Search

Introduction Huntington's chorea (HC) is commonly managed with neuroleptic medications, though there is little evidence to support their use. This study aimed to perform a real-world comparison of the efficacy of risperidone and olanzapine to tetrabenazine (TBZ) for HC. Methods The Enroll-HD database was used to perform a propensity score-matched comparison of risperidone and olanzapine to TBZ, regarding their efficacy in controlling chorea. Participants with motor manifest Huntington's disease (HD) were grouped according to their use of risperidone, olanzapine, or TBZ. For the three groups, independent propensity score matching was performed on participants' baseline total functional score (TFC), baseline total motor score (TMS), disease burden score, CAG repeat length, baseline age, region, sex, and body mass index. Independent samples t test was used to calculate the differences between the groups in the annual rate of change of the TMS from the baseline to the second available visit. Results The risperidone (n = 72) and olanzapine groups (n = 77) had annualized increases (worsening) in the TMS of only 1.47 points and 3.20 points, respectively, compared to 5.70 points in the two matched TBZ groups (n = 72) (P = 0.019) and (n = 77) (P = 0.143), respectively. Conclusions In the absence of prospective data, this analysis of the Enroll-HD database found that the neuroleptics risperidone and olanzapine seemed to at least be comparable to TBZ at controlling HC. These results demonstrate that neuroleptics may have comparable efficacy to TBZ for the treatment of HC. Further prospective studies are needed to confirm these findings.

An 88-year-old man presented with a 1-month history of altered mental status and seizures. His electrographic and imaging findings were suggestive of herpes simplex encephalitis (HSE), for which he was empirically treated with acyclovir. He underwent two lumbar punctures 3 days apart; both cerebrospinal fluid analyses tested negative for herpes simplex virus (HSV) by polymerase chain reaction (PCR). These negative results and his continued deterioration after 9 days of acyclovir therapy prompted treatment with steroids for possible autoimmune encephalitis. Shortly after the change in management, the patient died from cardiac arrest. At autopsy, his brain showed both gross and microscopic evidence of encephalitis and was positive for HSV by immunohistochemistry. This fatal case of HSE emphasizes the limitations of HSV PCR and the importance of clinical suspicion in the diagnosis and management of this disease.

ObjectiveTo determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation.MethodsIn this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression. Adjustments were made for CAG repeat length, total motor score, total functional capacity, Symbol Digit Modalities Test score, sex, disease duration, history of depression (when applicable), antipsychotic use, and antidepressant use.ResultsCompared to participants who were not using TBZ (n = 3,548), TBZ users (n = 543) did not have an increased risk of depression (odds ratio [OR] = 0.78, p = 0.064). Participants taking TBZ actually had a relatively lower risk of suicidality (OR = 0.61, p = 0.043). Among only participants with a history of depression, those using TBZ had a lower incidence of depression (OR = 0.71, p = 0.016) and suicidal ideation (OR = 0.57, p = 0.028) compared to those not using TBZ. Finally, among only participants with no history of depression, TBZ use was not associated with a higher incidence of depression (OR = 1.59, p = 0.18) or suicidality (OR = 1.43, p = 0.66) compared to those who were not using TBZ.ConclusionsTBZ use was not associated with an increased incidence of depression or suicidality. These findings suggest that TBZ may be safe to use in patients with Huntington disease who have a history of depression.

We thank Sampaio et al. for the comment on our article.1 The Enroll-HD dataset does not contain information regarding why participants abandoned a particular therapy.2 Therefore, making the assumption that abandonment of tetrabenazine (TBZ) therapy occurs secondary to depression/suicidality could falsely induce a spurious positive association between TBZ and depression/suicidality that is equally dangerous. Furthermore, participants who abandoned TBZ prior to their baseline visit were included in the TBZ nonuser group.1 If the assumptions being made by Sampaio et al. are accurate, then it is reasonable to assume that an increased percentage of participants in the TBZ nonuser group have a history of depression. However, the percentage of participants with a history of depression is nearly identical between the 2 groups,1 indicating that few participants discontinued TBZ due to depression/suicidality.

