Cortical reflex myoclonus in adult onset Huntington's disease]

We report a case of cortical reflex myoclonus in adult onset Huntington's disease (HD). The patient is a 51-year-old woman. Chorea and myoclonus were observed on her face and extremities. Neurophysiological tests showed C reflex and abnormal waves preceding myoclonus by jerk-locked back averaging method but no giant somatosensory evoked potential. Gene analysis revealed the prolongation of CAG repeats (13/44) in IT15 gene. Oral administration of clonazepam was transiently effective for myoclonus. We should inscribe that the cortical reflex myoclonus may exceptionally manifest in HD.     

Intention myoclonus in Huntington's disease.

A patient is described with severe intention myoclonus which was made worse by treatment with L-Dopa and improved by clonazepam. Family history and examination of several siblings suggested the diagnosis of Huntington's disease. Subsequent to improvement of the myoclonus the patient appeared to have the rigid form of Huntington's disease. This case represents a unique expression for an otherwise well defined genetic abnormality. Stimulus activated myoclonus in a common feature of a number of disorders of the nervous system. Intention, or action myoclonus has been the subject of increasing interest because of its association with the syndrome of post-anoxic encephalopathy (1), although it may occur with other disorders as well. Many abnormal movements have been reported in Huntington's disease, but myoclonus is a relatively uncommon feature of this disorder and to our knowledge intention myoclonus has not been reported as a major symptom. We recently have evaluated a patient with disabling intention myoclonus and examined several members of his family who have typical Huntington's disease. We therefore report this case, a unique presentation of an otherwise well described movement disturbance.     

Tourettism as clinical presentation of Huntington's disease with onset in childhood

Infantile Huntington's disease (HD) shows a wide clinical heterogeneity. Here we describe the case of a child affected by HD who showed unusual neurological features consistent with tourettism. The absence of family history and persisting normal magnetic resonance imaging (MRI) results long after the onset of symptoms delayed the diagnosis of the disease. An MRI exam performed 26 months after disease onset disclosed bilateral atrophy in the putamen, suggesting HD. The diagnosis was confirmed by genetic analysis. The present report underlines the need to consider HD in childhood cases of unusual and even unfamiliar progressive movement disorders.     

Action myoclonus in adult Huntington's disease]

In contrast to juvenile rigid form of Huntington's disease (HD) in which myoclonus is often seen, only 5 patients with myoclonus complicating adult HD have been reported. We herein described an adult HD patient who suffered from severe action myoclonus leading to physical disability. To our knowledge, this is the first case report in Japan. The patient, a 32-year-old female with a family history of chorea, developed choreiform movements and mental changes since the age of 24. Subsequently her motor disability has been aggravated by distinctively different involuntary movements characterized by sudden, violent, continuous muscular contractions of four extremities on any attempts at movement. Examination revealed moderate dementia and chorea complicated by frequent myoclonic jerks involving upper and lower extremities in posture or during movement. A head CT scan and MRI revealed caudate atrophy. The myoclonus, as recorded by surface electromyography over the right arm consisted of 40-60 msec-synchronous semirhythmic bursts. The cortical component of SEP was enlarged and C reflex was also observed. Clonazepam (4 mg a day) was instituted with a pronounced reduction in myoclonus and a return to her previous level of daily life activity. Although myoclonic jerks are often recognized in juvenile patients with rigid form of HD, they have been considered to exert a minor influence on physical disability. By contrast, our present observation and review of literature suggest that myoclonus may lead to severe motor impairment in adult HD.     

Cortical and striatal neurone number in Huntington's disease

The total cortical and striatal neurone and glial numbers were estimated in five cases of Huntington's disease (three males, two females) and five age-and sex-matched control cases. Serial 500-m-thick gallocyanin-stained frontal sections through the left hemisphere were analysed using Cavalieri's principle for volume and the optical disector for cell density estimations. The average cortical neurone number of five controls (mean age 53±13 years, range 36–72 years) was 5.97×10⁹±320×10⁶, the average number of small striatal neurones was 82×10⁶±15.8×10⁶. The left striatum (caudatum, putamen, and accumbens) contained a mean of 273×10⁶±53×10⁶ glial cells (oligodendrocytes, astrocytes and unclassifiable glial profiles). The mean cortical neurone number in Huntington's disease patients (mean age 49±14 years, range 36–75 years) was diminished by about 33% to 3.99×10⁹±218×10⁶ nerve cells (P0.012, Mann-Whitney U-test). The mean number of small striatal neurones decreased tremendously to 9.72×10⁶±3.64×10⁶ (–88%). The decrease in total glial cells was less pronounced (193×10⁶±26×10⁶) but the mean glial index, the numerical ratio of glial cells per neurone, increased from 3.35 to 22.59 in Huntington's disease. Qualitatively, neuronal loss was most pronounced in supragranular layers of primary sensory areas (Brodmann's areae 3,1,2; area 17, area 41). Layer IIIc pyramidal cells were preferentially lost in association areas of the temporal, frontal, and parietal lobes, whereas spared layer IV granule cells formed a conspicuous band between layer III and V in these fields. Methodological issues are discussed in context with previous investigations and similarities and differences of laminar and lobar nerve cell loss in Huntington's disease are compared with nerve cell degeneration in other neuropsychiatric diseases.Supported by a grant from the Deutsche Forschungsgemeinschaft (He 1430/3-3)     

