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Elevated plasma GFAP levels in MCI link APOE ε4 allele with impaired gait speed.

The presence of at least one copy of the apolipoprotein ε4 allele (APOE ε4) is a known predictor of gait impairment risk among older adults. However, the mechanisms by which APOE ε4 affects gait performance remain unclear. This cross-sectional study aimed to reveal underlying pathological mechanisms linking APOE ε4 carriage to slow gait. This secondary analysis used baseline assessments from the J-MINT multicenter intervention trial, focusing on older adults with mild cognitive impairment. Gait speed was measured at baseline, with slow gait (SG) defined as speeds one standard deviation below the age- and sex-specific mean. APOE phenotype and plasma biomarkers related to Alzheimer's disease (AD), including amyloid-β composite biomarker, phosphorylated Tau 181, neurofilament light, and glial fibrillary acidic protein (GFAP), were also measured. The analysis included 236 non-APOE ε4 carriers and 84 carriers of at least one APOE ε4. APOE ε4 carriers exhibited significantly slower gait speed than non-carriers (1.20 m/s [SD = 0.22] vs 1.26 m/s [SD = 0.23], p = 0.042). Significant interaction between APOE ε4 carriage and SG was observed only in plasma GFAP levels (F1, 312 = 7.17, p = 0.008), indicating that individuals with APOE ε4 and SG had significantly higher plasma GFAP levels. Elevated plasma GFAP levels fully mediated the association between APOE ε4 carriage and gait speed (partially standardized indirect effect = -0.059: -0.12 to -0.013]). No other AD-related biomarkers mediated this association. Our results suggest that APOE ε4-related gait changes may reflect AD pathology, as indicated by elevated GFAP levels, and could potentially accelerate dementia symptoms.

Aged

Ankle arthrodesis. Long-term follow-up with gait analysis.

A functional assessment of twelve patients after ankle arthrodesis for post-traumatic arthritis was carried out by means of an extensive clinical evaluation and gait analysis after an average follow-up of eight years. A weighted point system was developed to grade ankle function clinically. The data on gait analysis were examined to determine the effect of arthrodesis of the ankle on the over-all pattern of walking. Under conditions of normal daily living while wearing shoes, all patients functioned well after arthrodesis. The gait-analysis data obtained with the patients wearing shoes showed excellent gait characteristics, and the ankle motion that had been lost was compensated for by: (1) motion of the small joints of the ipsilateral foot; (2) altered motion of the ankle in the contralateral limb; and (3) appropriate footwear. While the patients were walking barefooted, some adverse effects of fusion of the ankle were evident. Velocity of gait was slowed and the length of stride was shortened in all twelve patients. One patient whose ankle had been fused in an equinus position had a back-knee deformity during stance phase, and another walked only on his toes when he was without shoes. The gait patterns of all patients were markedly improved when they were wearing shoes with appropriate heel heights.

Activities of Daily Living

[Encephalopathy during oral treatment with bismuth salts].

Side effects of orally administered bismuthic salts have been known for many years. Many systems are involved, including the digestive and urinary. The authors discuss a recently discovered effect on the central nervous system, termed "bismuth encephalopathy". In the light of the medical literature reviewed, two original aspects are stressed: the clinical symptoms are stereotyped and completely reversible, and the distribution of the disease is almost epidemic, being limited in time and space. The prodromes include confusion, asthenia, slowing of mental functions and disturbance of gait. The clinical picture is dominated by four major symptoms: confusion (again), ataxia, dysarthria and, above all, myoclonic jerks. In conclusion, various pathogenetic hypotheses are considered. The purpose of this study is to enable the general practitioner to detect the development of this condition early in treatment with oral bismuthic salts. Withdrawal of the medication always results in normalization of the patient's condition.

Administration, Oral

Walking patterns of men with unilateral surgical hip fusion.

The gait of men with unilateral hip fusion is somewhat slow, asymmetrical, and arrhythmic as compared with that of normal men. Compensation for absent hip motion is accomplished by increased transverse and sagittal rotation of the pelvis, increased motion in the sound hip, and increased flexion of the knee throughout the stance phase on the fused side. Relationships between the fusion position, certain physical traits, and walking performance suggest that the best gait can be expected in young patients who have free motion of the lumbar spine, the sound hip, and the knee on the side of fusion, and who have equal limb lengths and a hip fused in a position that does not include excessive adduction.

