Hereditary Spastic Paraparesis Patients Research Articles

Electrophysiological Findings of Subclinical Lower Motor Neuron Involvement in Degenerative Upper Motor Neuron Diseases

The present study is an examination of possible subclinical involvement of lower motor neuron (LMN) in patients with primary lateral sclerosis (PLS) and hereditary spastic paraparesis (HSP) electrophysiologically. Nine PLS patients and 5 HSP patients were prospectively analyzed. Jitter measurement with concentric needle electrode (25 mm, 30 G) (CN-jitter) recorded from right extensor digitorum muscle during voluntary contraction with 1 kHz high-pass frequency filter set. European Myelopathy Score (EMS) was used to evaluate disability. The relationship between disability score and jitter values was investigated. HSP patients had suffered from the disease for longer period of time (p<0.001). Mean jitter values of patients with PLS and HSP were 26.5±12.1 µs and 30.8±34.8 µs, and the number of individual high jitters (>43 microseconds) observed in the PLS and HSP groups was 16/180 and 9/100, respectively without a significant intergroup difference. The ratio of patients with an abnormal jitter study were higher in HSP group (60%) compared to PLS (22%) (p<0.05). Potential pairs with blocking were present in HSP group (7 of 100 potential pairs) but not seen in PLS patients. EMS values were significantly lower in patients having potential pairs with high jitter and blocking compared to those without high jitter and blocking. The present study has demonstrated that early signs of LMN dysfunction can be detected electrophysiologically by CN-jitter in patients with UMN involvement. These electrophysiological findings in these patients with longer disease duration and lower clinical scores may be explained by spreading of the disease to LMNs or transsynaptic degeneration and its contribution in disease progression.

Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia.

Cortical hyperexcitability has been identified as an important pathogenic mechanism in motor neuron disease (MND). The issue as to whether cortical hyperexcitability is a common process across the MND phenotypes, including amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), remains unresolved. Separately, the clinical distinction between PLS and 'mimic disorders' such as hereditary spastic paraparesis (HSP) may be difficult, potentially delaying diagnosis. Consequently, the aim of the present study was to determine the nature and spectrum of cortical excitability changes across the MND phenotypes, and to determine whether the presence of cortical dysfunction distinguishes PLS from HSP. Cortical excitability studies were undertaken on a cohort of 14 PLS, 82 ALS and 13 HSP patients with mutations in the spastin gene. Cortical hyperexcitability, as heralded by reduction of short interval intracortical inhibition (PLS 0.26%, -3.8% to 1.4%; ALS -0.15%, -3.6% to 7.0%; P < 0.01) and cortical silent period duration (CSPPLS 172.2 ± 5.4 ms; CSPALS 178.1 ± 5.1 ms; P < 0.001), along with an increase in intracortical facilitation was evident in ALS and PLS phenotypes, although appeared more frequently in ALS. Inexcitability of the motor cortex was more frequent in PLS (PLS 71%, ALS 24%, P < 0.0001). Cortical excitability was preserved in HSP. Cortical dysfunction appears to be an intrinsic process across the MND phenotypes, with cortical inexcitability predominating in PLS and cortical hyperexcitability predominating in ALS. Importantly, cortical excitability was preserved in HSP, thereby suggesting that the presence of cortical dysfunction could help differentiate PLS from HSP in a clinical setting.

63.: Cortical dysfunction in hereditary spastic paraparesis patients with the spastin mutation

In autosomal dominant hereditary spastic paraplegia (HSP), mutations in the spastin (SPG4) gene account for 45% of all cases. The key diagnostic clinical findings are lower limb spasticity, hyperreflexia and extensor plantar responses. The main neuropathological finding in HSP is axonal degeneration in the terminal portions of the long descending and ascending tracts in the spinal cord. Current hypothesis suggest impairment of axonal transport or disturbance of mitochondrial function. We utilised the threshold tracking transcranial magnetic stimulation (TTTMS) technique to evaluate if cortical abnormalities may coexist in these patients. Cortical excitability studies were undertaken on 12 HSP patients with the SPG4 mutation (five males and seven females, mean age 56 years). Patients were compared with age-matched controls. The mean spastic paraplegia rating scale was 17.3 ± 3.0 and the mean upper motor neuron score was 13.5 ± 0.5. Short-interval intracortical inhibition was significantly reduced in HSP patients when compared to controls (HSP 5.0 ± 1.6%; controls 11.8 ± 1.0%, p p p p

