Early modifications of auditory event-related potentials in carriers of the Huntington's disease gene

The P3 wave is one cognitive component of event-related potentials (ERP) used to investigate various types of dementia. The aim of this study was to use the odd-ball paradigm to evaluate the P3 in Huntington's Disease (HD) gene carriers who showed no symptoms of chorea, compared to a group of mildly affected HD patients. We selected 14 HD patients and six individuals who, despite testing positive for the HD gene, did not show any clinical evidence of the disease. Thirty-six normal subjects were also selected as controls. Statistical evaluation of N1, P2, N2 and P3 latencies and amplitudes was performed in each group. Both the N2 latency and the P3 latency corrected for age (cP3) were significantly correlated with the duration of illness in pooled symptomatic and presymptomatic gene carriers. However, these latencies did not correlate with any clinical scale or psychometric test, including WAIS subtests. As the individual P3 latency of the majority of HD patients and all presymptomatic gene carriers was distributed within normal confidence intervals, and no correlation existed between ERP parameters and the signs of illness progression, the data appear to provide preliminary evidence against the valence of P3 in detecting the early cognitive impairment of HD.     

Correlation between facial involuntary movements and abnormalities of blink and corneal reflexes in Huntington's chorea

Blink and corneal reflexes were studied in 11 patients with Huntington's chorea and the results compared with the severity of the disease. The latency of the R2 component of the blink reflex was delayed and the duration of R2 and of the corneal reflex (CR) prolonged. A greater habituation of the R2 component was found in the patients with involuntary movements in the face, and in some patients a long-lasting depression of R2 was present. A correlation was found between: (a) severity of involuntary face movements and R2 and CR latency and (b) severity of involuntary movements in the neck and latency of R2.     

Neurophysiological study of facial chorea in patients with Huntington's disease.

OBJECTIVE: Choreic movements of patients with Huntington's disease (HD) may result from an abnormal control of sensory inputs. In order to further examine the pathophysiology of facial choreic movements (FCM), we carried out a neurophysiological study, including prepulse inhibition of the blink reflex (BR), in HD patients with and without FCM. METHODS: The study was conducted in 20 genetically proven HD patients with Unified Huntington Disease Rating Scale (UHDRS) scores of FCM ranging between 0 and 3, and in 12 age-matched healthy volunteers who served as control subjects. We counted the number of spontaneous blinks, recorded the electromyographic activity underlying FCM, and analyzed latency, amplitude, and duration of the BR responses to electrical and auditory stimuli. Prepulse inhibition was studied by comparing the responses to test trials with those to control trials. In control trials BRs were obtained to either a single supraorbital nerve electrical stimulus (EBR) or to a 90dB auditory stimulus (ABR). In test trials, the same stimuli were preceded by the prepulse, which was either a weak acoustic tone or a weak electrical stimulus to the third finger, delivered 30-150 ms before. RESULTS: Spontaneous blinking rate was abnormally low in 3 patients, and abnormally high in 9 patients. Mean duration of the BR was longer in patients than in control subjects. In prepulse trials, the percentage inhibition of the BR was abnormally reduced in 15 patients to at least one sensory modality, and significantly correlated with the score of FCM. CONCLUSIONS: Our results suggest that the severity of FCM in patients with HD might be an expression of a disturbance in motor control partly related to an abnormal processing of sensory inputs. Such abnormality involves circuits used in prepulse inhibition of the BR.     

BLINK REFLEX IN HUNTINGTON''S CHOREA AND PARKINSON''S DISEASE

The electrically-evoked late response (R2) of the blink reflex has been determined in 8 well-documented cases of Huntington's chorea and in 19 Parkinsonian patients. The results obtained from the two groups are compared with those from 10 normal subjects. A statistically significant difference of some components of the blink reflex was obtained when the three groups were compared. In both pathological conditions, the habituation index, latency and differential latency can be considered to represent the opposite extremes from the same scale, providing further evidence of the neurophysiological antagonism between the two disease states. The blink reflex pattern in Huntington's chorea probably reflects a diminished brain-stem interneurone basal activity through an over-inhibition of dopaminergic receptors in the striatum. The electrophysiological analysis of the blink reflex in incipient Huntington's chorea can provide an objective diagnostic assessment. It might be an effective method of detection for dopaminergic-activated carriers asking for genetic counseling.     