Adolescent

Cortical cerebellar degeneration associated with a specific disorder of standing and locomotion.

The three patients presented showed a rhythmic bobbing of the body when standing with flexed legs. It was produced by slow, coarse, synchronous extensions-flexions in the legs. Platform and accelerometer records demonstrated an almost clockwork regularity of rate in the 2.5--3.5 c/sec range. In Romberg's test there occurred slow rhythmic extensions-flexions of the feet. The patients walked with a peculiar stiff "heel-gait", which was not conspicously broad-based, unsteady or trembling. On ascending a platform they displayed a slow leg tremor and a marked disorder of forward-vertical movement. This very uniform motor syndrome retained its specific features over the years. An upper limb involvement was observed in one of the patients. Post-mortem examination in one patient, a chronic alcoholic, showed a pronounced atrophy of the superior cerebellar vermis. Tomographic pneumoencephabgrams demonstrated the superior vermis atrophy in the two other patients.

Adult

Gait analysis in cerebral palsy.

Electromyography is the most frequently used laboratory method of assessing gait of patients with cerebral palsy. This method has shown that slow stretch testing is non-specific and that electromyograms obtained during walking are of greater value in planning treatment. If surgical treatment is necessary, only those muscles with phase reversal should be considered for transfer; lengthening is appropriate for those with phase prolongation. The addition of movement measurements and force-plate recording increases the amount of information available for analysis. Distinctions can then be attempted between primary abnormalities and compensatory mechanisms, and gait patterns with common demominators can be identified. Only by precise pre- and post-operative studies can treatment for locomotor problems be reliably assessed. Progress in the treatment of patients with cerebral palsy cannot be achieved without such objective assessment.

Cerebral Palsy

Non-hypertrophic familial neuropathy associated with intention tremor. A variety of Charcot-Marie-Tooth disease?

A family with an association of sensorimotor neuropathy and intention tremor is reported. Clinical examination of 3 affected family members showed in varying degrees areflexia, muscle wasting, impairment of deep sensation with an ataxic gait, pes cavus and disabling intention tremor. Motor nerve conduction velocities were moderately slowed. A superficial peroneal nerve biopsy showed axonal degeneration without segmental demyelination or onion bulb formation. Our observation seems to indicate an association of intention tremor with the non-hypertrophic variety of Charcot-Marie-Tooth disease. It can therefore be suggested that the two classical types of Charcot-Marie-Tooth syndrome possess variants which are associated with intention tremor. This association is well-known for the hypertrophic type; our report gives an example of the non-hypertrophic type.

Adult

Kuru plaques in the brain of two cases with Creutzfeldt-Jakob disease. A common origin for the two diseases?

We present two patients aged 66 and 69, with a rapidly progressive disease (10 and 15 months' duration) in which the presenting symptom was instability of gait. Later dementia was also a prominent feature. One case had myoclonus. Repeated EEGs showed symmetrical slowing in one case and periodic generalised bursts of triphasic waves at 1 cps superimposed upon a slow (3-4 cps) background activity in the other. The pathological findings consisted of classical Creutzfeld-Jakob disease (CJD), Kuru plaques (KP) were disseminated in the brain, but were more numerous in the cerebellum, putamen and thalamus. Neurons with large vacuoles in the cytoplasm were numerous in the putamen, thalamus and anterior horns. Stress is laid upon the common findings in both CJD and Kuru (K) (clinical features, pathological data, lack of antibody response, transmissibility, change in pattern on transmission). The possibility of a common origin of the two diseases is discussed.

Aged

Action of dantrolene sodium in spasticity with low dependence on fusimotor drive.

