Hereditary Spastic Paraplegia in Koreans: Clinical Characteristics and Factors Influencing the Disease Severity

Background and PurposeHereditary spastic paraplegia (HSP) progresses over time and is associated with locomotive dysfunction. Understanding the factors affecting disease severity and locomotive function is important in HSP. This study investigated the factors influencing disease severity and ambulation status of HSP.MethodsWe consecutively enrolled 109 Korean patients (64 males, and 45 females)from 84 families with a clinical diagnosis of HSP. HSP was primarily diagnosed based on clinical criteria including clinical findings, family history, and supported by genetic studies. Epidemiological and clinical features of the patients were analyzed, and the Spastic Paraplegia Rating Scale (SPRS) score and ambulatory status were used to evaluate disease severity.ResultsNinety-two (84.4%) patients had pure HSP, and 55 (50.4%) had a dominant family history. Thirty-one (28.4%) patients required a mobility aid for locomotion. A Kaplan-Meier analysis showed that HSP patients lost their independent gait ability after a median disease duration of 34 years. Those with an age at onset of ≤18 years had a longer median independent walking time. Pure HSP is characterized by predominant bilateral lower extremity weakness and spasticity, whereas complicated HSP presents more complex neurological findings such as ocular and bulbar symptoms, ataxia, and cognitive impairment. Complicated HSP was significantly correlated with the SPRS mobility score (β=3.70, 95% confidence interval=0.45–6.94). The age at onset and disease duration were significantly correlated with disease severity, and they were significant predictors of the use of a mobility aid (p<0.05).ConclusionsThese findings suggest that a later age at onset and longer disease duration are significant factors affecting the disease severity and ambulatory function in patients with HSP. These findings can help clinicians to identify subjects at risk of locomotive impairment.     

遗传性痉挛性截瘫2家系的临床特点与spastin基因突变分析

目的:探讨2个家系遗传3代以上常染色体显性遗传性痉挛性截瘫(AD-HSP)的临床特点及其与spastin基因突变的关系。方法:对2个AD-HSP家系进行详细的临床检查,总结所有患者临床特点,并应用PCR技术结合DNA序列分析方法,检测2家系先证者spastin基因的突变情况。结果:2家系中所有患者均具有HSP的典型表现,PCR-DNA序列分析2例先证者spastin基因的17个外显子均未发现有异常突变。结论:2家系HSP患者具有典型的AD-HSP临床表现,并非spastin基因外显子突变所致。     

Repeated motor cortex theta-burst stimulation produces persistent strengthening of corticospinal motor output and durable spinal cord structural changes in the rat

BackgroundThe strength of connections between motor cortex (MCX) and muscle can be augmented with a variety of stimulation protocols. Augmenting MCX-to-muscle connection strength by neuromodulation may be a way to enhance the intact motor system's capacity for acquiring motor skills and promote function after injury to strengthen spared connections. But this enhancement must be maintained for functional improvements.ObjectiveWe determined if brief MCX muscle evoked potential (MEP) enhancement produced by single-block intermittent theta burst stimulation (iTBS) can be converted into a longer and structurally durable form of response enhancement with repeated daily and longer-term application.MethodsElectrical iTBS was delivered through an implanted MCX epidural electrode and MEPs were recorded using implanted EMG electrodes in awake naïve rats. MCX activity was modulated further using chemogenetic (DREADDs) excitation and inhibition. Corticospinal tract (CST) axons were traced and immunochemistry used to measure CST synapses.ResultsA single MCX iTBS block (600 pulses) produced MEP LTP lasting ～30–45 min. Concatenating five iTBS blocks within a 30-min session produced MEP LTP lasting 24–48 h, which could be strengthened or weakened by bidirectional MCX activity modulation. Effect duration was not changed. Finally, daily induction of this persistent MEP LTP with daily iTBS for 10-days produced MEP enhancement outlasting the stimulation period by at least 10 days, and accompanied by CST axonal outgrowth and structural changes at the CST-spinal interneuron synapse.ConclusionOur findings inform the mechanisms of iTBS and provide a framework for designing neuromodulatory strategies to promote durable enhancement of cortical motor actions.     