A follow-up study of isolated cases of suspected Huntington's disease.

We reviewed 49 patients in whom a diagnosis of Huntington's disease (HD) seemed possible on clinical grounds, but who gave no history of definitely affected relatives. In 32 with the typical clinical features of HD (progressive chorea and dementia, postural instability, abnormal initiation of saccadic eye movements), the diagnosis was confirmed in 7 patients who had had autopsies, affected relatives were found in 5 others, and HD remained probable in a further 13 who were reexamined. In the 17 with a less typical clinical picture, a diagnosis of HD appeared most likely in 2; other causes for chorea such as cerebrovascular disease, neuroacanthocytosis, recrudescence of Sydenham's chorea, and drug-induced tardive dyskinesia could be invoked in the remainder. We conclude that the likelihood of HD in a patient with the typical clinical features of this disorder but no history of affected relatives is at least 75%, which for practical purposes implies a risk to their children hardly less than in familial HD. The most plausible explanations for seemingly sporadic patients with HD are nonpaternity and mild, late-onset disease that is overlooked by other family members.     

Reorganization of sensory input at brainstem in hemifacial spasm and postparalytic facial syndrome

We hypothesized the filtering of sensory input from face and hand at brainstem may reorganize in hemifacial spasm (HFS) and postparalytic facial syndrome (PFS). Thus, we examined the prepulse inhibition of blink reflex (BR-PPI) in HFS and PFS. We included 12 healthy subjects, 13 patients with HFS, and 11 patients with PFS. Baseline BR, BR recovery at interstimulus interval (ISI) of 300 ms and BR-PPI at ISI of 100 ms were performed on the right sides of healthy subjects and on both sides of patients. Within-subject analysis showed baseline BR and BR-PPI were similar between asymptomatic and symptomatic sides of patients with HFS whereas BR recovery was higher on the symptomatic side. In the PFS group, latency of R2 during baseline BR recording was longer (p = 0.022) and R2 amplitude (p = 0.046) was reduced on the symptomatic side compared to asymptomatic side. Reduction of R2 area in BR-PPI recordings was also the lowest in HFS compared to other two groups (p = 0.000); however, it was also lower in patients with PFS compared to healthy subjects (p = 0.018). BR-PPI was decreased on both sides of patients. The mean R2 recovery was higher on both sides of patients with HFS and PFS (p = 0.007). Filtering of facial sensory input is decreased probably to monitor and to correct the sequence of facial movements in these disorders.     

Blink reflex excitability cycle in hemifacial spasm

We studied electrically elicited blink reflex responses in patients with hemifacial spasm (HFS) by applying single isolated, as well as paired (conditioning and test), stimuli at both sides of the face. Responses after single stimuli were of larger size on the side of the spasm compared with the uninvolved side and controls. With paired stimuli, the inhibitory effect of the conditioning stimuli upon the test stimuli late response (R2), which was always observed in normals, was significantly less pronounced at short interstimuli intervals. This resulted in an enhanced recovery curve of R2, which was observed on the side of the spasm and the contralateral, clinically normal side. Patients with longer disease duration showed more striking abnormalities of the recovery curve. We suggest that there is enhanced excitability of facial motoneurons and of those brainstem interneurons that mediate the blink reflex pathway in patients with HFS.     

Hand muscle reflexes following electrical stimulation in choreatic movement disorders.