The effects of dantrolene sodium, an anti-spasticity drug with a site of action within the muscle fibres, were studied in 19 patients with spastic paresis. Oral doses were successively increased from 100 mg/day to a maximal tolerated level or up to 800 mg/day. Trial periods were 8-13 weeks. The responses of stretch reflexes to local cooling over the spastic muscles were used to differentiate alpha and gamma spasticity. In the knee extensor and flexor muscle groups, cryo-negative alpha-spasticity was seen in 25 and cryo-positive gamma-spasticity in 4 muscle groups. Ankle clonus was cryo-positive in 14 of 15 cases. Resistance to passive knee joint movements, ankle clonus and isometric or isokinetic muscle strength was determined quantitatively. The gait was recorded by intermittent-light photography and the muscle activation patterns in gait were studied in recordings of the average EMG from limb muscles. Functional disability and spasms were assessed from clinical examinations and interviews. Passive resistance at slow (6%/sec) and fast (30 degrees/sec) knee joint movements decreased by 32% in the extensor muscles (p = 0.005 resp. 0.001) and by 23-26% in the flexor muscles (not significant). Reduced passive resistance was observed in 16 of the muscles with alpha-spasticity and in all 4 of the muscle groups with gamma-spasticity. Clonus was diminished or abolished in 14 of 15 patients with this sign. Maximal isometric or isokinetic muscle strength was unaltered in the majority of the patients. In a few the strength was increased, in some it was decreased. The averaged EMG activity during walking as studied in 10 patients were increased in 35 of the 57 muscle groups examined. In some muscle groups, exaggerated activity attributable to spastic reflexes was reduced. Motor disability was decreased significantly in 10 patients. It was not significantly changed in 5 and deteriorated in 4 patients. Drowsiness and subjective muscle weakness were the most frequent side-effects. SGOT and SGPT were increased in 3 cases.

Adult

Adult metachromatic leukodystrophy. I. Clinical manifestation in a female aged 44 years, previously diagnosed in the preclinical state.

In a 5-year follow-up of a case of adult metachromatic leukodystrophy, already diagnosed in the preclinical stage, the development of the symptoms of this disease could be studied in detail: initially, lack of drive, emotional lability and depressive mood. At the same time, pain in the arms and beginning gait disturbance. Later, impairment of memory and concentration, disorientation, inadequate behavior and progression of gait disturbance. Finally spastic atactic gait with small steps and dyspractic components, coordination disturbances with writing dysfunction, fast dysarthric speech, hyperkinetic activity, compulsory emotional outbursts and progressive dementia. Only minor neurological signs such as reflex abnormalities. In the EEG, slight slowing of frequencies compared to earlier tracings. Increasing diminution of nerve conduction velocity in the lower limbs. Only minor increase of CSF protein (51 mg%). In spite of normal vision, evoked visual potentials abnormal, response of optical and electrical blink reflexes delayed. Imperfect filling of gallbladder. No significant quantitative changes of the biochemical parameters compared with the findings made 5 years earlier (excretion of urinary sulfatides, diminished activity of arylfulfatase A in urine and leukocytes).

Adult

Progressive dialysis encephalopathy.

The clinical features of 42 patients with the only recently recognized and generally fatal neurological syndrome of progressive dialysis encephalopathy are reviewed and the electroencephalographic and neuropathological findings are summarized. Despite apparently successful hemodialysis, these patients develop a wide spectrum of neurological abnormalities. Of these, sudden onset of hesitant, nonfluent speech is the most characteristic and usually the earliest sign. Both dysphasic and dysarthritic elements are found, though the former predominate. Myoclonus, dementia, seizures, and gait difficulty are also seen in the majority of these patients. EEGs are more abnormal than would be expected for the clinical severity, with some type of high-voltage spike-wave pattern intermixed with abundant slow activity. The combination of clinical and EEG features in the appropriate setting is virtually diagnostic. Transient episodes with variable periods of complete or partial remission have been recognized. Neuropathological changes are surprisingly mild and nonspecific. The cause is uncertain; current speculation focuses on aluminum as the offending neurotoxin. Treatment remains unsatisfactory.

Adult

The effect of denervation and dystrophy on the adaptation of sarcomere number to the functional length of the muscle in young and adult mice.

