Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy.

AIMS: To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). METHODS: We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age- and gender-matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. RESULTS: Compared to healthy controls skin biopsies showed: (i) non-length-dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). CONCLUSIONS: We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate.

Normalization of Functional Independence Measure variation improves assessment of stroke rehabilitation outcome.

BACKGROUND: Assessment of rehabilitation outcome is based on measuring the change in Functional Independence Measure (FIMTM) score between the start and end of rehabilitation. However, the raw FIMTM score gain is subject to a ceiling effect. Proposed solutions to this problem have incongruities that limit their use. AIM: The aim of this study was to determine the factors that influence functional outcome in stroke rehabilitation, exploring the possibility of developing an outcome index free of the ceiling effect and of the incongruities revealed by the proposed solutions. DESIGN: Retrospective study of the electronic clinical records of patients admitted to a rehabilitation unit over a period of 5 years. SETTING: Rehabilitation unit. POPULATION: A total of 224 patients admitted for first post-stroke rehabilitation of either ischaemic or hemorrhagic etiology. METHODS: Rehabilitation outcome was evaluated based on changes in both raw and "normalized" FIMTM motor and cognitive scores observed between hospital admission and discharge. Normalized differences are in the range 0-1 and may be considered an estimate of the actually attained fraction of the maximum expected recovery, while the modified algebraic formula (+1 to both numerator and denominator) is intended to correct the incongruities observed in available solutions. Seventeen prognostic factors were selected as possible effect modifiers of the outcome. A multivariable model-building strategy, based on fractional polynomials, was adopted to select the significant factors, and the stability of the results. RESULTS: The procedure adopted to normalize both FIMTM outcomes resolves the ceiling effect and corrects the incongruities noted with available solutions. The level of disability at admission is confirmed as the strongest prognostic factor associated with both cognitive and motor outcomes. The onset-admission interval negatively influence motor recovery, bat not cognitive one. CONCLUSION: There is strong evidence to support the proposal that it is advantageous to measure functional recovery by means of the normalized change in FIMTM score. Following a rehabilitation programme, functional recovery should be evaluated separately for motor and cognitive domains. Rehabilitation program should begin as soon as possible. CLINICAL REHABILITATION IMPACT: Improved assessment of rehabilitation outcome leads to increased achievement of a favourable treatment outcome.

Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state.

OBJECTIVES: Late recovery of awareness in vegetative state (VS) is considered as an exceptional outcome, and has been reported prevalently after traumatic brain injury (TBI). The present prospective study aimed to verify frequency of late recovery (later than 1 year postonset in TBI and 3 months postonset in patients without TBI) of responsiveness and consciousness in traumatic and nontraumatic long-lasting (more than 6 months after onset) VS. METHODS: Fifty inpatients with long-lasting VS (36% TBI, 36% hemorrhagic, and 28% anoxic) were enrolled and followed up for a mean of 25.7 months from onset (5 patients for more than 4 years). Level of responsiveness and functional disability were evaluated by means of validated scales (Coma Recovery Scale-Revised and Disability Rating Scale). RESULTS: At the end of the study, 21 patients (42%) had died, 17 patients (34%) were in VS, and 2 patients with TBI (4%) had recovered responsiveness within 12 months postonset. The remaining 10 (20%) patients with TBI and patients without TBI showed late recovery of responsiveness; 6 of them (12%) further progressed to consciousness. Late recovery was significantly associated with younger age and was relatively more frequent in TBI. Functional abilities were severely impaired in all patients. CONCLUSIONS: This clinical study demonstrates that late recovery of responsiveness and consciousness is not exceptional in patients with traumatic and nontraumatic VS, although with residual severe disability.

Electrophysiologic characterization in spinocerebellar ataxia 17.

The authors performed a multimodal electrophysiologic evaluation in nine patients belonging to four SCA17 (spinocerebellar ataxia type 17) families. Peripheral nerve and visual system were not involved. Brainstem auditory evoked potentials were constantly abnormal with central type lesions. Magnetic motor evoked potentials were abnormal only in the lower limbs, suggesting a length-dependent involvement of the pyramidal tract. Somatosensory evoked potentials were abnormal in almost all our patients, and abnormalities were consistent with a somatosensory pathway involvement along the brainstem.

Excitatory and inhibitory mechanisms in Wilson's disease: investigation with magnetic motor cortex stimulation.

We have evaluated cortical excitability in nine patients affected by Wilson's disease (WD) using transcranial magnetic (TMS) and electric (TES) cortical stimulation and central silent period (CSP) data. A clinical score was derived from the sum of scores assigned to extrapyramidal, pyramidal and cerebellar signs. All patients underwent TMS. Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles were recorded. MEP threshold and amplitude, central motor conduction time (CMCT), CSP threshold, CSP and peripheral silent period (PSP) duration were measured. Three patients also underwent transcranial bifocal electric cortical stimulation (TES) and MEPs were recorded from the APB muscle, and CMCT, MEP threshold and amplitude were measured. TMS MEPs were absent from relaxed muscles in six patients and from contracted muscles in three. CMCT was prolonged in six patients. APB CMCT correlated with clinical score. In three patients in whom TMS revealed abnormal or no MEP, TES MEPs were of normal threshold and amplitude. The CSP threshold was increased in seven patients, and CSP was absent in one. These results suggest an intracortical presynaptic motor dysfunction in WD.

