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Background: This study was aimed at investigating the causes of lower extremity weaknesses after posterior lumbar spine fusion surgery and looking at subsequent treatment strategies., Methods: Patients who underwent posterior lumbar spine fusion surgery in the Peking University First Hospital between January 2009 and December 2018 were counted. Those who needed secondary surgery because of subsequent lower extremity weaknesses were selected. CT scans and MRIs were used to evaluate the reasons for weaknesses before secondary surgery. Muscle strength was evaluated after surgery., Results: Thirty patients (30/4078, 0.74%) required a secondary surgery because of lower extremity weaknesses after posterior lumbar spine fusion surgery. The main causes of weakness were (1) internal fixation malposition and loosening (11 patients, 36%), (2) epidural hematomas (9 patients, 30%), (3) insufficient decompression (5 patients, 17%), and (4) nerve root edemas (5 patients, 17%). Weakness occurred on average 2.9 days after surgery (1-9 days). Twenty-seven patients (90%) got improved muscle strength after their secondary surgery., Conclusions: Iatrogenic neurologic deficits and lower extremity weaknesses were rare complications after posterior lumbar spine fusion surgeries, but important to recognize and manage. The main causes of weakness were internal fixation malposition and loosening, epidural hematomas, insufficient decompression, or root edemas. There may be positive, therapeutic effects to subsequent, active surgical exploration.

Hepatic myelopathy or spastic paraparesis of liver disease is an insidious onset condition with pure motor spastic paraparesis without sensory, bladder or bowel involvement in patients with chronic liver disease, in which the neurological dysfunction cannot be explained by other causes. It is a rare, relentlessly progressive and mostly irreversible neurological complication resulting from portosystemic shunts occurring spontaneously, created surgically or due to 'functional shunting'. In some cases, no evidence of shunting is elicitable due to difficulty in locating the hidden collaterals. We report this rare case of a 33-year-old man with chronic liver disease presenting with spastic paraparesis after 11 months of resolution of an episode of hepatic encephalopathy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Individuals with hereditary spastic paraparesis (HSP) are often impaired in their ability to control posture as a result of the neurological and musculoskeletal implications of their condition. This research aimed to assess postural stability during gait in a group of adults with HSP. Ten individuals with HSP and 10 healthy controls underwent computerized gait analysis while walking barefoot along a 10-m track. Two biomechanics methods were used to assess stability: the center of pressure and center of mass separation (COP-COM) method, and the extrapolated center of mass (XCOM) method. Spatiotemporal and kinematic variables were also investigated. The XCOM method identified deficits in mediolateral stability for the HSP group at both heel strike and mid-stance. The group with HSP also had slower walking velocity, lower cadence, more time spent in double stance, larger step widths, and greater lateral trunk flexion than the control group. These results suggest that individuals with HSP adjust characteristics of their gait to minimize the instability arising from their impairments but have residual deficits in mediolateral stability. This may result in an increased risk of falls, particularly in the sideways direction., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Rationale and Objectives: As a special movement disorder, hepatic myelopathy (HM) is characterized by spastic paraperesis and may be secondary to transjugular intrahepatic portosystemic shunt (TIPS). The prediction and diagnosis of HM is difficult due to largely unknown neuropathological underpinnings and a lack of specific biomarkers. We aimed to delve into the alterations in motor system of HM patients' brain and their potential clinical implication., Material and Methods: Twenty-three patients with HM and 23 without HM after TIPS and 24 demographically matched healthy controls were enrolled. High-spatial-resolution structural imaging and functional data at rest were acquired. Motor areas were included as seed regions for functional connectivity analysis. Then, we performed brain volume analysis., Results: We found decreased right supplementary motor area (SMA)-seeded functional connectivity with bilateral insula, thalamus and midbrain, left cerebellum and middle temporal gyrus, and right middle cingulate gyrus in HM compared to non-HM patients (p < 0.001). The right insula revealed decreased volume (p < 0.001), and white matter volume reduced in the right corona radiata beneath the right SMA (p < 0.001) in HM relative to non-HM patients. Furthermore, the strength of right SMA-seeded connectivity with insula was positively correlated with folic acid level in HM patients (r = 0.60, p = 0.03), showing an accuracy of 0.87 to distinguish HM from non-HM., Conclusion: Our study demonstrates the HM-specific dysconnectivity with an anatomical basis, and its correlation with laboratory findings and diagnostic value. Detecting these abnormalities might help to predict and diagnose post-TIPS HM., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD-deficient patients presented with unusual clinical phenotypes including pregnancy-induced symptoms, transient visual impairment, severe developmental delay, cortical blindness, and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G>A mutation and a novel missense variant c.1700G>A (p.G567E). The recombinantly expressed p.G567E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein. Genome sequencing of the affected son established compound heterozygosity for the c.1700G>A and an imperfect 115,731 bp inversion with breakpoints at chr1: 98,113,121 (intron 8) and chr1: 97,997,390 (intron 12) of the DPYD associated with a 4 bp deletion (chr1: 97,997,386&#95;97,997,389del). Whole exome and mitochondrial DNA analyses for the mother and daughter did not reveal additional mutated genes of significance. Thus, an inversion in DPYD should be considered in patients with an inconclusive genotype or unusual clinical phenotype., (© 2018 Wiley Periodicals, Inc.)