Cortical and brainstem LTP-like plasticity in Huntington's disease

Recent studies have reported abnormalities in short-term plasticity in patients with Huntington's disease (HD). However, is not known whether long-term potentiation (LTP)-like plasticity is also affected in these patients. We tested cortical and brainstem LTP-like plasticity in eight symptomatic HD patients and in 10 healthy age-matched controls. To probe motor cortex LTP-like plasticity we used paired associative stimulation (PAS), a technique that combines repetitive electric stimulation of the median nerve with subsequent transcranial magnetic stimulation (TMS) of the contralateral motor cortex at 25 ms. To investigate brainstem plasticity, we induced LTP-like phenomena in the trigeminal wide dynamic range neurons (WDR) of the blink reflex circuit by pairing an high-frequency train of electrical stimuli (HFS) over the right supraorbital nerve (SO) coincident with the R2 response elicited by a preceding SO stimulus. Our results demonstrate impairment of both cortical and brainstem LTP-like plasticity in symptomatic HD patients which is similar to LTP deficits previously reported in HD animal models. These findings might well represent the neurophysiological correlates of memory deficits often present in HD.     

Cortical glucose metabolism in Huntington's disease.

We measured cortical glucose metabolism with positron emission tomography in 39 patients with Huntington's disease (HD) and in 34 controls. In the 23 patients with symptoms for less than 5 years, there was a 15% decrease in metabolism in frontal and inferior parietal cortex. In 16 patients with symptoms for more than 5 years, all cortical areas (except temporal) were significantly involved, with metabolic rates 25 to 30% below those of controls. These data indicate the presence of a diffuse abnormality of cortical function with early involvement of frontal lobes in HD, suggesting that the clinical manifestations may not be related solely to basal ganglia pathology, even in early disease.     

Cortical myoclonus in children

Cortical myoclonus is a distinct clinical condition that can be defined electrophysiologically, and occurs in both children and adults. It is well known that patients sometimes exhibit stimulus-sensitive jerks and giant somatosensory-evoked potentials (SEPs). In contrast, imaging abnormalities are less prominent in many patients. Reports focusing on cortical myoclonus, except for epilepsia partialis continua, in childhood have been limited in Japan. One reason for this could be that Japanese pediatric neurologists are not familiar with the backaveraging technique. We describe the clinical and physiological features of cortical myoclonus in ten children. Routine EEG, EEG backaveraging, SEP measurement, CT/MRI (computed tomography/magnetic resonance imaging), and TMS (transcranial magnetic stimulation) were performed. All patients exhibited clear evidence of cortical myoclonus. In six patients, backaveraging was necessary since spikes were absent on routine EEG. A cortical source of the myoclonus was further supported by a TMS study performed on four patients. The etiologies of the myoclonus were diverse, cerebrovascular disease being the most common (three patients). Stimulus-sensitive or action-induced jerks were observed in three patients. Cortical SEPs were enlarged in one patient, and reduced or absent in six. Lesions were found on CT/MRI in nine patients, in five of whom the margin of the lesion was within, or adjacent to, the sensorimotor cortex. Complete destruction of the sensorimotor cortex was not observed. It was suggested that cortical neurons in the vicinity of a lesion, rather than in the lesion itself, play a role in the generation of focal myoclonus.     

Cortical reflex myoclonus

Three patients with a type of myoclonus produced by intention and somatosensory stimulation were studied with electrophysiologic techniques. Each jerk typically affected only a few contiguous muscles; agonist and antagonist muscles were activated simultaneously with a simple electromyographic (EMG) burst lasting 10 to 30 msec. Cranial nerve muscles were activated in an order indicating that the signal to produce the myoclonus traveled down the brainstem. In action-induced jerks a negative transient in the electroencephalogram (EEG) from the contralateral sensorimotor cortex consistently preceded the jerk with a fixed latency. In reflex-induced jerks this negative transient could be recognized as a component of the sensory evoked potential. The types of myoclonus are reviewed and it is argued that this type of myoclonus is mediated in cerebral cortex and that the negative transient represents a paroxysmal depolarization shift (PDS). The myoclonus may result from hyperactivity of a component of the long-latency stretch reflex.     