生物素葡聚糖胺皮质脊髓束顺行示踪技术在大鼠脊髓损伤模型中的应用

目的探讨生物素葡聚糖胺(BDA)神经示踪技术及脊髓半横断损伤模型在大鼠脊髓损伤修复的实验研究中应用。方法采用成年Sprague-Dawley大鼠,分为脊髓致伤组(n=10)和致伤对照组(n=10)。致伤组动物在相当于T7椎板水平横行剪断脊髓的后2/3;对照组动物术中仅切除椎板,不切断脊髓。术后第15d,右侧开颅,用10?A示踪剂注入右侧的感觉运动区皮质内。2周后取出大脑和脊髓组织,采用自由漂乳法行BDA染色显影。术后实验动物功能测评采用BBB运动功能评分,所得数据采用Student'st-test进行统计学原理。结果(1)脊髓损伤组动物双后肢瘫痪,BBB运动功能评分明显低于损伤对照组,统计学比较差异十分显著(P<0.01);(2)BDA顺行示踪显示大脑皮层BDA注射区内见大脑皮层的锥体细胞及其发出的轴突呈阳性染色,BDA阳性染色的皮质脊髓束神经纤维在同侧中脑、桥脑及延髓的腹侧面行走,在锥体交叉后皮质脊髓束主要在对侧脊髓白质的后索中行走。在致伤组动物中,位于脊髓白质后索中的皮质脊髓束纤维在脊髓损伤处终止;对照组皮质脊髓束BDA染色可一直延伸至L1水平。结论大鼠半脊髓切断结合应用BDA顺行示踪技术可以对脊髓损伤后的神经修复状况进行可靠的形态学评判,是研究脊髓损伤后中枢神经纤维再生修复较为理想的动物模型     

Mutation analysis of SPAST,ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

Background and Purpose

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively.

Methods

Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes.

Results

Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected.

Conclusions

We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.     

Olfactory ensheathing cells promote collateral axonal branching in the injured adult rat spinal cord

In recent years, injection of olfactory ensheathing cells (ECs) into the spinal cord has been used as an experimental strategy to promote regeneration of injured axons. In this study, we have compared the effects of transplanting encapsulated ECs with those injected directly into the spinal cord. The dorsal columns of adult rats were cut at T(8-9) and rats in experimental groups received either EC-filled porous polymer capsules or culture medium (CM)-filled capsules with ECs injected at the injury site. Control rats were in three groups: (1) uninjured, (2) lesion with transplantation of CM-filled capsules and (3) lesion with transplantation of CM-filled capsules and injections of CM. Three weeks after injury, Fluororuby was injected into the hindlimb motor and somatosensory cortex to label corticospinal neurons. Observations indicated that there were a few regenerating fibres, up to 10, in the EC-treated groups. In rats that received encapsulated ECs, regenerating fibres were present in close association with the capsule. Rats that received EC injections demonstrated a significant increase in the number of collateral branches from the intact ventral corticospinal tract (vCST) compared with the corresponding control, CM-injected group (P=0.003), while a trend for increased collateral branches was observed in rats that received encapsulated ECs (P=0.07).     

Organization in the descending tracts of the dorsolateral funiculus in the cat

Organization of the fibers in the descending tracts of the dorsolateral funiculus of the cervical spinal cord was investigated in cats. The spinal cord was penetrated with microelectrodes at 400 mum intervals in the medio-lateral direction at the c5/c6 and c6/c7 segmental borders. Silicon substrate microelectrodes with a linear arrangement of activated iridium contacts were used. The stimulus consisted of a 20 ms train of charge balanced biphasic current pulses at 330 Hz. The evoked activities from selected forelimb muscles were acquired into computer. Only the data points with an activation threshold of less than 35 muA were considered in the analysis. Muscle contractions were mostly in the form of short twitches. In both spinal segments, an area of high threshold was found in the middle of the dorsolateral funiculus. Majority of the muscles studied had a dorsal or ventral concentration of activation points. The distal muscles were mostly activated in the ventro-lateral aspect of the funiculus, while the elbow muscle maps spread to both dorsal and ventral sides. These results show a functional organization in both cervical segments studied, with overlapping regions between the areas dedicated for each forelimb muscle.     

The effect of pyramidal stimulation upon tail muscle motoneurons in the decerebrate cat

This study aimed to determine the effects of the corticospinal tract (CST) on the motoneurons innervating the tail muscles in cats. The stimulation of the pyramidal tract predominantly evoked excitatory postsynaptic potentials (EPSPs; 48/90 motoneurons: 53%). Single-pulse stimulation produced EPSPs in 18 of 48 motoneurons, but double shocks evoked postsynaptic potentials in most of the remaining cells (26/48). Monosynaptic excitatory connections between pyramidal tract fibers and tail motoneurons were confirmed in 4 motoneurons. Inhibitory postsynaptic potentials (IPSPs) were recorded from motoneurons innervating long tendinous tail muscles (7/90: 8%) and the shortest neuronal pathways of IPSPs were shown to be disynaptic pathways. Interactions between the CST and reflex pathways from low-threshold muscle and cutaneous afferents innervating the tail and hindlimbs were observed.     