Objectives: Cooling of the lower limb in people with Hereditary and Spontaneous Spastic Paraparesis (pwHSSP) has been shown to affect walking speed and neuromuscular impairments. The investigation of practical strategies, which may help to alleviate these problems is important. The potential of superficial heat to improve walking speed has not been explored in pwHSSP. Primary objective was to explore whether the application of superficial heat (hot packs) to lower limbs in pwHSSP improves walking speed. Secondary objective was to explore whether wearing insulation after heating would prolong any benefits., Methods: A randomised crossover study design with 21 pwHSSP. On two separate occasions two hot packs and an insulating wrap (Neo-G™) were applied for 30minutes to the lower limbs of pwHSSP. On one occasion the insulating wrap was maintained for a further 30minutes and on the other occasion it was removed. Measures of temperature (skin, room and core), walking speed (10 metre timed walk) and co-ordination (foot tap time) were taken at baseline (T1), after 30 mins (T2) and at one hour (T3)., Results: All 21 pwHSSP reported increased lower limb stiffness and decreased walking ability when their legs were cold. After thirty minutes of heating, improvements were seen in walking speed (12.2%, P<0.0001, effect size 0.18) and foot tap time (21.5%, P<0.0001, effect size 0.59). Continuing to wear insulation for a further 30minutes gave no additional benefit; with significant improvements in walking speed maintained at one hour (9.9%, P>0.001) in both conditions., Conclusions: Application of 30minutes superficial heating moderately improved walking speed in pwHSSP with effects maintained at 1hour. The use of hot packs applied to lower limbs should be the focus of further research for the clinical management of pwHSSP who report increased stiffness of limbs in cold weather and do not have sensory deficits., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Recovery of voluntary movement is a main rehabilitation goal. Efforts to identify effective upper limb (UL) interventions after stroke have been unsatisfactory. This study includes personalized impairment-based UL reaching training in virtual reality (VR) combined with non-invasive brain stimulation to enhance motor learning. The approach is guided by limiting reaching training to the angular zone in which active control is preserved ("active control zone") after identification of a "spasticity zone". Anodal transcranial direct current stimulation (a-tDCS) is used to facilitate activation of the affected hemisphere and enhance inter-hemispheric balance. The purpose of the study is to investigate the effectiveness of personalized reaching training, with and without a-tDCS, to increase the range of active elbow control and improve UL function., Methods: This single-blind randomized controlled trial will take place at four academic rehabilitation centers in Canada, India and Israel. The intervention involves 10 days of personalized VR reaching training with both groups receiving the same intensity of treatment. Participants with sub-acute stroke aged 25 to 80 years with elbow spasticity will be randomized to one of three groups: personalized training (reaching within individually determined active control zones) with a-tDCS (group 1) or sham-tDCS (group 2), or non-personalized training (reaching regardless of active control zones) with a-tDCS (group 3). A baseline assessment will be performed at randomization and two follow-up assessments will occur at the end of the intervention and at 1 month post intervention. Main outcomes are elbow-flexor spatial threshold and ratio of spasticity zone to full elbow-extension range. Secondary outcomes include the Modified Ashworth Scale, Fugl-Meyer Assessment, Streamlined Wolf Motor Function Test and UL kinematics during a standardized reach-to-grasp task., Discussion: This study will provide evidence on the effectiveness of personalized treatment on spasticity and UL motor ability and feasibility of using low-cost interventions in low-to-middle-income countries., Trial Registration: ClinicalTrials.gov, ID: NCT02725853 . Initially registered on 12 January 2016.

Cerebrotendinous xanthomatosis (CTX) is a lipid-storage disease caused by mutations in CYP27A1. Current publications of Chinese CTX were mainly based on case reports. Here we investigated the clinical manifestations, genetic features in Chinese CTX patients. The clinical materials of 4 Chinese CTX pedigrees were collected. The genetic testing was done by polymerase chain reaction plus Sanger sequencing. The features of Chinese CTX patients reported previously were also reviewed. Three novel mutations of p.Arg513Cys, c.1477-2A > C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in our study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4, tendon xanthoma plus spastic paraparesis in family 2, asymptomatic tendon xanthoma in family 3. Three known mutations of p.Arg137Gln, p.Arg127Trp and p.Arg405Gln were found respectively in Family 2, 3 and 4. For the Chinese patients reviewed, the most common findings were xanthomatosis (100%), pyramidal signs (100%), cerebellar ataxia (66.7%), cognitive impairment (66.7%), cataracts (50.0%), and peripheral neuropathy (33.3%). Chronic diarrhea was infrequently seen (5.6%). No mutation was found associated with any given clinical features. We identified 3 novel mutations in CYP27A1. In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent. The special features in Chinese CTX patients might caused by the lack of serum cholestanol test and should be confirmed in larger number of patients in the future.

Background: The aim of this study was to investigate the lower limb muscle coactivation and its relationship with muscles spasticity, gait performance, and metabolic cost in patients with hereditary spastic paraparesis., Methods: Kinematic, kinetic, electromyographic and energetic parameters of 23 patients and 23 controls were evaluated by computerized gait analysis system. We computed ankle and knee antagonist muscle coactivation indexes throughout the gait cycle and during the subphases of gait. Energy consumption and energy recovery were measured as well. In addition to the correlation analysis between coactivation indexes and clinical variables, correlations between coactivation indexes and time-distance, kinematic, kinetic, and energetic parameters were estimated., Findings: Increased coactivity indexes of both knee and ankle muscles throughout the gait cycle and during the subphases of gait were observed in patients compared with controls. Energetic parameters were significantly higher in patients than in controls. Both knee and ankle muscle coactivation indexes were positively correlated with knee and ankle spasticity (Ashworth score), respectively. Knee and ankle muscle coactivation indexes were both positively correlated with energy consumption and both negatively correlated with energy recovery., Interpretation: Positive correlations between the Ashworth score and lower limb muscle coactivation suggest that abnormal lower limb muscle coactivation in patients with hereditary spastic paraparesis reflects a primary deficit linked to lower limb spasticity. Furthermore, these abnormalities influence the energetic mechanisms during walking. Identifying excessive muscle coactivation may be helpful in individuating the rehabilitative treatments and designing specific orthosis to restrain spasticity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The purpose of this study was to examine whether combination therapy of serial casting and botulinum toxin type A injection can further enhance the effects of botulinum toxin type A in children with cerebral palsy with scissoring of both legs. This study was a prospective and randomized trial. The children were divided into 2 groups, one of which received serial casting after botulinum toxin type A (n = 40), and the other which only received botulinum toxin type A (n = 40). Serial casting started 3 weeks after the botulinum toxin type A. Both groups received physiotherapy. Groups were assessed at baseline then compared at 6 and 12 weeks following the intervention. Significant improvements in Gross Motor Function Measure-66 and Caregiver Health Questionnaire were recorded in both groups ( P < .001). The modified Ashworth scale improved significantly following botulinum toxin type A in the serial casting group ( P < .05), but not in botulinum toxin type A only group. These results suggest that serial casting after botulinum toxin type A can enhance the benefits of botulinum toxin type A in children with cerebral palsy.