16.: Cortical excitability in hereditary spastic paraparesis patients with SPAST mutations

In autosomal dominant hereditary spastic paraplegia (HSP), mutations in the SPAST (SPG4) gene account for 45% of all patients. The key diagnostic clinical findings are that of lower limb spasticity, hyperreflexia and extensor plantar responses. The main neuropathological finding in HSP is of axonal degeneration in the terminal portions of the long descending and ascending tracts in the spinal cord. The current hypothesis suggests impairment of axonal transport or disturbance of mitochondrial function. We utilised the threshold tracking transcranial magnetic stimulation technique to evaluate if cortical abnormalities may coexist in these patients. Cortical excitability studies were undertaken on 12 HSP patients with the SPG4 mutation (five males and seven females, mean age 56 years). Patients were compared with age-matched controls. The mean spastic paraplegia rating scale was 17.3 ± 3.0 and the mean upper motor neuron score was 13.5 ± 0.5. Short-interval intracortical inhibition (SICI) was not significantly reduced in HSP patients when compared to controls (HSP 9.1 ± 1.5%; controls 11.8 ± 1.0%, p = 0.09). The cortical silent period duration was significantly reduced (HSP 192.9 ± 11.5 ms; controls 214.2 ± 3.9, p = 0.05). Resting motor threshold was significantly reduced amongst HSP patients (HSP 51.8 ± 2.2%; controls 60.3 ± 1.4%, p

The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry

The c.1529C >T change in the SPG7 gene, encoding the mutant p.Ala510Val paraplegin protein, was first described as a polymorphism in 1998. This was based on its frequency of 3 % and 4 % in two separate surveys of controls in the United Kingdom (UK) population. Subsequently, it has been found to co-segregate with disease in a number of different populations. Yeast expression studies support its having a deleterious effect. In this paper a consanguineous sibship is described in which four members who are homozygous for the p.Ala510Val variant present with a spectrum of disease. This spectrum encompasses moderately severe hereditary spastic paraparesis (HSP) with more minor ataxia in two siblings, moderately severe ataxia without spasticity in the third, and a very mild gait ataxia in the fourth. Two of the siblings also manifest vestibular failure. The remaining eight unaffected siblings are either heterozygous for the p.Ala510Val variant, or do not carry it at all. Homozygosity mapping using a high-density SNP array across the whole genome found just 11 genes (on two regions of chromosome 3) outside the SPG7 region on chromosome 16, which were homozygously shared by the affected siblings, but not shared by the unaffected siblings; none of them are likely to be causative. The weight of evidence is strongly in favour of the p.Ala510Val variant being a disease-causing mutation. We present additional data from the Auckland City Hospital neurogenetics clinic to show that the p.Ala510Val mutation is prevalent amongst HSP patients of UK extraction belying any suggestion that European p.Ala510Val haplotypes harbour a disease-causing mutation which the UK p.Ala510Val haplotypes do not. Taken together with previous findings of a carrier frequency of 3-4 % in the UK population (giving a homozygosity rate of 20-40/100,000), the data imply that the p.Ala510Val is the most common mutation causing neurogenetic disease in adults of UK ancestry, albeit the penetrance may be low or the disease caused may be mild.

3D gait analysis in patients with hereditary spastic paraparesis and spastic diplegia: A kinematic, kinetic and EMG comparison

The predominant clinical feature of patients with Hereditary Spastic Paraparesis (HSP) is gait disturbance owing to spasticity and weakness of the lower limbs; the spasticity in early-onset disease (infancy or childhood) often cannot be distinguished from mild form of spastic diplegia (SD). The aim of this study was to quantify the gait strategy in HSP and SD children, focusing on the differences between groups as concerns functional limitation during gait. 9 HSP and 16 SD children were evaluated using Gait Analysis; kinematic and kinetic parameters and EMG pattern during walking were identified and calculated to compare the two gait strategies. The results revealed that these two pathologies are characterised by different gait strategies. In particular we found that knee joint, in terms of kinematics and kinetics, and rectus femoris pattern represent discriminatory aspects in order to compare and differentiate gait patterns of HSP and SD children. The findings strongly support the issue that HSP and SD patients need individualised therapeutical program, either neurosurgical or pharmacological treatment, based on the quantification of gait deficiencies and in order to address the peculiarity of their motor limitations and to prevent the onset of compensatory strategies.