Thenar reflexes following electrical stimulation of the median nerve (containing proprioceptive and cutaneous afferents) and the radial superficial nerve (cutaneous afferents only) were investigated in 23 patients with manifest Huntington's disease (HD) at an early stage, in 17 clinically healthy descendants of HD-patients and in 18 patients with choreatic hyperkinesia due to various aetiologies other than HD. In 61% of the patients with early HD the long-latency reflexes (LLR) were uni- or bilaterally absent in response to both median nerve and radial superficial nerve stimulation. The remaining patients had a diminished mean amplitude and mean duration of their LLR. In contrast, offspring and patients with symptomatic chorea had preserved LLR which did not differ in amplitude or duration from normal controls. Additionally, the mean amplitude and mean duration of the Hoffmaan-reflex (HR) was found to be increased in patients with HD and their offspring but not in patients with other aetiologies. It is concluded (1) that the loss of LLR is not related to the choreatic hyperkinesia itself but to the degeneration of a hitherto poorly defined neuronal circuit in HD; (2) that among a variety of diseases presenting with chorea, the loss of LLR seems to be specific for HD; (3) that the testing of hand muscle reflexes in choreatic movement disorders is helpful for the differential diagnosis of early HD but not for the detection of gene carriers among offspring of patients with HD.     

Dystonia-predominant adult-onset Huntington disease: association between motor phenotype and age of onset in adults

BACKGROUND: In juvenile Huntington disease (HD), dystonia as well as parkinsonism and eye movement abnormalities may be the predominant motor signs rather than chorea. Several patients have come to our attention with adult-onset HD in whom there is prominent dystonia and minimal chorea (ie, an adult-onset form of HD that resembles juvenile HD). OBJECTIVES: To estimate the prevalence of these cases of dystonia-predominant HD in a clinic and to study the relationship between the motor phenotype and age of onset in HD. METHODS: The Unified Huntington's Disease Rating Scale (UHDRS) was administered to 127 subjects during their initial visit to the Huntington's Disease Center at the New York State Psychiatric Institute, where dystonia, chorea, bradykinesia, rigidity, and eye movements were rated. The dystonia score was the mean UHDRS rating of dystonia in 5 body regions; the chorea score, the mean rating of chorea in 7 regions; the bradykinesia score, the mean rating of axial and limb bradykinesia; the rigidity score, the mean rating of rigidity in both arms; and the eye movement score, the mean rating of ocular pursuit, saccade initiation, and velocity. Dystonia-predominant HD was defined by the severity of dystonia relative to the severity of chorea. RESULTS: Fifteen (11.8%) of 127 subjects had dystonia-predominant HD. Age of onset correlated negatively (r= -0. 22, P=.02) with the dystonia score divided by the chorea score and negatively (r= -0.28, P=.002) with the severity of dystonia, bradykinesia, and eye movement abnormalities relative to chorea (ie, [(dystonia score + bradykinesia score + eye movement score)/3] - chorea score), suggesting that subjects with younger ages of onset had more severe dystonia, bradykinesia, and eye movement abnormalities relative to chorea. CONCLUSIONS: Cases of adult-onset HD with prominent dystonia and a paucity of chorea may represent 1 in 8 cases in specialty clinics. Age of onset was clearly associated with the motor phenotype. A younger age of onset was associated with more severe dystonia, bradykinesia, and eye movement abnormalities relative to chorea, supporting the notion that in adult-onset HD, the motor phenotype forms a continuum with respect to age of onset.     

Masseter inhibitory reflex in movement disorders. Huntington's chorea, Parkinson's disease, dystonia, and unilateral masticatory spasm.

Evoked by electrical stimulation of the mental nerve, the masseter inhibitory reflex consists of an early and a late silent period (SP1 and SP2), which interrupt the voluntary electromyographic (EMG) activity in the masseter muscle. We recorded the masseter inhibitory reflex and measured its latency, depth of suppression, duration and recovery cycle to paired stimuli, in patients with Huntington's chorea. Parkinson's disease, dystonia, or unilateral masticatory spasm. In patients with Huntington's chorea the reflex data and recovery cycle were normal. In patients with Parkinson's disease or dystonia, although the reflex data were normal, SP2 recovered far more rapidly than it did in control subjects. This is possibly due to hypoactivity of an inhibitory control of the polysynaptic chain of ponto-medullary interneurons that mediate SP2. In patients with unilateral masticatory spasm, both SP1 and SP2 were absent. Suppression is probably absent because this involuntary movement originates at a point along the peripheral course of the nerve.     