Background: People with hereditary and spontaneous spastic paraparesis (HSSP) report that their legs are stiffer and walking is slower when their legs are cold., Objectives: This study explored the effects of prolonged superficial cooling and warming of the lower leg on walking speed and local measures of neuromuscular impairments., Methods: This was a randomised pre- and post-intervention study of 22 HSSP participants and 19 matched healthy controls. On 2 separate occasions, one lower leg was cooled or warmed. Measurements included walking speed and measures of lower limb impairment: ankle movement, passive muscle stiffness, spasticity (stretch reflex size), amplitude and rate of force generation in dorsi- and plantarflexors and central and peripheral nerve conduction time/velocity., Results: For both participants and controls, cooling decreased walking speed, especially for HSSP participants. For both groups, cooling decreased the dorsiflexor rate and amplitude of force generation and peripheral nerve conduction velocity and increased spasticity. Warming increased dorsiflexor rate of force generation and nerve conduction velocity and decreased spasticity., Conclusions: Superficial cooling significantly reduced walking speed for people with HSSP. Temperature changes were associated with changes in neuromuscular impairments for both people with spastic paraparesis and controls. This study does not support the use of localised cooling in rehabilitation for people with spastic paraparesis as reported in other neurological conditions. Rehabilitation interventions that help prevent heat loss (insulation) or improve limb temperature via passive or active means, particularly when the legs and/or environment are cool, may benefit people with spastic paraparesis., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Spastic gait is a key feature in patients with hereditary spastic paraparesis, but the gait characterization and the relationship between the gait impairment and clinical characteristics have not been investigated., Objectives: To describe the gait patterns in hereditary spastic paraparesis and to identify subgroups of patients according to specific kinematic features of walking., Methods: We evaluated fifty patients by computerized gait analysis and compared them to healthy participants. We computed time-distance parameters of walking and the range of angular motion at hip, knee, and ankle joints, and at the trunk and pelvis. Lower limb joint moments and muscle co-activation values were also evaluated., Results: We identified three distinct subgroups of patients based on the range of motion values. Subgroup one was characterized by reduced hip, knee, and ankle joint range of motion. These patients were the most severely affected from a clinical standpoint, had the highest spasticity, and walked at the slowest speed. Subgroup three was characterized by an increased hip joint range of motion, but knee and ankle joint range of motion values close to control values. These patients were the most mildly affected and had the highest walking speed. Finally, subgroup two showed reduced knee and ankle joint range of motion, and hip range of motion values close to control values. Disease severity and gait speed in subgroup two were between those of subgroups one and three., Conclusions: We identified three distinctive gait patterns in patients with hereditary spastic paraparesis that correlated robustly with clinical data. Distinguishing specific features in the gait patterns of these patients may help tailor pharmacological and rehabilitative treatments and may help evaluate therapeutic effects over time., Competing Interests: The authors have declared that no competing interests exist.

Background: Hereditary spastic paraparesis (HSP) is a rare neurodegenerative condition characterized by slowly progressive spastic weakness of the lower limbs and urinary sphincter dysfunction. Complex HSP involves additional neurologic symptoms and signs like ataxia, extra pyramidal signs, polyneuropathy, and cognitive decline. Little is known about the disease burden for adults with HSP beyond the described core symptoms., Methods: A cross-sectional survey of 108 adults aged 30 years and older (Mage = 57.7 years, SD = 11.5, range 30 to 81; 54.2 % females) recruited from a national center of expertise for rare disorders and a patient advocacy organization in Norway. Self-report data from the HSP sample was compared to self-report data from a large Norwegian population study, HUNT3 (N = 46,293), covering health-related variables such as overall life satisfaction, mental wellbeing, memory function, perceived pain, and co-morbid diseases. In addition, the HSP sample reported specific items developed for this study in co-operation with the patient advocacy organization., Results: The HSP sample more frequently lived alone. Overall, the HSP sample reported lower life satisfaction, lower mental wellbeing and lower social support, as well as poorer memory and sleep, compared to controls. Furthermore, the HSP sample more frequently reported musculoskeletal pain, constipation, and urinary incontinence compared to controls. There was no difference between samples in frequency of physical activity and alcohol and tobacco use. Men with HSP reported higher impact of HSP, lower life satisfaction, and less ability to perform activities of daily living compared to women with HSP., Conclusions: Adults with HSP experience disease burden on a larger number of areas than previously documented, and men with HSP may represent a particularly vulnerable group.

We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

Neuromyelitis optica (NMO) and myasthenia gravis (MG) are rare autoimmune disorders. The coexistence of the two disorders, although rare, has been documented. This is a case report of a 16-year-old student who presented with recurrent episodes of transverse myelitis and optic neuritis, 8 years after diagnosis of MG. She presented with visual impairment, relapsing and remitting weakness, numbness and paraesthesia of her lower limbs, with bladder and bowel incontinence. Her examination revealed bilateral optic atrophy, spastic paraparesis of the lower limbs and patchy sensory loss up to thoracic level (T4-5). She had a positive acetylcholine receptor antibody, a positive aquaporin-4 antibody and chest CT finding of thymic enlargement. We therefore confirmed the previous diagnosis of MG and performed a recent diagnosis of background NMO. A high index of suspicion is needed to make a diagnosis of this rare coexistence of NMO and MG in resource-limited settings such as Nigeria., (2015 BMJ Publishing Group Ltd.)