Background There is evidence to suggest that 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) may be beneficial in Huntington's disease (HD). Objective This study aimed to determine if statin use was associated with delayed motor diagnosis in participants with premotor HD. Methods Among premotor HD participants from the Enroll-HD database, statin users were propensity score matched with statin nonusers based on cytosine-adenine-guanine-age product score, cytosine-adenine-guanine repeat length, baseline age, sex, and region. A Cox regression survival analysis compared the annualized hazard ratio (HR) of receiving a motor diagnosis between the 2 groups. Results The annualized HR of progressing to an HD motor diagnosis was lower in the statin users (n = 89) when compared with the statin nonusers (n = 89; HR = 0.27 [95% CI 0.18-0.50], P Conclusions In patients with premotor HD, statin use was associated with a delayed motor diagnosis of HD. Further studies are warranted to investigate if statins would be an effective disease-modifying therapy for HD. © 2018 International Parkinson and Movement Disorder Society.

Therapeutic decision-making in Huntington's disease (HD) is often guided by clinical experience, because of the limited empirical evidence available. The only medication for HD that has met the regulatory hurdle for approval is tetrabenazine, indicated for the treatment of chorea. However, its use has limitations, and in the setting of specific contraindications or comorbidities the treatment of choice for chorea is still the multipurpose antipsychotics. For the management of psychiatric disturbances, selective serotonin reuptake inhibitors (SSRIs) and mood stabilizers are often used, although empirical evidence is lacking. Finally, no known effective treatment is available for cognitive dysfunction in HD. We discuss the limited evidence available and current expert opinion on medical treatment of the dominant motor, psychiatric, and cognitive features of HD. This follows a brief introduction on the general principles of HD management and on evidence-based medicine in relation to clinical practice. © 2014 International Parkinson and Movement Disorder Society

Objectives: We aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study. Methods: The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington’s Disease Rating Scale (UHDRS) by investigators unaware of participants9 gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27–35, and nonexpanded controls Results: Fifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group9s scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups. Conclusions: In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

Background By permitting remote assessments of patients and research participants, telemedicine has the potential to reshape clinical care and clinical trials for Parkinson disease. While the majority of the motor Unified Parkinson's Disease Rating Scale (UPDRS) items can be conducted visually, rigidity and retropulsion pull testing require hands-on assessment by the rater and are less feasible to perform remotely in patients' homes. Methods In a secondary data analysis of the Comparison of the Agonist pramipexole vs. Levodopa on Motor complications in Parkinson's Disease (CALM-PD) study, a randomized clinical trial, we assessed the cross-sectional (baseline and 2 years) and longitudinal (change from baseline to 2 years) reliability of a modified motor UPDRS (removing rigidity and retropulsion items) compared to the standard motor UPDRS (all items) using intraclass correlation coefficients (ICC), stratified by treatment group. Internal consistency of the modified UPDRS (mUPDRS) was measured using Cronbach's alpha, and concurrent validity was assessed using Pearson's correlation coefficient (r) between the standard motor UPDRS and mUPDRS. Results The mUPDRS versus standard motor UPDRS is cross-sectionally (ICC ≥ 0.92) and longitudinally (ICC ≥ 0.92) reliable for both treatment groups. High internal consistencies were also observed (α ≥ 0.96). The mUPDRS had high concurrent validity with the standard UPDRS at both time points and longitudinally (r ≥ 0.93, p Conclusions A modified version of the motor UPDRS without rigidity and retropulsion pull testing is reliable and valid and may lay the foundation for its use in remote assessments of patients and research participants.