Visual processing disorders in patients with Huntington's disease and asymptomatic carriers

Deficits in visual processing are early cognitive abnormalities in patients with Huntington's disease (HD) and may be found in presymptomatic gene carriers. We investigated the nature and evolution of deficits in visual processing in HD, and whether subtle deficits could be recognized by formal testing in asymptomatic carriers. We studied 35 patients with HD in stages 1–3 of functional disability, and 26 symptomfree relatives at 50% risk for the disease. We administered the Mini Mental State Examination to assess overall cognitive function and tests to assess visuospatial skills such as visual attention and ocular scanning (Cancellation Task and Line Bisection Test), visuoconstructive abilities (Copy of Rey's Complex Figure), and visuoperception (Hooper Visual Organization Test). The group at risk comprised 15 asymptomatic carriers (AC) and 11 non-carriers (NC) and was assessed by investigators blinded to gene status. HD patients were impaired in most of the tasks compared with AC and NC, and the scores declined steadily from stage 1 to 3. However, the difference between patients in stage 1 of HD and AC and NC in most of the tasks was not significant. Only the Hooper Test, which requires complex visual integration, was highly discriminative of early symptomatic from asymptomatic carriers (P < 0.05). There were no significant differences between AC and NC in any of the tasks. We conclude deficits in visual processing develop with other manifestations of the disease and are not significant on formal testing at presymptomatic stages; also, early visual deficits in HD seem to be related to disorders in complex visual processing.     

Central motor conduction to hand and leg muscles in Huntington's disease

Using electromagnetic stimulation of motor cortex and cervical or lumbar roots, central conduction times to the thenar and abductor hallucis muscles bilaterally were determined in a population of 32 patients with definite Huntington's disease (HD) and 14 subjects at risk. The HD patients showed a wide variety of different severity of choreatic movements, disease duration, and total disability. None of the stimulation parameters (latency after cortical stimulation, amplitude, threshold, or central conduction time) revealed statistically significant abnormalities compared with a normal control group as well as between patient subgroups. The data indicate that central motor conduction to upper and lower extremity muscles remains normal in Huntington's disease irrespective of the severity of the disorder.     

瞬目反射、面神经电图和面肌肌电图对面神经炎的诊断、治疗和预后的评估

目的 探讨瞬目反射(BR)和面神经电图(ENG)、面肌肌电图(EMG)对面神经炎的诊断、治疗和预后的价值.方法 53例面神经炎患者在发病后1周内首次进行BR检查以及ENG、EMG测定,发病后1,3,6个月重复上述检查.结果 首次检查患侧R1、R2及R2'缺如者23例,其余有30例患侧R1、R2及R2'与健侧相比潜伏期延长,差异有统计学意义(P＜0.01).异常率达91%.37例患侧面神经运动传导与健侧相比潜伏期延长、波幅降低,差异有统计学意义(P＜0.05),异常率为75%.23例患侧出现正锐波、纤颤电位,运动单位电位波幅降低,时限延长,多相渡增多,病理性干扰相.1个月后复查,上述检查完全恢复者26例.3个月后复查完全恢复者42例,6个月后复查完全恢复者51例,2例未恢复者1年后仍遗留有后遗症.结论 BR测定是诊断面神经炎的敏感指标.BR结合ENG、EMG检测能评估面神经炎的病情、疗效及预后.     