This position paper introduces an assessment method using staged calculation of coefficients of impairment in spastic paresis, with its rationale and proposed use. The syndrome of deforming spastic paresis superimposes two disorders around each joint: a neural disorder comprising stretch-sensitive paresis in agonists and antagonist muscle overactivity, and a muscle disorder ("spastic myopathy") combining shortening and loss of extensibility in antagonists. Antagonist muscle overactivity includes spastic cocontraction (misdirected descending command), spastic dystonia (tonic involuntary muscle activation, at rest) and spasticity (increased velocity-dependent reflexes to phasic stretch, at rest). This understanding of various types of antagonist resistance as the key limiting factors in paretic movements prompts a stepwise, quantified, clinical assessment of antagonist resistances, elaborating on the previously developed Tardieu Scale. Step 1 quantifies limb function (e.g. ambulation speed in lower limb, Modified Frenchay Scale in upper limb). The following four steps evaluate various angles X of antagonist resistance, in degrees all measured from 0°, position of minimal stretch of the tested antagonist. Step 2 rates the functional muscle length, termed XV1 (V1, slowest stretch velocity possible), evaluated as the angle of arrest upon slow and strong passive muscle stretch. XV1 is appreciated with respect to the expected normal passive amplitude, XN, and reflects combined muscle contracture and residual spastic dystonia. Step 3 determines the angle of catch upon fast stretch, termed XV3 (V3, fastest stretch velocity possible), reflecting spasticity. Step 4 measures the maximal active range of motion against the antagonist, termed XA, reflecting agonist capacity to overcome passive (stiffness) and active (spastic cocontraction) antagonist resistances over a single movement. Finally, Step 5 rates the residual active amplitude after 15 seconds of maximal amplitude rapid alternating movements, XA15. Amplitude decrement from XA to XA15 reflects fatigability. Coefficients of shortening (XN-XV1)/XN, spasticity (XV1-XV3)/XV1, weakness (XV1-XA)/XV1 and fatigability (XA-XA15)/XA are derived. A high (e.g., >10%) coefficient of shortening prompts aggressive treatment of the muscle disorder--e.g., by stretch programs, such as prolonged stretch postures -, while high coefficients of weakness or fatigability prompt addressing the neural motor command disorder, e.g. using training programs such as repeated alternating movements of maximal amplitude., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Hyperargininemia due to mutations in ARG1 gene is an autosomal recessive inborn error of metabolism caused by a defect in the final step of the urea cycle. Common clinical presentation is a variable association of progressive spastic paraparesis, epilepsy, and cognitive deficits., Methods: We describe the clinical history of an Italian child presenting progressive spastic paraparesis, carrying a new homozygous missense mutation in the ARG1 gene. A detailed clinical, biochemical, and neurophysiological follow-up after 7 months of sodium benzoate therapy is reported., Results: Laboratory findings, gait abnormalities, spastic paraparesis, and electroencephalographic and neurophysiological abnormalities remained quite stable over the follow-up. Conversely, a mild cognitive deterioration has been detected by means of the neuropsychologic assessment., Conclusions: Further longitudinal studies by means of longer follow-up and using clinical, biochemical, radiological, and neurophysiological assessments are needed in such patients to describe natural history and monitor the effects of treatments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To investigate short-term and long-term effects of repetitive peripheral magnetic stimulation (rpMS) on spasticity and motor function., Design: Monocentric, randomized, double-blind, sham-controlled trial., Setting: Neurologic rehabilitation hospital., Participants: Patients (N=66) with severe hemiparesis and mild to moderate spasticity resulting from a stroke or a traumatic brain injury. The average time ± SD since injury for the intervention groups was 26 ± 71 weeks or 37 ± 82 weeks., Interventions: rpMS for 20 minutes or sham stimulation with subsequent occupational therapy for 20 minutes, 2 times a day, over a 2-week period., Main Outcome Measures: Modified Tardieu Scale and Fugl-Meyer Assessment (arm score), assessed before therapy, at the end of the 2-week treatment period, and 2 weeks after study treatment. Additionally, the Tardieu Scale was assessed after the first and before the third therapy session to determine any short-term effects., Results: Spasticity (Tardieu >0) was present in 83% of wrist flexors, 62% of elbow flexors, 44% of elbow extensors, and 10% of wrist extensors. Compared with the sham stimulation group, the rpMS group showed short-term effects on spasticity for wrist flexors (P=.048), and long-term effects for elbow extensors (P<.045). Arm motor function (rpMS group: median 5 [4-27]; sham group: median 4 [4-9]) did not significantly change over the study period in either group, whereas rpMS had a positive effect on sensory function., Conclusions: Therapy with rpMS increases sensory function in patients with severe limb paresis. The magnetic stimulation, however, has limited effect on spasticity and no effect on motor function., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine whether local injection of botulinum toxin type A (BoNT-A) into the spastic muscles has any added benefits to repetitive transcranial magnetic stimulation (RTMS)/occupational therapy (OT) in patients with spastic upper limb hemiparesis., Methods: The study subjects of 80 post-stroke patients with spastic upper limb hemiparesis (age: 60.2 ± 13.0 years, time after stroke: 55.3 ± 43.0 months), were divided into the BoNT-A plus RTMS/OT group and RTMS/OT group. BoNT-A was injected into the spastic muscles (total dose: 240 units) before RTMS/OT. The latter included 12 sessions of 40 min RTMS over the non-lesional hemisphere and 240-min intensive OT daily over 15 days. Spasticity was evaluated by the modified Ashworth scale (MAS) and the motor function of the affected upper limb was evaluated serially with Fugl-Meyer Assessment and Wolf Motor Function Tests., Results: Both groups showed significant improvements in spasticity and motor function. The addition of BoNT-A resulted in better improvement in FMA score and MAS of finger flexor muscles (p < 0.05)., Conclusions: The triple-element protocol of local injection of BoNT-A into spastic finger muscles, RTMS and intensive OT, is a promising therapeutic program for post-stroke spastic upper limb hemiparesis, although its significance should be confirmed in randomized, placebo-controlled trials., (© 2014 S. Karger AG, Basel.)