In young animals the elongation of the limb bones increases the functional lengths of the muscles. In adult animals the functional length of a muscle can be increased by immobilizing it in the lengthened position. In both cases the muscle adapts by adding on more sarcomeres in series. The role of the nerve supply in this adaptation has been investigated using denervated muscles and muscles from dystrophic animals where there is thought to be an abnormality of the nerve supply. Postnatal sarcomere addition in denervated muscles falls short of that of controls. Although this might mean that the nerve supply is necessary for normal addition of sarcomeres, it is just as likely that there is a change in gait resulting from denervation, which affects the sarcomere number. Sarcomere number in fully grown mice is not affected by denervation, nor is the ability of the muscle to adapt to immobilization in the lengthened position. This is true for fast-twitch as well as slow-twitch muscles. In dystrophic muscles postnatal sarcomere addition is normal, although the presence of a few short fibres in the muscle may mean that some muscle fibres cannot adapt to an increase in the functional length of the muscle accompanying bone growth. Adult dystrophic muscle is capable of adapting to immobilization in the lengthened position. However, although the total number of additional sarcomeres is the same as in normal immobilized muscle, they are added on at a slower rate. The experiments show that although denervated and dystrophic muscle fibres are in a state of atrophy they are still capable of adding on sarcomeres in series when the functional length of the muscle is increased. It would appear that the mechanism which enables the muscle to respond in this way to an increased functional length does not involve the nerve supply. This work was supported by a grant from the National Fund for Research into Crippling Diseases.

Age Factors

Acute cerebral symptomatology, a rare presentation of scleromyxedema.

A 65 year old male with the entity, scleromyxedema, experienced exacerbation of the disease in which the main clinical features involved the central nervous system. He presented with clouded sensorium, disorganized thinking, combative behavior, headache, unsteady gait and grand mal seizures. A few days after hospital admission the symptoms abated. After a 6 day hiatus, the symptoms suddenly recurred, continuing for another week. The symptomatology again suddenly ceased with complete clearance of mental status. During the full-blown delirium, the electroencephalogram had demonstrated diffuse slowing while lumbar puncture, brain scan, E.M.I. scan and cerebral arteriogram failed to contribute to the understanding of the clinical presentation. Scleromyxedema rarely involves the central nervous system. This case illustrates a very unusual manifestation of scleromyxedema, prominent central nervous system involvement presenting as an acute organic brain syndrome. It is the only case which includes formal mental status examination, cerebrospinal fluid findings and electroencephalogram results.

Aged

Familial progressive bulbar-spinal muscular atrophy: case report with muscle biopsy study.

A case of familial progressive bulbar and spinal muscular atrophy was presented. The patient was a 59-year-old male with chief complaints of gait disturbance and nasal voice. His illness started at the age of 39 and very slowly progressed over 20 years. The clinical symptoms and signs were characterized by muscle weakness and atrophy due to lower motor neuron disease in the brain stem below the lower pons and the spinal cord. The electromyograms and muscle biopsy findings are basically neurogenic. In spite of the bulbar signs, the course of the disease is extremely slow. The diagnostic criteria was proposed after reviewing eight other cases reported in the literature.

Adult

["Colloid cyst" of the lateral ventricle--report of a case (author's transl)].

Colloid cyst is a relatively rare benign tumor which is usually found in the third ventricle. A patient who had a "colloid cyst" in his right lateral ventricle was experienced. A 33-year-old man had suffered from intermittent attacks of headache and vomiting for five months. On July 22, 1974, he was hospitalized to our clinic because of headache, memory and gait disturbance. At the time of admission his consciousness was clear but he had slight memory disturbance and urinary incontinence. Incipient papilledma was noted and the deep tendon reflexes of the lower extrimities were slightly accentuated. Lumbar puncture revealed a clear CSF and its pressure was within normal limit and the protein was 59 mg/dl. The plain skull films showed no abnormal findings. EEG showed an asymmetry of alpha-wave, and paroxysmal high voltage of slow wave was found in the right frontal area. Right cerebral angiography demonstrated an unrolling of the pericallosal arteries suggesting dilatation of the lateral ventricles. On the 9th hospital day, he suddenly began to complain of severe headache and became drowsy. Mannitol and hydrocortisone were injected intravenously without producing any remarkable effects. A ventricular drainage was done, and the patient recovered rapidly. A conray ventriculography revealed a round filling defect in the right lateral ventricle. A transventricular approach through a short linear incision in the right frontal cortex was preformed on the 25th hospital day. A cyst containing colloid substance, about 5x4 cm in size, was found to be attached to the medial wall of the right lateral ventricle anterior to the foramen of Monro. This cyst was almost completely removed. Histological findings revealed inner lining of epithelial cells, He died on the 25th postoperative day from bacterial meningitis. Autopsy confirmed the cyst to have originated from the right lateral ventricle. A review of the literature was made and the pathogenesis and diagnosis of this disease and the mechanism of development of the symptoms were discussed.