Influence of GAA expansion size and disease duration on central nervous system impairment in Friedreich's ataxia: contribution to the understanding of the pathophysiology of the disease.

OBJECTIVE: To verify if GAA expansion size could account for the severity of the central nervous system involvement in Friedreich's ataxia (FA). METHODS: Retrospective study of 52 FA patients (mean age 26.9+/-12.1 years; mean disease duration 10.6+/-7.6 years) homozygous for GAA expansion. Median nerve somatosensory evoked potentials (SSEPs) were available in 36 FA patients, upper limb motor evoked potentials (MEPs) to transcranial magnetic stimulation in 32, brainstem auditory evoked potentials (BAEPs) in 24, and visual evoked potentials (VEPs) in 34. N20, P100, MEP amplitude, SSEP and MEP central conduction time (CCT and CMCT), P100 latency and I-III and I-V interpeak latency, and a BAEP abnormality score were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) allele in each pair. RESULTS: The GAA1 size inversely correlated with the N20 amplitude (r = -0.49; P<0. 01). Disease duration directly correlated with CMCT (r = 0.57; P<0.01) and BAEP score (r = 0.61; P<0.01) and inversely with MEP (r = -0.40; P<0.05) and P100 amplitude (r = -0.39; P<0.05). CONCLUSIONS: Our data suggest that central somatosensory pathway involvement in FA is mainly determined by GAA1 expansion size. Vice versa, degeneration of pyramidal tracts, auditory and visual pathways seems to be a continuing process during the life of FA patients.

Subclinical peripheral nerve involvement in patients with rheumatoid arthritis.

OBJECTIVE: Clinical involvement of the peripheral nervous system is uncommon in rheumatoid arthritis (RA); the most common disorders are multiple mononeuritis, sensorimotor neuropathy, and entrapment neuropathy. This study was undertaken to investigate the occurrence of electrophysiologically evident peripheral nerve involvement in RA patients without a clinical history of peripheral nerve involvement. METHODS: Forty RA patients were examined neurologically and electrophysiologically, and sural nerve biopsies were performed in 4. RESULTS: No patient reported symptoms or signs of peripheral nerve involvement. Twenty-six patients (65%) exhibited electrophysiologic findings consistent with a sensorimotor neuropathy (in 2 of them a carpal tunnel syndrome was also present), while 3 patients showed isolated carpal tunnel syndrome. There was a moderate loss of myelinated fibers in 3 of the 4 nerve biopsy samples, and all showed an increased number of endo- and perineurial vessels and some signs of axonal degeneration. CONCLUSION: Patients with RA may have electrophysiologic and histologic findings of peripheral nerve damage, even in the absence of clinical evidence of peripheral nerve involvement.

Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients.

A multimodal electrophysiological study was performed on 41 patients from 24 families with autosomal dominant cerebellar ataxia type I (ADCA I). Upper- and lower-limb motor evoked potentials (MEPs) to transcranial magnetic stimulation, median and tibial nerve somatosensory evoked potentials (Mn and Tn-SSEPs), orthodromic sensory (SCV) and motor conduction (MCV) velocity along median and tibial nerve, brainstem auditory evoked potentials (BAEPs), and visual evoked potentials (VEPs) were examined. Molecular analysis showed 2 SCA1 families and 2 families linked to the SCA2 locus. A sural nerve biopsy was performed in 5 patients. Brainstem damage of the auditory pathway was observed in 79% of patients examined. VEP abnormalities possibly of central origin were found in 52% of patients. MEP and SSEP abnormalities were differently distributed along the pathways examined: the longer the pathway, the higher the occurrence and severity of impairment. Peripheral dying-back neuropathy (confirmed by nerve bioptic data) was a frequent finding (56%). A progressive degenerative process involving first the longest tracts of the central motor and central and peripheral branches of somatosensory pathways is hypothesized in ADCA I. MEP abnormalities were more frequent in SCA1, and the sensory-motor neuropathy was more severe in SCA2.

Evaluation of the motor cortex by magnetic stimulation in patients with Alzheimer disease.

Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles elicited by transcranial magnetic stimulation of the motor cortex were studied in 15 patients with Alzheimer disease (AD). An abnormally higher MEP threshold in APB, frequently associated with absence of the MEP in relaxed TA muscles, was found in 40% of patients, almost all of them in the more severe stage of the disease. The MEP amplitude and averaged MEP/MAP ratio were reduced respectively by 20% and 26% in the APB muscle, and by 46.7% and 53.3% in the TA muscle. The less frequent prolongation of the central conduction time (CCT) (20%) might reflect preservation of the impulse propagation along the surviving pyramidal fibers. In 63.6% of the patients the central silent period (cSP) duration in the APB muscle was shortened; the mean value was significantly different between patients and controls. The results of this study suggest that loss and/or dysfunction of motor cortex neurones, including pyramidal cells and inhibitory interneurones may occur in AD patients before clinical signs become apparent.

Evoked potentials in inherited ataxias: a multimodal electrophysiological study.

A multimodal electrophysiological study, including median nerve somatosensory evoked potentials (SSEPs), motor cortical stimulation (CS) and brainstem evoked potentials (BAEPs), was performed on 34 patients with hereditary ataxias (HAs): 15 with Friedreich's disease (FD), 10 with early onset cerebellar ataxia (EOCA), and 9 with autosomal dominant cerebellar ataxia (ADCA). A higher incidence of abnormal central motor conduction was observed in FD than in EOCA patients, but was never observed in ADCA. A relationship between central motor conduction abnormalities and disease duration and clinical impairment was found only in FD patients. All FD patients showed severe impairment of the SSEPs that was not related to disease duration. In EOCA patients, less frequent and more variable SSEP abnormalities were observed. The lowest incidence of central SSEP abnormalities was observed in ADCA. The BAEP findings in all 3 groups of patients (but particularly those with EOCA) suggest prevalent brainstem damage.

How many alien hand syndromes? Follow-up of a case.

We report the follow-up of a patient affected by a persistent alien left nondominant hand. CT and MRI showed an ischemic lesion localized to the mesial frontal region and involving the supplementary motor area and anterior fibers of the corpus callosum. These findings support theories suggesting a critical role of both these lesions in determining "chronic" forms of alien hand of either upper limb.

Is early onset cerebellar ataxia with retained tendon reflexes identifiable by electrophysiologic and histologic profile? A comparison with Friedreich's ataxia.

An electrophysiologic and histologic study was performed on 18 patients affected by early onset cerebellar ataxia with retained tendon reflexes (EOCA). Sensory and motor conduction velocity (SCV, MCV) was measured along peripheral nerves in all patients, somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) were recorded in 13; cortical stimulation (CS) in 12, and sural nerve biopsy in 4 patients were also performed. The results as a whole allow a division of EOCA patients into 2 groups: with (7 patients) and without (11 patients) peripheral neuropathy. Among EOCA patients with neuropathy a differential diagnosis with Friedreich's disease patients was not possible according to BAEPs and CS, while SSEPs could differentiate 2 out 5 patients in whom they were performed.

Motor and somatosensory evoked potentials in hereditary spastic paraplegia.

Motor evoked potentials (MEPs) from the arms and legs to transcranial stimulation of the motor cortex and somatosensory evoked potentials (SSEPs) from stimulation of the nerves of the arms and legs, were recorded in 11 patients with hereditary spastic paraplegia. Electrophysiological abnormalities were found to be distributed differently among the systems examined; the longer the pathway, the higher the incidence and severity of impairment. MEPs from the leg were either absent or clearly reduced or prolonged in all patients. Eight patients showed abnormal cortical SSEPs on stimulation of the leg (absent or reduced responses in four, slowed central conduction velocity in seven), but only two of these patients had abnormal MEPs from the arm (absent responses). Cortical SSEPs on stimulation of the median nerve were reduced in two patients. Mean values of amplitude and central conduction velocity for MEPs and SSEPs from the leg were significantly different between patients and controls. Such differences were not found for either MEPs or SSEPs from the arm. This distribution of abnormalities, which suggests a differential involvement of the spinal pathways, parallels the reported pathological pattern in which degeneration of axons is more common and severe in the motor and sensory fibres supplying the leg.

Somatosensory evoked potentials and motor cortex stimulation in myelopathies.

Short latency somatosensory evoked potentials (SSEPs) to stimulation of the tibial nerve at the ankle and at the knee and motor action potentials (MAPs) recorded from the tibial muscle during transcranial stimulation of the motor cortex were recorded in 21 patients with myelopathy. The electrophysiological results were compared with the clinical evolution over 12 months. Both scalp SSEPs and MAPs were absent in 10 patients with clinically 'complete cord transection.' The clinical and electrophysiological data remained unchanged in these patients. Scalp SSEPs were present at the first examination in all 11 patients with clinically 'incomplete cord lesion.' All these patients improved in the following year. The clinical recovery was almost complete in 3 patients who had normal scalp SSEPs but varied markedly in 8 patients with abnormal SSEPs. Normal MAPs were obtained in 1 of the 3 patients who showed the best clinical recovery. In the other subjects, MAP findings did not show a clear correlation with either the clinical signs or the course.