Objective: To determine how postural sway is affected in people with spastic paraparesis (pwSP) and the impact of different impairments., Methods: In 20 pwSP and 18 matched healthy controls standing postural sway was measured with eyes open and closed. Vibration threshold, isometric ankle and hip muscle strength and ankle stiffness with the participant at rest or preactivating the muscle was measured., Results: Antero-posterior (AP) and medio-lateral (ML) sway was higher in pwSP. Muscle strength was reduced and ankle stiffness increased in pwSP. Increased vibratory threshold was seen in 35% of participants. Higher total ankle stiffness (R2=0.44) was associated with lower AP sway with eyes open whilst hip abductor weakness was associated with increased ML sway with eyes open (R2=0.36) or closed (R2=0.47) or AP sway with the eyes closed (R2=0.48)., Conclusions: The degree of postural sway was related to muscle paresis of the hip abductors particularly in the ML direction and under conditions of reduced sensory input. People with higher total ankle stiffness have less AP sway suggesting that this may help to stabilise the body., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Objectives: The contribution of spasticity to postural imbalance in patients with upper motor neuron syndrome is still unclear. This study aimed to evaluate the responses to support-surface perturbations in patients with hereditary spastic paraparesis (HSP). These patients typically suffer from bilateral spasticity with relatively preserved muscle strength of the lower limbs. Particularly toes-up rotations were expected to be destabilizing due to insufficient suppression of calf muscle stretch reflexes., Methods: Participants were seventeen symptomatic community-dwelling patients with autosomal dominant pure HSP and seventeen healthy controls. All patients had increased muscle tone of the triceps surae (TS) but no muscle contractures. Perturbations were applied by rotating or translating a platform with increasing intensity in four sagittal-plane directions. The primary outcome was maximum intensity ('limit of stability') sustained without stepping or grabbing in each type of perturbation. Leg muscle tone and strength were assessed with the Modified Ashworth Scale and Medical Research Council (MRC) scale, respectively., Results: For toes-up perturbations, limits of stability in patients were substantially lower than in controls, which were related to TS muscle tone but not to tibialis anterior (TA) strength. Toes-down rotations were indiscriminative. For backward perturbations, patients also had lower limits of stability, unrelated to TA strength or TS muscle tone. In forward perturbations, patients with TS strength MRC 4 were less stable than patients with normal TS strength and controls., Conclusion: Calf muscle spasticity and weakness differently contribute to postural imbalance in patients with HSP. This notion could have implications for the clinical management of spasticity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: People with Hereditary and Sporadic Spastic Parapresis (SP) walk with a stiff legged gait characterised by a lack of knee flexion., Objective: We investigated the relationship between lower limb strength and stiffness and knee flexion during swing phase while walking in 20 people with SP and 18 matched controls., Methods: Maximal isometric strength was measured using a dynamometer. Passive stiffness and spasticity was assessed during motor-driven slow (5°/s) and fast (60°/s) stretches at the ankle and knee while the subject was relaxed or preactivating the muscle. Walking was assessed using 3D motion analysis., Results: Isometric muscle strength was decreased in people with SP with over a 50% reduction in strength being found in the ankle dorsiflexors. Passive stiffness, assessed during slow stretches, was 35% higher in the plantarflexors in people with SP (P<0.05). Faster stretches induced large stretch evoked muscle activity and over a 110% increase in stiffness at the ankle and knee in people with SP reflecting the presence of spasticity (P<0.05). However, stretch reflex size and stiffness was similar between the groups following identical stretches of the pre-activated muscle (P>0.05). Lower knee flexion during swing phase was associated with reduced knee flexion velocity at the end of stance phase which in turn was associated with reduced plantarflexor strength and increased passive stiffness in the knee extensors., Conclusions: The relative importance of muscle paresis and passive stiffness in limiting walking in SP suggests that these impairments should be the target of future therapies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Intrathecal baclofen (ITB) is an efficient treatment modality for severe spasticity that is considered to act at the spinal level. Its influence on phasic spasticity is usually determined clinically by testing muscle reflexes, and on tonic spasticity by using scores such as the Modified Ashworth Scale (MAS). Neurophysiological techniques, e.g., soleus H reflex, may provide additional information regarding ITB efficacy. There is, however, only scarce information available on time-response relationships of clinical and neurophysiological measures of spasticity obtained at different levels along the neuroaxis., Methods: Fourteen patients with severe spastic paraparesis underwent serial evaluation of MAS in upper and lower limbs and serial testing of H reflex in soleus and flexor carpi radialis muscles, T wave in quadriceps and biceps brachii muscles, and blink reflex (BR) with and without prepulse, at baseline, and 15, 30, 60, 90, 120, and 180 min following ITB bolus application., Results: ITB bolus application caused significant suppression of soleus H reflex after 15 min and of quadriceps T wave after 30 min, while MAS dropped significantly after 60 min together with significant suppression of BR R2 area without and with prepulse stimulation. H reflex in flexor carpi radialis and T wave in biceps brachii were not significantly suppressed by ITB. The time course of early changes in soleus H(max)/M(max) ratio and quadriceps T wave indicates a suppression of hyperreflexia at the spinal level, while a later reduction of MAS synchronously with suppression of BR with and without prepulse concurs with a brainstem effect of ITB., Conclusion: Temporal concurrence between suppression of brainstem reflexes and desired suppression of lower limb muscle hypertonia after ITB bolus application suggests that both may be at least partially mediated from a common CNS region of activity., Significance: Our data concur with a significant brainstem action of ITB., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Object: The primary aim of this prospective cohort study was to evaluate the short-term (1 year) and long-term (mean 6 years) effects of selective dorsal rhizotomy (SDR) on gross motor function and spasticity in ambulatory children with spastic diplegia. Secondary aims were to investigate side effects, additional treatment during follow-up (botulinum toxin type A injections or orthopedic surgery), and parental satisfaction., Methods: Thirty-three children who had undergone SDR at a mean age of 6 years and 7 months (± 2 years) were included. There were 7 children at Gross Motor Function Classification System (GMFCS) Level I, 7 at Level II, and 19 at Level III. Gross motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66). Spasticity was measured according to a modified Tardieu scale. Side effects, additional treatment, and parental satisfaction were recorded using a parental questionnaire and medical records., Results: At 1-year follow-up, mean GMFM-66 scores improved significantly by 4.3 ± 4.1 points. Children at GMFCS Levels I and II showed significantly more improvement (7.2 points) on the GMFM-66 compared with children at GMFCS Level III (2.9 points). On long-term follow-up (mean 6 years ± 22 months), mean GMFM-66 scores improved significantly by 6.5 ± 5.9 points, without a difference between children at GMFCS Levels I and II and Level III. No relapse of spasticity was noted. Ten children (30%) needed orthopedic surgery and 13 children (39%) received botulinum toxin type A treatment after SDR. Twenty (91%) of the 22 parents who answered the questionnaire at long-term follow-up believed that their child's functioning had improved after SDR., Conclusions: Selective dorsal rhizotomy resulted in short- and long-term improvements in gross motor function, without relapse of spasticity. However, the majority of the children still needed additional surgery or botulinum toxin A treatment.