Amygdala Size Reduction Is Associated with Memory Deficits in Complicated Hereditary Spastic Paraparesis: An MRI Study

Neuroimaging findings in hereditary spastic paraparesis (HSP), especially in complicated HSP (cHSP), are heterogenous. This study aimed to investigate possible in vivo morphological alterations of the whole brain and the amygdala in cHSP as a correlate of cognitive impairment in contrast to pure variants (pHSP). Amygdalar and whole brain volumes of 33 HSP patients (21 pHSP and 12 cHSP) were measured using three-dimensional magnetic resonance imaging (MRI) data sets by region of interest-based volumetry. A neuropsychological test battery was also performed. A significant reduction in whole brain volume compared with the controls, as well as significant correlations with reduced amygdalar volume and a worse neuropsychological test performance was observed only in cHSP patients. Our findings of disproportional amygdalar atrophy only in cHSP substantiate the association of morphologically assessable cerebral degeneration with cognitive impairment in cHSP.

Is oxidative damage in operation in patients with hereditary spastic paraparesis?

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.

Botulinum toxin injection in patients with hereditary 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.

Restless Legs Syndrome in Hereditary Spastic Paraparesis

This study was designed to investigate the prevalence and determinants of the association of restless legs syndrome (RLS) and hereditary spastic paraparesis (HSP). Therefore, 132 patients with HSP were evaluated concerning the symptoms of RLS by a standardized questionnaire. RLS was supposed when patients met all of the established four essential criteria of RLS defined by the International RLS Study Group. In addition, we studied the relationship between RLS and age at HSP symptom onset and evaluated the severity of RLS symptoms. Out of 59 responses, RLS was found in 27 HSP patients (15 male, 12 female) so that RLS was more frequent in the total HSP group (20.5%; 27/132) than in previous population-based studies (about 11%). In all 27 patients, the diagnosis of RLS was established based on an additional personal interview. The probability to develop RLS did not increase with higher age. Age at onset of HSP symptoms in the HSP group with RLS (27.7 ± 12.6 years) and the HSP group without RLS (37.0 ± 16.9 years) differed significantly (p = 0.04). Most of the patients with RLS showed a moderate and severe grade on the RLS severity score. Only 8 patients had previously been diagnosed to have RLS and were on medication. The data of this screening for RLS provided evidence that patients with HSP are particularly susceptible to develop RLS. Consequently, special emphasis should be put on the diagnosis criteria of RLS in HSP patients.

Brain atrophy in pure and complicated hereditary spastic paraparesis: a quantitative 3D MRI study

Hereditary spastic paraparesis (HSP) is a heterogeneous group of neurodegenerative disorders with progressive lower limb spasticity, categorized into pure (p-HSP) and complicated forms (c-HSP). The purpose of this study was to evaluate if brain volumes in HSP were altered compared with a control population. Brain volumes were determined in patients suffering from HSP, including both p-HSP (n = 21) and c-HSP type (n = 12), and 30 age-matched healthy controls, using brain parenchymal fractions (BPF) calculated from 3D MRI data in an observer-independent procedure. In addition, the tissue segments of grey and white matter were analysed separately. In HSP patients, BPF were significantly reduced compared with controls both for the whole patient group (P < 0.001) and for both subgroups, indicating considerable brain atrophy. In contrast to controls who showed a decline of brain volumes with age, this physiological phenomenon was less pronounced in HSP. Therefore, global brain parenchyma reduction, involving both grey and white matter, seems to be a feature in both subtypes of HSP. Atrophy was more pronounced in c-HSP, consistent with the more severe phenotype including extramotor involvement. Thus, global brain atrophy, detected by MRI-based brain volume quantification, is a biological marker in HSP subtypes.