Experimental studies on spinal cord injuries in the last fifteen years

Abstract

Experimental studies on spinal cord (SC) injuries published from 1975 to 1989 in some of the most widely circulating neurosurgical journals were reviewed. The relatively large number of animal species utilized as well as the intensely variable dynamic or static methods employed to induce SC injury represent elements of confusion more than objective necessities in this field of research. In fact, the objective of SC injury research should be to solve the problem of severe SC injuries by either preventing and/or repairing SC damage, rather than looking for modalities to provoke a large spectrum of SC injuries with the result of establishing a correlation between for example, the clinical picture and trauma magnitude. It should be time to study all variables and treatments mainly in only one experimental model. The rat with a permanent paraplegia should represent such a model; the abdominal aorta occlusion for 45 minutes, distal to the renal arteries in rabbits should be the experimental model of choice for ischaemia. If a significant result, such as reversing permanent paraplegia, were obtained in rats, it would be logical to repeat the study in higher mammals and if successful' in humans. For the last decade of this century it is necessary to further study all the mechanisms implied in secondary SC damage as well as to attempt to repair definitive SC damage by using grafts and enhancing the potential regenerative ability of the SC with known and new growth factors. Presently, methylprednisolone, dexametasone, thiopental, naloxone, and hypothermia seem to have some clinical potentials that require studies in humans.     

Dynamic mapping of the corticospinal tract in open cordotomy and myelomeningocele surgery

ObjectSpinal cord surgeries carry a high risk for significant neurological impairments. The initial techniques for spinal cord mapping emerged as an aid to identify the dorsal columns and helped select a safe myelotomy site in intramedullary tumor resection. Advancements in motor mapping of the cord have also been made recently, but exclusively with tumor surgery. We hereby present our experiences with dynamic mapping of the corticospinal tract (CST) in other types of spinal cord procedures that carry an increased risk of postoperative motor deficit, and thus could directly benefit from this technique.Case reportsTwo patients with intractable unilateral lower extremity pain due to metastatic disease of the sacrum and a thoraco-lumbar chordoma, respectively underwent thoracic cordotomy to interrupt the nociceptive pathways. A third patient with progressive leg weakness underwent cord untethering and surgical repair of a large thoracic myelomeningocele. In all three cases, multimodality intraoperative neurophysiologic testing included somatosensory and motor evoked potentials monitoring as well as dynamic mapping of the CST.ConclusionCST mapping allowed safe advancement of the cordotomy probe and exploration of the meningocele sac with untethering of the anterior-lateral aspect of the cord respectively, resulting in postoperative preservation or improvement of motor strength from the pre-operative baseline. Stimulus thresholds varied likely with the distance between the stimulating probe and the CST as well as with the baseline motor strength in the mapped myotomes.     

Endocannabinoid signaling in the spinal locomotor circuitry

To understand how the spinal central pattern generators produce locomotor movements, it is necessary to characterize the network's connectivity, the intrinsic properties of the constituent neurons and the modulatory mechanisms. Modulation operating within spinal locomotor networks is required for the generation of the final motor output. In this review, we have summarized how endocannabinoids released by locomotor network neurons contribute to setting the baseline locomotor frequency. They are synthesized on demand as a result of activation of mGluR1 and act as retrograde messengers to depress inhibitory synaptic transmission. We also discuss how endogenous activation of mGluR1 contributes to the normal operation of the spinal locomotor network and the underlying cellular and synaptic mechanisms.     

Age-related changes of the myelinated fibers in the human corticospinal tract: a quantitative analysis

A quantitative analysis was made of the myelinated fibers in the lateral corticospinal tract (LCST) at the levels of the 6th cervical, 7th thoracic and 4th lumbar spinal segments in 20 patients between 19 and 90 years old, and who died of non-neurological diseases. The diameter frequency histograms of myelinated fibers of LCST showed a bimodal pattern with a sharp peak of the small myelinated fibers and broad slope of the large myelinated fibers. The ratio of small fiber to large fiber densities was significantly higher in the 6th cervical (P<0.05) and 4th lumbar segments (P<0.01) than in the 7th thoracic segments. The density of small myelinated fibers was significantly lowered with advancing age (P<0.050.001), while that of large myelinated fibers was not significantly decreased in the aged patients, although it showed a slight age-dependent declining tendency. Age-dependent decline of small fiber density was more prominent in the cervical and lumbar segments. Retraction of the axon-collaterals from large-diameter myelinated fibers, which are abundant in the cervical and lumbar segments, may contribute to the age-related diminution of the small myelinated fibers in the LCST.Part of this work was supported by grants from the Ministry of Welfare and Health of Japan, and a grant from Uehara Memorial Research Foundation     