The authors present the case of a 50 years old woman who during 3 years had a transient right limbs palsy, and numerous episodes of unilateral/bilateral optic neuropathy. The CSF and MRI examinations did not sustain the diagnosis of multiple sclerosis (MS). After 2 years from the onset, she presented bilateral trigeminal neuropathy, and after 9 months the anti-SS-A and anti SS-B antibodies were positive. The sialography and the minor salivary ducts biopsy (in the absence of xerostomia and xerophthalmia) have established the diagnosis of primary Sjögren's syndrome (pSS). Subsequently, the patient presented spastic paraparesis, the clinical and imagistical features have suggested the diagnosis of acute transverse myelitis C4-T4. The treatment administered (corticosteroids and IGIV) improved the clinical state. The authors analyse then cases with SLE and cases with pSS, whose initial diagnosis was MS possibly with no evidence of collagen tissue disorders (CD) for many years. In conclusion, screening for biomarkers of SLE or pSS should be systematically performed in a case of acute or chronic myelopathy. Some laboratory tests as CSF examination, the antibodies type, cranial and spinal MRI, are useful for the differential diagnosis with MS. In a neurological clinically isolated syndrome (CIS) the diagnosis of MS should be precautiously established; the close follow-up of patients is always necessary, those with atypical neurological symptoms for MS, relapsing-remitting form, or lack of response to the common treatment for MS, should be examined for CD.

Among the three main factors of motor impairment that emerge in chronological order following a lesion to central motor pathways, the last two antagonize movement: 1) stretch-sensitive paresis, a reduction of agonist motor unit recruitment upon voluntary command, worsened by antagonist stretch; 2) soft tissue contracture, and 3) muscle overactivity. Types of muscle overactivity include 1) spasticity, an increase in the velocity-dependent response to muscle stretch, measured at rest; 2) spastic dystonia, i.e., chronic tonic muscle activity at rest, sensitive to stretch of the dystonic muscle and 3) spastic co-contraction, an inappropriate degree of antagonistic contraction during voluntary agonist command, sensitive to stretch of the co-contracting muscle. A five-step clinical assessment may closely parallel this phenomenology, in which the first four steps aim at quantifying the antagonistic potential of each muscle group. Step-1 measures passive range of motion, i.e., the angle of arrest upon slow stretch of the muscle group assessed (minimizing spastic dystonia), which provides insight on soft tissue length and extensibility. Step-2 measures the angle of catch or clonus upon fast passive stretch of the muscle group assessed, which provides insight on stretch reflex excitability. Step-3 measures the range of active motion against the muscle group assessed, a net result of agonist recruitment minus the combined resistance from passive soft tissue stiffness and spastic co-contraction in the muscle group assessed. Step-4 measures the maximal frequency of rapid alternating movements along the maximal active range of motion, evaluating Step-3 performance repeatability. Step-5 evaluates active function, using for example a walking test (10 m or 2 min) for lower limb and the Modified Frenchay Scale for upper limb assessment, and perceived function through patient global subjective assessment.

We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2.

Botulinum neurotoxin type-A (BoNT-A) has been used in association with other interventions in the management of spasticity in children with cerebral palsy (CP) for almost two decades. This consensus statement is based on an extensive review of the literature by an invited international committee. The use of BoNT-A in the lower limbs of children with spasticity caused by CP is reported using the American Academy of Neurology Classification of Evidence for therapeutic intervention. Randomized clinical trials have been grouped into five areas of management, and the outcomes are presented as treatment recommendations. The assessment of children with CP and evaluation of outcomes following injection of BoNT-A are complex, and therefore, a range of measures and the involvement of a multidisciplinary team is recommended. The committee concludes that injection of BoNT-A in children with CP is generally safe although systemic adverse events may occur, especially in children with more physical limitations (GMFCS V). The recommended dose levels are intermediate between previous consensus statements. The committee further concludes that injection of BoNT-A is effective in the management of lower limb spasticity in children with CP, and when combined with physiotherapy and the use of orthoses, these interventions may improve gait and goal attainment.

Lower limb disorders of movement and muscle tone in adults significantly impact quality of life. The management of the patient with hypertonia is complex and requires a multidisciplinary team working with the patient and family/carers. Botulinum neurotoxin type A (BoNT-A) has been used as a component of this management to reduce lower limb hypertonia, increase passive range of motion and reduce associated pain and requirements for bracing. Adjunctive treatments to augment the effect of BoNT-A include electrical muscle stimulation of the injected muscles and stretching. When determining suitability for injection, the patient's main goals for intervention need to be established. Muscle overactivity must be distinguished from contracture, and the effect of underlying muscle weakness taken into account. Explanation of the injection process, potential adverse effects and post-injection interventions is essential. Assessment at baseline and post-treatment of impairments such as hypertonia, range of motion and muscle spasm are appropriate; however, the Goal Attainment Scale and other validated patient-centred scales can also be useful to assess therapy outcomes. In the future, initiatives should be directed towards examining the effectiveness of BoNT treatment to assist with achievement of functional and participation goals in adults with hypertonia and dystonia affecting the lower limb.