Hereditary spastic paraparesis and psychosis

Hereditary spastic paraparesis (HSP) is characterized by progressive spasticity and weakness of the legs with or without additional abnormalities. Reports of psychiatric disorders in patients with HSP are limited to mood disturbances rather than to psychosis. We had noted significant psychotic illness in several patients recruited to a survey of HSP in Ireland and therefore set about examining the frequency and nature of psychosis in our patients with HSP. Cases with HSP and psychotic illness were identified from a nationwide epidemiological and clinical study. Psychiatric case notes were reviewed and Operational Diagnostic Criteria Checklist (OPCRIT) applied. Six patients from four families with HSP had evidence of psychosis in addition to paraparesis. OPCRIT diagnoses were 'narrow schizophrenia' (n = 2), 'broad schizophrenia' (n = 2) and 'schizo-affective/manic disorder' (n = 2). Patients were from families with Kjellin's syndrome and SPG4-HSP but not other kindreds and psychosis was not evident in family members without HSP. We found a higher than expected rate of psychosis in the Irish HSP population. Two groups of HSP patients may have increased risk of developing psychosis: those with Kjellin's syndrome and those with SPG4-HSP.

Magnetic Resonance Investigation of the Upper Spinal Cord in Pure and Complicated Hereditary Spastic Paraparesis

Neuropathological studies of hereditary spastic paraparesis (HSP) have described axonal loss involving corticospinal and somatosensory tracts in the spinal cord. This MRI-based study was intended to investigate in vivo diameter alterations of the spinal cord in HSP, including both pure HSP (p-HSP, n = 20) and complicated HSP (c-HSP, n = 10). Standard MRI examinations of the cervical and thoracic spinal cord in HSP patients and a control group (n = 54) were analyzed by standardized spinal cord planimetry. In HSP patients, significant atrophy of the upper spinal cord compared to controls was observed at p<0.001 both at the cervical and at the thoracic level. Myelon diameters at both levels were also significantly reduced in the two HSP subgroups in an additional comparison with age-matched subgroups of controls each, but p-HSP and c-HSP groups themselves did not differ. Marked atrophy of the upper spinal cord seems to be associated with HSP, assumedly due to the central-distal axonopathy. However, the differences between p-HSP and c-HSP could not be visualized by structural MRI at spinal cord level.

Clinically silent dysfunction of dorsal columns and dorsal spinocerebellar tracts in hereditary spastic paraparesis

Hereditary spastic paraparesis (HSP) is a neurodegenerative disorder, of which progressive spastic paraparesis is the clinical hallmark. Given the neuropathological evidence of degeneration of pyramidal tracts, dorsal columns, and dorsal spinocerebellar tracts, it is surprising that sensory symptoms are so indistinct compared to motor symptoms. We investigated the involvement of peripheral conduction and spinal proprioceptive pathways by nerve conduction studies, somatosensory evoked potentials of the median and tibial nerves, and quantitative assessment of the vibration perception thresholds of the hands and feet respectively in 32 patients suffering from HSP and healthy control groups. We did not find peripheral conduction abnormalities in HSP patients. Log-transformed vibration perception thresholds of the feet were abnormal in 13 32 HSP patients and in 0 64 controls ( p < 0.00001), while tibial nerve somatosensory evoked potentials were abnormal in 20 32 patients and in 1 17 controls ( p = 0.00001). The values for the upper extremities were within normal limits for nearly all subjects. In the HSP group, the neurophysiological disturbances did not correlate significantly with duration or severity of the disease, when age was controlled for, except for median nerve SSEP latency, which was affected by severity ( p = 0.0072). We conclude that neurophysiological methods detected proprioceptive, subclinical abnormalities in several HSP patients, which may reflect degeneration of the dorsal columns, and/or dorsal spinocerebellar tracts. Since we found no correlation with several disease variables, the fact that not all HSP patients displayed these abnormalities may be caused by anatomical variations in proprioceptive pathways, rather than by phenotypical heterogeneity.