Adult

Downbeat nystagmus without ataxia as an early manifestation of spinocerebellar ataxia, autosomal recessive type 10 (SCAR10): a case report.

The differential diagnosis of dizziness is broad and can include both vestibular and autonomic pathology. Vestibular dizziness is typically described as a sensation of movement (e.g. the world is spinning) while dizziness related to autonomic dysfunction is typically described as symptoms of orthostatic intolerance (e.g. postural lightheadedness). It is important to differentiate the type of dizziness to guide proper diagnostic and therapeutic workup. We describe the case of a young patient evaluated in the autonomic clinic for dizziness, ultimately found to have a rare cerebellar neurodegenerative disorder. A 23-year-old female with a past medical history of migraine without aura presented in autonomic clinic with a four-month history of slow, progressive onset of vestibular dizziness. Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated. Subsequent vestibular evaluation was consistent with central vestibular dysfunction. Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy. The patient subsequently underwent genetic testing which demonstrated a pathogenic and likely pathogenic variant in the Anoctamin 10 (ANO10) gene, which is seen in Autosomal Recessive Spinocerebellar Ataxia, Autosomal Recessive Type 10 (SCAR10). To our knowledge, this case represents the first reported instance of SCAR10 presenting with the sole neurologic exam finding of downbeat nystagmus without cerebellar ataxia. Additionally, the finding of severe cerebellar atrophy seen on MRI, without gait or limb ataxia on exam is an interesting clinicoradiological dissociation. This case suggests that nystagmus may represent an early disease marker, even in the absence of clinical ataxia in patients with SCAR10.

Humans

Significance of free-dorsiflexion of the toes in walking.

Dissection reveals that the ball of the foot contains a connective tissue framework with transverse, vertical, and sagittal fibers, all connecting the skin with the proximal phalanges of the toes. Dorsiflexion of the toes tightens the framework and thereby restricts passive movements of the skin, enabling shear forces to be transferred to the skeleton. An electromechanical oscillator was constructed that applied oscillatory shear forces of constant amplitude (+/- 0.2 N) to the skin and at the same time measured the resulting motions. It was found that the toes should be dorsiflexed by 35--40 degrees to restrict skin mobility to 50 per cent and by 50 degrees to restrict it maximally. The results were compared to actual dorsiflexions of toes during walking. These dorsiflexions were measured on slow motion film and with still pictures with light tracks formed by light emitting diodes. Maximal dorsiflexion during push off was found to be 60 degrees for feet walking without shoes, 45--50 degrees for feet walking in soft shoes, and 25--30 degrees for feet walking in a stiff shoe of the minus-heel type. Dorsiflexion was further found significant for arch support and for the mechanics of the forefoot during push-off.

Biomechanical Phenomena

Electrical properties of motor units in Parkinsonism and a possible relationship with bradykinesia.

The electrical activity of single motor units was recorded from the first dorsal interosseous muscles of nine patients with Parkinson's disease. Six of these patients had a combination of the following abnormal motor unit properies: (1) a variable delay period of 20 seconds to 3 minutes between the initiation of voluntary effort and the recruitment of the first group of motor units; (2) after recruitment, some of the motor units stopped firing for durations of 10s, 40s, 75s... 3 min.; (3) some of the motor units fired at abnormally low frequencies of 2-3 per second. All these six patients had slowed finger movement, and five of the six were studied while off levodopa for two to seven days. One of these patients, reinvestigated after levodopa therapy had been restarted, demonstrated improvement in motor unit control. The three remaining patients who were studied while on uninterrupted levodopa therapy could make rapid finger movements, could recruit motor units without delay, and could fire recruited motor units continuously at normal frequencies of 6-14 per second. These results suggest that levodopa therapy is effective in Parkinson's disease at least partly because of its ability to correct abnormalities in the recruitment of motor units. Levodopa also corrects the abnormal motor unit firing pattern. The abnormal motor unit properties found in these patients could account for some aspects of bradykinesia.

Action Potentials