Background: Knowledge of sitting and standing performance in a total population of children with cerebral palsy (CP) is of interest for health care planning and for prediction of future ability in the individual child. In 1994, a register and a health care programme for children with CP in southern Sweden was initiated. In the programme information on how the child usually sits, stands, stands up and sits down, together with use of support or assistive devices, is recorded annually., Methods: A cross-sectional study was performed, analysing the most recent report of all children with CP born 1990-2005 and living in southern Sweden during 2008. All 562 children (326 boys, 236 girls) aged 3-18 years were included in the study. The degree of independence, use of support or assistive devices to sit, stand, stand up and sit down was analysed in relation to the Gross Motor Function Classification System (GMFCS), CP subtype and age., Result: A majority of the children used standard chairs (57%), could stand independently (62%) and could stand up (62%) and sit down (63%) without external support. Adaptive seating was used by 42%, external support to stand was used by 31%, to stand up by 19%, and to sit down by 18%. The use of adaptive seating and assistive devices increased with GMFCS levels (p < 0.001) and there was a difference between CP subtypes (p < 0.001). The use of support was more frequent in preschool children aged 3-6 (p < 0.001)., Conclusion: About 60% of children with CP, aged 3-18, use standard chairs, stand, stand up, and sit down without external support. Adding those using adaptive seating and external support, 99% of the children could sit, 96% could stand and 81% could stand up from a sitting position and 81% could sit down from a standing position. The GMFCS classification system is a good predictor of sitting and standing performance.

Growing evidence suggests that axonal degeneration rather than demyelination is the pathological substrate underlying chronic, irreversible disability in multiple sclerosis. However, direct evidence linking clinical disability measured in vivo with corresponding post-mortem measures of axonal pathology is lacking. Our objective in this study was to investigate the relationship between motor disability accumulated by patients with multiple sclerosis during life and the degree of axonal loss observed in their descending motor tracts after death. Human spinal cord derived at autopsy from 45 patients with multiple sclerosis was investigated. The medical records of each patient were reviewed by a multiple sclerosis neurologist to determine the degree of motor disability reached before death. Spinal cord sections were stained immunohistochemically. The degree of demyelination and the number of surviving corticospinal tract axons were measured in each patient. Patients who had accumulated higher levels of motor disability prior to death demonstrated fewer surviving corticospinal axons. Motor disability did not correlate with degree of demyelination. This study provides for the first time, direct clinico-pathological evidence that axonal loss is the pathological substrate of established disability in multiple sclerosis.

Oxidative stress resulting from increased free radical production and/or defects in antioxidant defences may be the cause of various neurodegenerative disorders. In this study, the roles of oxygen free radicals, nitric oxide, superoxide dismutase, vitamin E and vitamin C were investigated in pure and complicated hereditary spastic paraparesis (HSP) patients. The results showed that plasma SOD, vitamin E and nitric oxide levels were significantly low in HSP patients. These findings indicate the influence of oxidative damage in the degenerative process of HSP., (2008 Elsevier B.V. All rights reserved.)

Background: Hereditary spastic paraparesis (HSP) is a heterogeneous group of disorders characterized by progressive bilateral lower limb spasticity. Functional imaging studies in patients with corticospinal tract involvement have shown reorganization of motor circuitry. Our study investigates functional changes in sensorimotor brain areas in patients with HSP., Methods: Twelve subjects with HSP and 12 healthy subjects were studied. Functional magnetic resonance imaging (fMRI) was used to measure brain activation during right-hand finger tapping. Image analysis was performed using general linear model and regions of interest (ROI)-based approach. Weighted laterality indices (wLI) and anterior/posterior indicies (wAI and wPI) were calculated for predefined ROIs., Results and Discussion: Comparing patients and controls at the same finger-tapping rate (1.8 Hz), there was increased fMRI activation in patients' bilateral posterior parietal cortex and left primary sensorimotor cortex. No differences were found when comparing patients and controls at 80% of their individual maximum tapping rates. wLI of the primary sensorimotor cortex was significantly lower in patients. Subjects with HSP also showed a relative increase in the activation of the posterior parietal and premotor areas compared with that of the primary sensorimotor cortex. Our findings demonstrate an altered pattern of cortical activation in subjects with HSP during motor task. The increased activation probably reflects reorganization of the cortical motor system.

Background: Amyotrophic lateral sclerosis (ALS) affects people of all ages, but whether the wide range of age at onset is due to distinct diseases or merely reflects phenotypic variability of the same disorder is still unknown. The purpose of this study is to describe clinical and prognostic features of young-adult ALS, with onset before age 40 years, and to compare them with features of the common adult-onset type., Methods: We analyzed clinical features and long-term follow-up of 57 young-adult ALS patients, with disease onset between 20 and 40 years, and compared them with 450 patients affected by adult-onset ALS., Results: We found that the majority of young-adult patients showed a predominant upper motor neuron (p-UMN) ALS, characterized by marked spastic paraparesis, with lower motor neuron signs confined to the upper limbs. The proportion of patients with p-UMN ALS phenotype was 59.6% in the young-adult patients and 17.4% in the adult-onset form (p < 0.0001). Young-adult ALS with p-UMN phenotype had longer survival than did the classic phenotype: median survival was 74 months (range 10-226, 95% CI 60.61-87.38) in the former and 56 months (range 6-106, 95% CI 48.65-63.34) in the latter (p = 0.03). In the young-adult patients, a marked male excess was observed in the p-UMN ALS group (5.8:1), whereas the ratio of men to women was 1.1:1 in the classic phenotype (p = 0.01)., Conclusions: Our findings show that young-adult amyotrophic lateral sclerosis with the predominant upper motor neuron phenotype represents a distinctive clinical variant characterized by a unique clinical pattern, longer survival, and male prevalence.

Central motor conduction time (CMCT) is usually abnormally prolonged in leg muscles of patients with pure hereditary spastic paraparesis (PHSP). One consequence of such abnormality should be an abnormal timing in the modulation of segmental reflexes, which might be more relevant for the pathophysiology of spasticity-related gait disturbances than just the CMCT delay. We examined the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex in 13 control subjects and 11 PHSP patients using a conditioning (TMS) and test (H reflex) paradigm. Interstimulus interval (ISI) was 0-100 ms in steps of 10 ms. The amplitude of the H reflex at each interval was expressed as percentage of the control H reflex and the conditioned curves were compared between control subjects and patients. In control subjects, TMS-induced facilitation of the H reflex with two well-defined phases: early (ISIs 10 and 20 ms) and late (ISIs 70-90 ms). In patients, the early phase of facilitation was significantly reduced, while there was facilitation at 40 ms that was not present in control subjects. However, neither the characteristics of the MEP nor the differential modulation of the H reflex correlated significantly with clinical measures of motor dysfunction. Our results indicate an abnormal effect of TMS on the H reflex in PHSP patients. This suggests that the excitability of interneurons and soleus motoneurons is not modified in tune with the arrival of descending inputs. Desynchronization of the descending volley may contribute to both the lack of early facilitation and the presence of abnormal facilitatory phases.