Blink reflex in stroke: follow-up and correlation with function and CT parameters

Blink reflex (BR) was examined serially in patients 1, 2 and 3 months after unilateral hemispheric cerebrovascular accident and compared with functional state and CT findings of lesion extent and location. BR R2 components were depressed and correlated with lesion size. Initial walking ability was correlated with latency and amplitude of both direct and consensual R2 elicited by stimulation of the paretic side. No correlation was found between BR and arm function or the final ambulatory ability. A model suggesting a close association between BR projection-facilitating fibers and those mediating facial movements is presented.     

Huntington disease in a nonagenarian mistakenly diagnosed as normal pressure hydrocephalus

In the absence of family history or overt chorea, the protean manifestations (cognitive, motor and behavioral) of Huntington disease (HD) may suggest alternative disease processes, particularly in elderly patients. Herein, we report on a nonagenarian with HD who did not manifest overt chorea until 91 years of age and was mistakenly diagnosed with normal pressure hydrocephalus at 89 years of age. The gait abnormalities seen in early HD should be readily distinguished from those of normal pressure hydrocephalus.     

电刺激诱发瞬目反射对脑桥梗死患者的预后价值

目的 探讨电刺激诱发瞬目反射(blink reflex,BR)对脑桥梗死患者的预后价值.方法 对43例脑桥梗死患者和37例健康对照组进行电刺激诱发BR的检测,采用欧洲脑卒中评分(The European stroke scale,ESS)和日常生活活动(activity of daily life,ADL)量表对每位患者在BR检查当日和4周末分别进行神经功能缺损程度评分.结果 脑桥梗死组病灶侧R1的潜伏期较对照组明显延长,病灶侧R1的潜伏期较健侧也显著延长(P＜0.001).脑桥梗死组BR各波的异常率以R1最高,占81.4%,而R2和R2′的异常率分别为23.3%和25.6%.R1的异常率显著高于R2和R2′(P＜0.001).双侧脑桥梗死(双侧均有病灶,每侧病灶直径均＞3mm),导致BR各波均未引出.一侧脑桥单个梗死灶,梗死灶直径＞3mm,主要引起R1潜伏期延长;一侧脑桥单个梗死灶,梗死灶直径0.5～3mm,BR各波潜伏期均正常.R1波未引出组神经功能缺损程度最重,ESS评分和ADL评分显著低于R1潜伏期延长组和R1潜伏期正常组(P＜0.001);R1潜伏期正常组预后最好,4周末其ESS评分和ADL评分均较1周内显著提高(P＜0.01和0.001);R1潜伏期延长组次之.结论 脑桥梗死患者的BR异常以R1潜伏期延长为特征.脑桥的病灶主要引起R1异常,进一步提示R1的反射中枢位于脑桥.BR的异常类型可大致反映脑桥梗死病灶的范围,BR的R1异常可作为脑桥梗死患者神经功能缺损程度和预后评价的电生理指标之一.     

Cerebral metabolism and atrophy in Huntington's disease determined by 18FDG and computed tomographic scan

Patterns of local cerebral glucose utilization were measured with positron emission, computed tomography using the 18F-fluorodeoxyglucose method in 13 patients with Huntington's disease (HD), 15 subjects at risk for HD, and 40 normal control subjects. These data were compared with computed tomographic measures of cerebral atrophy, with age, and with duration and severity of symptoms. The results indicate that in HD there is a characteristic decrease in glucose utilization in the caudate and putamen and that this local hypometabolism appears early and precedes bulk tissue loss. In contrast to patients with senile dementia, in these HD patients glucose utilization typically was normal throughout the rest of the brain, regardless of the severity of symptoms and despite apparent shrinkage of brain tissue. Our results suggest the possibility that the caudate may be hypometabolic in some asymptomatic subjects who are potential carriers of the autosomal dominant gene for HD.     

Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene

OBJECTIVE: To confirm that subtle changes in motor function and reaction time are present in presymptomatic individuals carrying the expanded Huntington disease (HD) allele. DESIGN: A case-control, double-blind study comparing presymptomatic HD gene carriers (PSGCs) and nongene carriers (NGCs) at risk for HD. SETTING: The Department of Medical and Molecular Genetics at a general clinical research center in a midwestern city. PARTICIPANTS: Two hundred sixteen individuals at risk for HD who were asymptomatic by self-report and who did not have manifest HD on results of clinical examination, including PSGCs (n = 61) and NGCs (n = 155). MEASURES: Molecular testing was used to determine the number of CAG repeats in the HD gene. A quantified neurologic examination and a battery of physiological measures of central nervous system function measuring speed of movement and reaction time were administered. RESULTS: On neurologic examination, the PSGCs exhibited significantly more definite or possible abnormalities than NGCs for overall oculomotor function, saccade velocity, optokinetic nystagmus, chorea of the extremities, and dystonia of the extremities (P<.05). The PSGCs also had significantly slower performance for auditory reaction time, visual reaction time, visual reaction time with decision, movement time, movement time with decision, and button-tapping time, compared with the NGCs (P<.05). CONCLUSIONS: Subtle changes in motor function, speed of movement, and reaction time are present in HD gene carriers who do not exhibit definite choreiform movements and who do not have sufficient signs to make a clinical diagnosis of HD. In addition, a trend toward slower speed of movement and reaction time was observed among this population as their neurologic abnormalities increased.     

Saccadic eye movements in juvenile variant of Huntington disease

Background and purposeHuntington disease (HD) is a neurodegenerative disease leading to involuntary movements, cognitive and behavior decline. The juvenile variant of HD (JHD) manifests in people younger than 21 and is characterized by a different clinical presentation, i.e. rigidity and bradykinesia. Rapid eye movements were not extensively studied in patients with JHD. Aims of our study were to describe the saccadic eye movements in JHD patients and to find a correlation between the saccade abnormalities, severity of the disease and cognitive and behavior deterioration.Materials and methodsWe studied 10 patients with JHD and 10 healthy subjects. Reflexive and volitional saccades were assessed with the Saccadometer Advanced. The battery of cognitive and behavior tests was performed as well.ResultsWe found a prolonged latency, slowness and decreased velocity of reflexive and voluntary saccades and reduced amplitude of voluntary saccades. Moreover, patients with JHD executed a significantly lower number of volitional saccades and made more incorrect cued saccades than controls. We noted a significant correlation between prolonged latency of reflexive saccades with gap task and disease severity and significant inverse correlation between prolonged latency of reflexive saccades with overlap task, an increased number of incorrect saccades made on a cue and impairment in working memory.ConclusionAbnormalities of saccade eye movements in patients with JHD were similar to those reported in patients with HD. Our findings did not confirm abnormalities previously reported in patients with early onset HD. Abnormal saccade parameters correlated also with a disease severity and cognitive deterioration.     

Nociceptive inputs transmission in Huntington's disease: a study by laser evoked potentials

The aim of the present study was to evaluate pain perception and evoked responses by laser stimuli (LEPs) in mild not demented Huntington's Disease (HD) patients. Twenty-eight HD patients and 30 control subjects were selected. LEPs were obtained by four scalp electrodes, (Fz, Cz, referred to the nasion; T3, T4, referred to Fz), stimulating the dorsum of both hands. All patients were also evaluated by somatosensory evoked potentials (SEPs) by median nerve stimulation. Only 3 patients referred pain of arthralgic type. Laser pain perception was similar between HD patients and controls. An abnormal N2, P2 and N1 latency increase was evident in the majority of HD patients. LEPs features were similar between patients taking and not taking neuroleptics. The N2 and P2 latencies, showed a negative correlation with functional score and Mini Mental State Examination, and a positive correlation with the severity of hyperkinetic movements. A delay in nociceptive input processing emerged in HD, concurring with the main features of the disease, in absence of clinical evidence of abnormalities in pain perception. The dysfunction of pain signals transmission in HD may induce sub-clinical changes of sensory functions, which may probably interfere with sensory-motor integration and contribute to functional impairment.