Disulfide oxidoreductases are viewed as foldases that help to maintain proteins on productive folding pathways by enhancing the rate of protein folding through the catalytic incorporation of disulfide bonds. SrgA, encoded on the virulence plasmid pStSR100 of Salmonella enterica serovar Typhimurium and located downstream of the plasmid-borne fimbrial operon, is a disulfide oxidoreductase. Sequence analysis indicates that SrgA is similar to DsbA from, for example, Escherichia coli , but not as highly conserved as most of the chromosomally encoded disulfide oxidoreductases from members of the family Enterobacteriaceae . SrgA is localized to the periplasm, and its disulfide oxidoreductase activity is dependent upon the presence of functional DsbB, the protein that is also responsible for reoxidation of the major disulfide oxidoreductase, DsbA. A quantitative analysis of the disulfide oxidoreductase activity of SrgA showed that SrgA was less efficient than DsbA at introducing disulfide bonds into the substrate alkaline phosphatase, suggesting that SrgA is more substrate specific than DsbA. It was also demonstrated that the disulfide oxidoreductase activity of SrgA is necessary for the production of plasmid-encoded fimbriae. The major structural subunit of the plasmid-encoded fimbriae, PefA, contains a disulfide bond that must be oxidized in order for PefA stability to be maintained and for plasmid-encoded fimbriae to be assembled. SrgA efficiently oxidizes the disulfide bond of PefA, while the S. enterica serovar Typhimurium chromosomally encoded disulfide oxidoreductase DsbA does not. pefA and srgA were also specifically expressed at pH 5.1 but not at pH 7.0, suggesting that the regulatory mechanisms involved in pef gene expression are also involved in srgA expression. SrgA therefore appears to be a substrate-specific disulfide oxidoreductase, thus explaining the requirement for an additional catalyst of disulfide bond formation in addition to DsbA of S. enterica serovar Typhimurium.

If gene therapy is to be an effective treatment modality for hemophilia A, therapeutic levels and tissue-restricted expression of factor VIII (FVIII) must be achieved through optimization of transgene expression. To this end, we incorporated three types of sequence elements into a canine B domain-deleted FVIII transgene cassette and individually evaluated their effect on FVIII transgene expression. Functional FVIII activity was initially assessed in vitro and hydrodynamic injection of the different transgene constructs into mice was subsequently used as a model to compare in vivo expression of the various modified transgenes. Our results demonstrate that in vitro transgene expression is, in these studies, not a good predictor of in vivo transgene performance. In vivo analysis of a hybrid tissue-restricted promoter element, consisting of a concatemer of five hepatocyte nuclear factor 1 (HNF-1) consensus-binding motifs juxtaposed to the human FVIII proximal promoter, indicates that it is as efficient at mediating expression of the FVIII protein as the cytomegalovirus promoter. Addition of the full-length canine FVIII 3'-UTR also enhances transgene expression of FVIII in vivo. Sequence analysis of the canine FVIII 3'-UTR and human FVIII 3'-UTR indicates that the former lacks instability sequences and may therefore be more effective in stabilizing FVIII mRNA. Subsequent inclusion of FVIII introns 16 and 17 into the natural locations of the transgene disrupted mRNA processing and abolished expression of the FVIII protein. Introduction of intron 17 proximal to the FVIII cDNA did not enhance in vivo expression of canine FVIII from the transgene.

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder, typically affecting young middle-aged individuals. It is characterized by progressive decline in motor, psychiatric and cognitive functioning. These features, which lead to progressive disability and death, are managed symptomatically and supportively, with limited benefit. In North America, there are approximately 30,000 individuals affected with HD and another 150,000 thought to be genetically at risk for developing the disease. At-risk individuals may undergo predictive genetic testing while still ‘pre manifest’, prior to a clinical motor diagnosis (which is subjectively determined by physical examination findings). However, the pathologic processes are believed to start up to 20 years prior to clinical diagnosis. Therefore, the ultimate research goal for HD therapeutics is to develop a disease-modifying treatment that would be started in the premanifest period with the aim of delaying (or even preventing) the development of clinical manifestations and functional disability. In those already exhibiting signs of HD, such disease-modifying treatment would function to slow the progression of the disease. The ability to identify individuals years prior to clinical diagnosis through the availability of predictive gene testing makes HD an ideal condition in which to study potential diseasemodifying therapeutics. However, evaluation of these treatments requires objective outcome measures to track progression in efficacy trials. The Unified Huntington’s Disease Rating Scale is commonly used in HD research. However, it is subjective, often insensitive to subtle changes, as well as susceptible to bias and intraand inter-rater variability [1]. For subjects in the premanifest HD period, there may be no or limited appreciable clinical findings on examination. Ultimately, the benefit of treatment in