Preservation of central motor conduction in patients with spinal muscular atrophy type II

We evaluated the central (motor cortex to C8 motoneuron) and peripheral (C8 motoneuron to the muscle) motor conduction in 14 limbs of 7 patients with the intermediate form of spinal muscular atrophy (SMA II). The central motor conduction time (CMCT) was calculated using motor evoked potentials (MEPs) by transcranial magnetic stimulation and the results of a conventional F wave study. Peripheral conduction abnormality was found in 6 median nerves (43%) and 10 ulnar nerves (71%). Even in these patients with peripheral conduction abnormalities, the CMCT was consistently normal whenever the MEP was recorded. These results indicate that the motor conduction of the corticospinal fibers remains normal in SMA II.     

The lateral corticospinal tract and spinal ventral horn in X-linked recessive spinal and bulbar muscular atrophy: a quantitative study

A quantitative study was performed on spinal cord lesions in seven patients with X-linked recessive spinal and bulbar muscular atrophy. The myelinated fiber density of the lateral corticospinal tracts at the T7 cord level was well preserved for both large and small myelinated fibers. On the other hand, neurons in the L4 ventral horn were markedly depleted; marked loss was noted of the large alpha and medium-sized gamma motor neurons located in the lateral and medial nuclei as well as the small neurons in the intermediate zones of the ventral horn. These results suggest that myelinated fiber density and fiber-size distribution in the corticospinal tract are well preserved and that neuronal loss in the ventral horns is not restricted to alpha and gamma motoneurons but also involves small interneurons. Received: 8 May 1996 / Accepted: 31 July 1996     

Thinning of the Corpus Callosum and Cerebellar Atrophy is Correlated with Phenotypic Severity in a Family with Spastic Paraplegia Type 11

Background

Mutations in the spatacsin gene are associated with spastic paraplegia type 11 (SPG11), which is the most-common cause of autosomal recessive hereditary spastic paraplegia. Although SPG11 has diverse phenotypes, thinning of the corpus callosum is an important feature.

Case Report

Clinical, genetic, and radiological evaluations were undertaken in a large family from Gujarat in North India with hereditary spastic paraplegia, whose affected members presented with varying degrees of spasticity, ataxia, and cognitive impairment. The clinical severity and the degree of corpus callosum and cerebellar atrophy varied among the four affected individuals in the family. Genetic testing of the affected members revealed recessive mutations in the spatacsin gene, consistent with a diagnosis of SPG11.

Conclusions

We believe that the extent of corpus callosum thinning and cerebellar atrophy is correlated with disease severity in affected patients. The addition of extrapyramidal features in the most-affected members suggests that SPG11 exhibits considerable phenotypic heterogeneity.     

Immediate plasticity in the motor pathways after spinal cord hemisection: implications for transcranial magnetic motor-evoked potentials

The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine (p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI).     

A re-assessment of the effects of a Nogo-66 receptor antagonist on regenerative growth of axons and locomotor recovery after spinal cord injury in mice

This study was undertaken as part of the NIH "Facilities of Research-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeated a study reporting that treatment with the NgR antagonist peptide NEP1-40 results in enhanced growth of corticospinal and serotonergic axons and enhanced locomotor recovery after thoracic spinal cord injury. Mice received dorsal hemisection injuries at T8 and then received either NEP1-40, Vehicle, or a Control Peptide beginning 4-5 h (early treatment) or 7 days (delayed treatment) post-injury. CST axons were traced by injecting BDA into the sensorimotor cortex. Serotonergic axons were assessed by immunocytochemistry. Hindlimb motor function was assessed using the BBB and BMS scales, kinematic and footprint analyses, and a grid climbing task. There were no significant differences between groups in the density of CST axon arbors in the gray matter rostral to the injury or in the density of serotonergic axons caudal to the injury. Tract tracing revealed that a small number of CST axons extended past the lesion in the ventral column in some mice in all treatment groups. The proportion of mice with such axons was higher in the NEP1-40 groups that received early treatment. In one experiment, mice treated with either NEP1-40 or a Control Peptide (reverse sequence) had higher BBB and BMS scores than Vehicle-treated controls at the early post-injury testing intervals, but scores converged at later intervals. There were no statistically significant differences between groups on other functional outcome measures. In a second experiment comparing NEP-treated and Vehicle controls, there were no statistically significant differences on any of the functional outcome measures. Together, our results suggest that treatment with NEP1-40 created a situation that was slightly more conducive to axon regeneration or sprouting. Enhanced functional recovery was not seen consistently with the different functional assessments, however.