Carol Moskowitz

Validity and reliability of a rating scale for the primary torsion dystonias

For quantitative assessment of the primary torsion dystonias, a rating scale is proposed that has two sections—a Movement Scale, based on examination, and a Disability Scale, based on the patients statements about seven activities of daily living. We assessed the validity of the Movement Scale by comparing scores with a ranking of patients according to dystonia severity and with ratings of the patients on the Disability Scale. In addition, we assessed the inter-and intra-rater reliability of the scale by comparing independent scorings of patients by four examiners and by comparing scorings by the same examiners performed at different times. We found that the Movement Scale was a valid and reliable indicator of the severity of primary torsion dystonia.

Double‐blind, placebo‐controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis

We enrolled 55 patients in a double-blind, placebo-controlled, parallel design study of the effectiveness of botulinum toxin (Botox) injections for the treatment of spasmodic torticollis. Patients received a standard series of injections, either placebo or Botox. We determined the sites of injection and dose per muscle by the nature of head deviation. Compared with placebo, Botox produced statistically significant improvement in the severity of torticollis, disability, pain, and degree of head turning. There were no serious side effects. During the double-blind phase, 61% of patients injected with Botox improved; 74% of patients subsequently improved during a later open phase at a higher dose of Botox. Direction of head turning, severity of torticollis, and presence or absence of jerky movements did not significantly influence the response rate. We conclude that Botox is a valuable treatment for spasmodic torticollis.

Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2′-deoxyguanosine (8OH2′dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

Human Gene for Torsion Dystonia Located on Chromosome 9q32-q34

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.

A teaching videotape for the assessment of essential tremor

Teaching videotapes, developed to aid in the evaluation of several movement disorders, have not been used in essential tremor research. As part of the Washington Heights‐Inwood Genetic Study of Essential Tremor (WHIGET), we developed a reliable and valid tremor rating scale. Because this rating scale is currently being used by investigators at other centers, we developed a teaching videotape to aid in the consistent application of this scale.

Predictors of nursing home placement in Huntington disease

Objective: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. Methods: Subjects were participants in the Huntington Study Group’s Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using χ2 and Student’s t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. Results: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents’ average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. Conclusions: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

Age of onset for Huntingtons disease (HD) varies inversely with the length of the disease‐causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R‐squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two‐segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log‐transformed age of onset against CAG repeat length reveals this segmental relationship. This two‐segment exponential regression on age of onset data increases the adjusted R‐squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two‐segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 × 10−5] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 × 10−16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult‐onset range of CAG repeats than in the juvenile‐onset range.

A study of idiopathic torsion dystonia in a non–jewish family: Evidence for genetic heterogeneity

A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.

Essential tremor centralized brain repository: Diagnostic validity and clinical characteristics of a highly selected group of essential tremor cases

We studied essential tremor (ET) cases enrolled in the Essential Tremor Centralized Brain Repository to (1) assess the validity of their diagnoses and (2) characterize the clinical features in a group of highly selected cases who might reflect a far end of the disease spectrum. Our over‐arching goal was to provide a perspective of ET that complements that derived from population‐based and clinic‐based studies. Based on a history and videotaped examination, 94 of 100 ET cases had their diagnoses confirmed; most of the remainder had Parkinsons disease. When compared with ET cases ascertained through populations and clinics, a large proportion had been prescribed medication for tremor (87.2%), had a family history of tremor (88.3%), had rest tremor (33.0%), or had neck tremor (60.6%). One patient had facial tremor, which has not been reported previously. As has been reported once before, a large proportion wore hearing aids (26.9% of the 67 participants age ≥ 70). In summary, diagnostic validity was high. In terms of their clinical characteristics, the high proportion of cases with severe tremor and varied disease manifestations (neck tremor, rest tremor) make these cases a valuable resource in pathological studies; the high proportion with familial tremor would provide an enriched sample for genetic studies.

Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: A clinical–pathological study

A new tremor–ataxia syndrome, fragile X–associated tremor/ataxia syndrome (FXTAS), has been described among carriers of premutation expansions (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The prevalence of FMR1 premutation alleles has been reported to be 1 in 813 among men. Patients with FXTAS may also have features of parkinsonism. Postmortem findings have been described in eight patients with FXTAS and detailed descriptions of the pathological features of this syndrome have been published in two of these. We present a detailed description of the postmortem findings in a third patient. The patient had parkinsonism and was a carrier of a premutation expansion in the FMR1 gene. As in previous reports, the most prominent finding was the presence of eosinophilic nuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and regional vacuolation of the cerebral white matter. As in one previous report, nuclear inclusions were also present in ependymal and choroid plexus cells. A new finding is that of nuclear inclusions in both the adeno‐ and neurohypophysis. These findings confirm the diffuse nature of this pathology. Further studies of clinical–pathological correlation in a larger sample of brains would provide additional insight into the mechanisms of the tremor, ataxia, and parkinsonism in these patients.