Electroencephalographic correlate of juvenile Huntington's disease

The spectrum of clinical disease in juvenile Huntington's disease differs from that seen in adults. Younger patients often present with seizures, dystonia and rigidity. The mechanism and type of seizures, timing of onset and electrographic features have not been well characterized in either adults or children. We describe the electroencephalographic findings observed in a young child with Huntington's disease who presented with motor regression and seizures. Recordings demonstrated bilateral posterior quadrant epileptiform discharges and occipital intermittent rhythmic delta activity, generally considered a nonspecific abnormality. These findings have not been reported in adult or juvenile Huntington's disease. Its presence in proximity to bilateral posterior spikes suggests that occipital intermittent rhythmic delta activity is an epileptiform abnormality, on a continuum with the posterior spike-and-wave discharges. Intermittent rhythmic delta activity can occur secondary to either the subcortical gray-matter disease or the associated seizure disorder. Huntington's disease should be considered in the differential diagnosis of young children who present with seizures and developmental regression.     

Cortical myoclonus in angelman syndrome

Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11–13. This region encompasses three GABA_A receptor subunit genes (β3, α5, and γ3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a <3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompained by rhythmic 5- to 10-Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 ± 13 msec and had a frequency of 11 ± 2.4 Hz. Burst-locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 ± 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.     

Cortical myoclonus and cerebellar pathology

OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve the cerebellar system, but there has only been one report of cerebellar pathology in a patient in whom cortical myoclonus was physiologically characterized antemortem. METHODS: Cortical somatosensory evoked potentials (SEPs) were recorded and EEG activity was averaged preceding myoclonic electromyographic activity. In one patient cortico-cortical inhibition was tested using two paired ipsilateral magnetic stimuli over the motor strip. Neuropathologic examination was carried out, including linear Purkinje cell densities/millimeter calculations for different regions of the cerebellum. RESULTS: The electrophysiology showed evidence of dysfunction of the sensorimotor cortex with enlarged SEPs and a time-locked cortical potential preceding the action myoclonus. In addition, motor cortical inhibition was abnormal in one case. Pathology showed unremarkable primary sensory, motor, and premotor cerebral cortices, except for unilateral gliosis of the motor cortex in one case. The cerebellum showed patchy atrophy and ongoing degeneration. A striking feature was the greater severity of Purkinje cell loss and Bergmann gliosis in the outer aspects than in the depths of the folia. CONCLUSIONS: Pathologic abnormalities are paradoxically mainly located in the cerebellum in some patients with cortical myoclonus, despite clear electrophysiologic evidence of cortical dysfunction. This observation suggests that enhanced excitability of the sensorimotor cortex may arise as a distant effect of cerebellar pathology.     

Cortical dopamine dysfunction in symptomatic and premanifest Huntington's disease gene carriers

We used ¹¹C-raclopride PET, a marker of D₂ dopamine receptor binding, and statistical parametric mapping (SPM) to localise cortical D₂ receptor dysfunction in individual Huntington's disease (HD) gene carriers (16 symptomatic and 11 premanifest subjects) and assess its clinical significance.62.5% of symptomatic HD patients and 54.5% of premanifest carriers showed cortical reductions in D₂ binding. The most frequent decreases in cortical binding in individual HD subjects were seen in temporal and frontal areas. Symptomatic HD subjects with decreased cortical D₂ binding had worse scores on neuropsychological tests assessing attention and executive functions than subjects without cortical dopamine dysfunction, notwithstanding comparable reduction in striatal D₂ binding and motor disability. Our results indicate that cortical dopaminergic dysfunction is common in both symptomatic and premanifest HD gene carriers. It is an early event in HD pathophysiology and could contribute to the impairment in neuropsychological performance in these patients.     

Visuomotor integration deficits precede clinical onset in Huntington's disease

Objectives

Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset (‘premanifest’). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback.

Methods

239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance.

Results

Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses.

Conclusions

Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.     

Cortical reactivity in progressive myoclonus epilepsy

We studied 4 patients with progressive myoclonus epilepsy (Unverricht-Lundborg disease; ULD). Somatosensory evoked fields (SEFs), auditory evoked fields (AEFs), and spontaneous activity over the somatomotor cortex were recorded with a 24-channel SQUID gradiometer. All patients had “giant” 20–45 msec median nerve SEFs at the first somatomotor cortex, with 2–6 times larger amplitudes than the healthy control subjects. Later deflections were not similarly enhanced. The dependence of SEF amplitudes on interstimulus interval (0.2–4 sec) and on successive ulnar-median nerve stimulation (stimulus interval 40 msec) was comparable to that in controls. Cortical AEFs were attenuated and delayed. In 3 patients, the spontaneous activity consisted of 6–8 Hz mu rhythm, which originated within 2 cm from the sources of SEFs and was abolished by clenching of the contralateral fist. Control subjects had major spectral peaks around 10 and 20 Hz. The SEF amplitudes and the strength of the 6–10 Hz mu correlated strongly, suggesting that some components of evoked and spontaneous activity obtain contributions from overlapping neuronal populations. The results imply that ULD is associated with thalamo-cortical hyperreactivity in the sensorimotor but not in the auditory system.