Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland.

BACKGROUND: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. AIM: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. METHODS: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. RESULTS: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. CONCLUSIONS: The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.

Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype.

Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance. Sensory abnormalities are present in AOPTD and also in unaffected relatives, possibly indicating non-manifesting gene carriage (acting as an endophenotype). The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous. We aimed to compare the sensitivity and specificity of three different TDT tasks (visual, tactile and mixed/visual-tactile). We also aimed to examine the sensitivity of TDTs in different AOPTD phenotypes. To examine tasks, we tested TDT in 41 patients and 51 controls using visual (2 lights), tactile (non-painful electrical stimulation) and mixed (1 light, 1 electrical) stimuli. To investigate phenotypes, we examined 71 AOPTD patients (37 cervical dystonia, 14 writer's cramp, 9 blepharospasm, 11 spasmodic dysphonia) and 8 musician's dystonia patients. The upper limit of normal was defined as control mean +2.5 SD. In dystonia patients, the visual task detected abnormalities in 35/41 (85%), the tactile task in 35/41 (85%) and the mixed task in 26/41 (63%); the mixed task was less sensitive than the other two (p = 0.04). Specificity was 100% for the visual and tactile tasks. Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians. The visual and tactile tasks were found to be more sensitive than the mixed task. Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians.

Temporal discrimination threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia.

Familial adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary torsion dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary torsion dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary torsion dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary torsion dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary torsion dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary torsion dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder.

Abnormal reorganization in focal hand dystonia--sensory and motor training programs to retrain cortical function.

Dystonia is a disabling movement disorder, which is characterized by an abnormal pattern of muscle activity with co-contraction of agonist and antagonist muscles. In the case of focal hand dystonia (FHD), these abnormal movements affect muscles of the forearm and hand while performing a specific task. Patients may initially present with dystonic symptoms occurring with a selective task (simple writer's cramp or musician's cramp), and may progress to develop symptoms with multiple tasks (dystonic writer's cramp). The underlying cause of this disabling condition remains unclear. This review examines recent studies designed to further elucidate the underlying pathophysiological processes in focal dystonia. Animal research work, and neurophysiological and neuroimaging studies in humans, have identified several possible mechanisms that may contribute to the underlying pathophysiology, including impaired sensorimotor integration, motor cortex activation and surround inhibition. Pharmacological treatment for dystonia is currently suboptimal. Based on these recent pathophysiological findings, several promising and novel non-pharmacological treatment modalities have recently been developed. Attempts at modulating impaired sensorimotor integration and cortical inhibition using sensorimotor retraining, and the range of sensory training techniques recently described, are further discussed in this review.

Chemical characteristics of a polysaccharide from Porphyra capensis (Rhodophyta).

The structure of a polysaccharide from the red seaweed, Porphyra capensis, growing along the coast of Namibia and South Africa was investigated. Algae growing at different sites and collected at different times gave a polysaccharide extract with similar chemical components. FTIR and NMR spectral analysis showed that the polysaccharide from P. capensis had a typical porphyran structure. It has the linear backbone of alternating 3-linked beta-D-galactose and 4-linked alpha-L-galactose-6-sulfate or 3,6-anhydro-alpha-L-galactose units. The ratio of alpha-L-galactose-6-sulfate and the 3,6-anhydrogalactose is 1.2:1, as reflected by a 1H NMR spectrum. A high degree of methylation occurred at the C-6 position of the D-galactose units. The degree of methylation was 0.64 for the D-galactose residues.

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia.

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.

Fatal toxic leukoencephalopathy: clinical, radiological, and necropsy findings in two patients.

BACKGROUND: Toxic leukoencephalopathy has been described with inhalation and intravenous consumption of heroin and cocaine. The clinical picture varies widely but the imaging and histological features are characteristic. Magnetic resonance imaging (MRI) typically reveals diffuse bihemispheric white matter lesions. Histologically there is extensive spongiform degeneration of the cerebral white matter. OBJECTIVE: To report two cases of fatal toxin associated leukoencephalopathy, along with detailed imaging and neuropathological studies. RESULTS: MRI revealed diffuse white matter changes. Histologically there was widespread confluent vacuolar degeneration of the deep white matter. In both cases, there was sparing of the brain stem and cerebellar white matter. There was evidence of severe and extensive axonal injury. CONCLUSIONS: This pattern of radiological involvement and histological findings has not previously been reported and may reflect the presence of a yet unidentified impurity.

Abnormalities of spatial discrimination in focal and generalized dystonia.