Objective: To report the successful treatment of a patient with lymphomatoid granulomatosis (LYG), a rare Epstein-Barr virus-positive lymphoproliferative disorder, using rituximab (anti-CD20 monoclonal antibody). The prognosis for LYG has been reported to be poor, and no satisfactory treatment has been established. Because central nervous system (CNS) involvement of LYG has been known to show poor prognosis, the establishment of an effective treatment for CNS LYG with mild adverse effects is desired., Design: Case report., Setting: University hospital., Patient: A 48-year-old Japanese man presenting with slowly progressive spastic paraparesis diagnosed as LYG involving the CNS and lungs., Interventions: The patient was treated with rituximab (375 mg/m2, once weekly for 1 month) alone. Main Outcome Measure Improvement of the lesions on imaging., Results: The neurological signs resolved and the lesions in the CNS and lungs were mostly diminished after the rituximab monotherapy without any adverse effects. The patient stayed in remission for 18 months., Conclusion: Rituximab monotherapy was effective in treating the patient; hence, rituximab should be considered as the initial treatment against LYG involving the CNS.

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

A 39-year-old man with a 4-month history of transient pins and needles sensations occurring below the waist while walking and difficulty walking presented to our outpatient clinic. He had an approximate 1-year history of bilateral hearing loss, the etiology of which was unknown. His symptoms had been progressive, and there was no significant family history. He demonstrated a spastic gait and required assistance for walking. Deep tendon reflexes were hypertonic; a sensation deficit was defined as originating from the 12th thoracic vertebra. Babinski's sign was positive bilaterally. Sphincter abnormalities were seen in the patient's bladder and bowel functions. Cerebral and spinal magnetic resonance images with contrast media were unremarkable. An analysis of the patient's cerebrospinal fluid was consistent with neurobrucellosis. Owing to spastic paraparesis and hearing loss, the diagnosis of neurobrucellosis was made. Combined antimicrobial therapy was started and continued 6 months. His neurologic condition improved, and he was able to walk without help after 3 months' treatment. Our case illustrates that acquired progressive spastic paraparesis may occur during the course of neurobrucellosis. Neurobrucellosis should be borne in mind when patients present with spastic paraparesis.

Early onset familial Alzheimer's disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.

Familial Alzheimer's disease due to presenilin 1 (PSEN1) mutations shows considerable phenotypic variability with differences in neuropathology and neurological symptoms. Spastic paraparesis is a common neurological phenotype associated with Alzheimer's disease arising from PSEN1 mutations. To investigate whether known genes that cause spastic paraparesis could act as Alzheimer's disease-modifier genes, we sequenced nine spastic paraparesis genes in three Alzheimer's disease families with PSEN1 exon 9 deletions. We did not observe any correlation of polymorphisms or mutations in the nine spastic paraparesis genes with the variable phenotype seen in families with Alzheimer's disease and spastic paraparesis. These results suggest a need for a continuing search for genes that cause the phenotypic variation in Alzheimer's disease and spastic paraparesis.

In an open label study, we analyzed the efficacy of botulinum toxin injection at the lower limbs of patients with hereditary spastic paraparesis (HSP). Fifteen patients who showed disabling spasticity with no or poor effect of oral treatment were recruited consecutively. Botulinum toxin was injected (400 U; Botox) into the spastic muscles identified by clinical examination (equinus, varus, and pathological hip adduction). Patients were regularly assessed from the first day to the fifth month: spasticity (Ashworth), motor strength, range of movements, Functional Ambulation Categories (FAC), gait parameter, Rivermead Motor Assessment, self-analysis of benefit and satisfaction. We observed a moderate and significant (P < 0.05) reduction of ankle plantar flexor and hip adductor spasticity, with a partial increase in the range of the active and passive motion at the ankle and in gait velocity. At an individual level, six of 15 patients showed an increase in gait velocity. The FAC and RMA did not change. Patients often reported partial improvement in foot position and lower limb propulsion, and fair satisfaction. In conclusion, botulinum toxin injection can be effective in HSP patients with relatively ancient spasticity. This technique can be introduced into the therapeutic panel, which also includes physiotherapy, oral treatment and baclofen pump.

Background: 1-bromopropane was recently substituted for traditional ozone-depleting solvents in the industrial setting., Case Series: We report a cohort of six cases of 1-bromopropane neurotoxicity occurring in foam cushion gluers exposed to 1-bromopropane vapors from spray adhesives. Patients 1-5 were exposed 30-40 hours per week over three years; patient 6 had been employed for the previous three months. Exposure had peaked over the previous month when ventilatory fans were turned off. All patients complained of subacute onset of lower extremity pain or paresthesias. Five of six complained of difficulty walking and on examination had spastic paraparesis, distal sensory loss, and hyperreflexia. Three patients initially had nausea and headache. Serum bromide concentrations ranged from 44 to 170 mg/dL (reference 0-40 mg/dL). Apparent hyperchloremia was present with serum chloride concentrations of 105 to 139 mmol/L (reference 98-107 mmol/L). Air samples taken at the workplace during gluing operations revealed the mean air concentration of 1-bromopropane to be 130 ppm (range 91-176 ppm) with a seven hour time-weighted average of 108 ppm (range 92-127 ppm), well above the EPA-proposed limit of 25 ppm. Two years after exposure, the two most severely affected patients had minimal improvement of function and they, with a third patient, continued to experience chronic neuropathic pain., Conclusion: This report supports the growing recognition of 1-bromopropane neurotoxicity in humans consisting most commonly of headache, nausea, and subacute spastic paraparesis with distal sensory loss. The pathogenesis of 1-BP neurotoxicity in humans has yet to be fully elucidated but may reflect a central distal axonopathy syndrome.