This suggests that LG neurons are heavily influenced by the activity of the nearby laminar glutamatergic neurons in the IC. J. Comp. Neurol. 522:3539–3554, 2014. © 2014 Wiley Periodicals, Inc.     

Mutations in the mitofusin 2 gene are the most common cause of Charcot-Marie-Tooth type 2 disease

In contrast to Charcot-Marie-Tooth type 1 disease (CMT1), which is most commonly caused by 17p11.2-p12 duplication (in 70% of CMT1 cases), the axonal form of hereditary motor and sensory neuropathy (CMT2) seemed to be a genetically heterogeneous disease group, with no single gene playing a major pathogenetic role. In 2004, 10 mutations were identified in CMT2A families in the MFN2 gene coding for the mitochondrial protein mitofusin-2, previously mapped to the 1p35-36 locus. In the last two years, MFN2 gene mutations were shown to be the most common cause of autosomal dominant hereditary axonopathy. In addition, MFN2 gene mutations were also identified in CMT type 6 (axonal neuropathy with optic nerve atrophy). Recent reports indicate that some MFN2 gene mutations may by inherited as autosomal recessive traits. As MFN2 gene mutations are the most common cause of autosomal dominant CMT2 disease (33% of cases), MFN2 gene testing may be considered a diagnostic test for CMT2.     

A specialized type of neuron in the visual cortex of cat: A Golgi and electron microscope study of chandelier cells

The axonal arborization of chandelier cells is characterized by its conspicuous, vertically oriented, bouton aggregates. The efferent synaptic relationships established by these terminal formations were investigated by electron microscopy of Golgi preparations after gold toning and deimpregnation. In all cases examined form layers II and III of cat areas 17 and 18, the terminal formations, here denominated specific terminal portions (stp), make symmetric synapses upon axon initial segments of pyramidal neurons. Some identified stp's were reconstructed from ultrathin serial sections with the aid of a microcomputer-based system, and the number of synaptic contacts established on axon initial segments was evaluated. No evidence was found that parts of the axonal tree other than stp's also engage in synaptic contacts. Specific terminal portions are rather variable in complexity. However, the synaptic contacts they engage in are constant and the complexity of stp's from the same axonal arborization varies. It is, therefore, clear that all stp's are terminal axonal formations of a unique, specialized type of neuron. Computer techniques and conventional Golgi observations were used to study further details of chandelier cell morphology. Axonal plexuses are preferentially, although not exclusively, local and distribute within spheric, ovoid, or disk-shaped spaces In most chandelier cells, the main axonal trunk descends to the white matter, where we have been unable to follow it further.     

Axonal injury, a neglected cause of CNS damage in bacterial meningitis

The contribution of axonal injury to CNS damage in bacterial meningitis was studied by histology and immunohistochemistry for amyloid-beta precursor protein in humans and experimental rabbits. Axonal injury in the white matter caused predominantly but not exclusively by ischemia was detected in all autopsy cases (n = 5) and in 11 of 15 brains of rabbits 18 to 24 hours after intracisternal infection with Streptococcus pneumoniae. This suggests a substantial contribution of axonal pathology to neurologic sequelae after bacterial meningitis.