Sensory processing is impaired in focal hand dystonia (FHD), with most previous studies having evaluated only the symptomatic limb. The purpose of this study was to establish whether the sensory system is affected in other types of dystonias and whether the contralateral hand is also involved in FHD. We used a spatial acuity measure (Johnson-Van Boven-Phillips domes) to evaluate sensory spatial discrimination in both hands of patients with different forms of dystonias including primary generalized DYT1 dystonia (associated with a unique deletion in the DYT1 gene) (n = 13), FHD (n = 15), benign essential blepharospasm (n = 9), cervical dystonia (n = 10) and in age-matched controls. Clinical evaluation included the Fahn dystonia scale for the focal dystonia groups and the Marsden-Burke-Fahn scale for the generalized dystonia group. Spatial discrimination was normal in patients with DYT1 dystonia, despite all of these patients having hand dystonia. However, spatial discrimination thresholds were significantly increased in both hands in the focal dystonia groups (thresholds were similar for each group) and did not correlate significantly with either severity or duration of dystonic symptoms. Thresholds were significantly increased in the dominant hand compared with the non-dominant hand only within the FHD group. Our observations demonstrate involvement of both the dominant and non-dominant somatosensory cortices, and suggest that abnormal sensory processing is a fundamental disturbance in patients with focal dystonia. These findings of altered sensory processing in idiopathic focal but not generalized DYT1 dystonia suggest both a primary pathophysiological role for the phenomenon in focal dystonia and divergent pathophysiological processes in the two conditions.

Increased brainstem excitability in stiff-person syndrome.

The recovery cycle of the R2 component of the blink reflex was studied in five patients with stiff-person syndrome (SPS) and in seven healthy control subjects. R2 recovery was enhanced in patients with SPS. This result is suggestive of hyperexcitability of brainstem interneuronal circuits in SPS. Hyperexcitability may result from abnormal input from suprasegmental structures or loss of inhibition by interneurons and is compatible with the proposal that there is a widespread dysfunction of central inhibitory mechanisms in SPS.

Accuracy of muscle localization without EMG: implications for treatment of limb dystonia.

Although botulinum toxin is an effective treatment for focal dystonia, the importance of electromyography (EMG) in identifying muscles and guiding injections is unclear. The authors examined the accuracy of muscle localization in 38 muscles in patients with focal hand dystonia without EMG guidance. Only 37% of needle placement attempts reached the target muscles or muscle fascicles. This study demonstrates that EMG guidance is needed for correct localization of desired muscles.

Thalidomide neuropathy in patients treated for metastatic prostate cancer.

We prospectively evaluated thalidomide-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic androgen-independent prostate cancer in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection.

Bilateral painful hand-moving fingers: electrophysiological assessment of the central nervous system oscillator.

We describe a 35-year-old woman who presented with the syndrome of painful hand-moving fingers on the right side. Eight months later, she developed similar finger movements and hand discomfort on the left side. She had a history of hand trauma and recurrent shoulder dislocation on the right side. Kinesiologic electromyography suggested a common central oscillator for finger movements in both hands. Electrophysiological assessment of spinal alpha motor neuron excitability, reciprocal inhibition, and Renshaw cell inhibition failed to show any abnormalities. Somatosensory evoked potential test showed marked attenuation of N20 potential recorded from the left somatosensory cortex; paired transcortical magnetic stimulation of the left motor cortex suggested failure of cortical facilitation. The data suggest that the central oscillator responsible for finger movements is located above the spinal cord level in this patient.

Maternal Bilateral Radial Neuropathy During Childbirth in Hereditary Neuropathy With a Predisposition to Pressure Palsies (HNPP).

A 30-year-old woman developed severe bilateral radial neuropathies during vaginal delivery of twins, likely secondary to positioning and muscular effort. Subsequent evaluation led to the diagnosis of hereditary neuropathy with predisposition to pressure palsies. Avoidance of prolonged muscular effort in the arms in conjunction with medial intervention to shorten the second stage of labor may help prevent debilitating radial nerve injury in women with this disorder.

Inflammatory myopathy in thyrotoxicosis.

A 45-year-old man with a 3-month history of episodic muscle weakness, MRC grade 4/5 symmetric hip flexor weakness, elevated CK, and an inflammatory myopathy was found to have elevated free thyroxine and T3. Treatment with carbimazole resulted in complete resolution of symptoms and return of muscle power to normal. A repeat biopsy revealed resolution of the inflammatory endomysial infiltrate and an absence of necrosis. Complete clinical and pathologic resolution of a thyrotoxicosis-associated inflammatory myopathy without steroid therapy has not been previously described. The favorable outcome experienced by this patient indicates that steroids may not be necessary in thyrotoxicosis-associated inflammatory myopathy.