OPINION STATEMENT: There is no specific treatment for Huntington's disease (HD). Its many symptoms of motor, psychiatric, and cognitive deterioration are managed with symptomatic relief, rehabilitation, and support. The only drug approved by the US Food and Drug Administration (FDA) for the treatment of HD is an antichoreic agent, tetrabenazine, but this drug is used sparingly because of uneasiness regarding its propensity to cause depression and suicidality in this population, which is already at risk for these complications. Neuroleptics are still first-line treatments for chorea accompanied by comorbid depression and/or behavioral or psychotic symptoms, as is often the case. Psychiatric features, which have a significant impact on a patient's professional and personal life, often become the major focus of management. In addition to neuroleptics, commonly used medications include antidepressants, mood stabilizers, anxiolytics, and psychostimulants. In contrast, few treatment options are available for cognitive impairment in HD; this remains an important and largely unmet therapeutic need. HD patients typically lack insight into their disease manifestations, failing to recognize their need for treatment, and possibly even arguing against it. Multipurpose medications are employed advantageously to simplify the medication regimen, so as to facilitate compliance and not overwhelm the patient. For example, haloperidol can be prescribed for a patient with chorea, agitation, and anorexia, rather than targeting each symptom with a different drug. This approach also limits the potential for adverse effects, which can be difficult to distinguish from the features of the disease itself. With HD's complexity, it is best managed with a multidisciplinary approach that includes a movement disorders specialist, a genetic counselor, a mental health professional, a physical therapist, and a social worker for support and coordination of services. As the disease progresses, there may be need for other specialists, such as a speech and occupational therapist, a nutritionist for weight loss, and ultimately, a palliative care specialist.

This report describes the case of a 4 1/2-year-old female with developmental delay and tonic-clonic seizures, persistently elevated serum alkaline phosphatase activity, and low serum pyridoxal 5'-phosphate. Born at term to consanguineous parents, she was dysmorphic and delayed at 5 months. At 11 months, seizures and microcephaly were evident but skeletal and cerebral imaging, karyotyping, and genetic metabolic tests were unremarkable. Serum alkaline phosphatase activity, however, was elevated (1.3 +/- 0.6 times greater than the upper limit of normal) on seven occasions between 5 months and 4(1/2) years of age. Hyperphosphatasia with neurologic deficit (MIM #239300), a rare autosomal recessive disorder, was diagnosed. The low serum levels of pyridoxal 5'-phosphate (6 nmol/L; normal >20 nmol/L) prompted a pyridoxine challenge. A clinically significant but paradoxical response was observed. On electroencephalography, diffuse delta slow waves (1-2 Hz) were observed, suggestive of stage 3 or 4 slow-wave sleep. With daily administration of 100 mg pyridoxine and withdrawal of phenobarbital, seizures were not evident. We suggest that serum alkaline phosphatase should be measured in cases of seizures with paradoxical electroencephalographic response to pyridoxine. Conversely, pyridoxine challenge should be considered in cases of hyperphosphatasia with seizures and neurologic deficit.

Objective: To explore the behavioral phenotype of individuals with an intermediate CAGn expansion in a cohort of subjects at-risk for Huntington disease (HD). Background Recent reports suggest that some individuals with intermediate CAGn repeat expansions in the huntingtin gene develop manifest HD (Mov Disord 2007;22:127). We previously demonstrated that PHAROS participants with the intermediate alleles had behavioral scores on the Unified Huntington Disease Rating Scale 999 (UHDRS 999) similar to gene expanded participants. We now further explore the behavioral features associated with the intermediate CAGn expansion. Design/Methods: Subjects at-risk for HD in the Prospective Huntington At Risk Observational Study (PHAROS) were assessed in all domains of the UHDRS by investigators unaware of participant gene status. Data were analyzed according to CAG repeat length: expanded > 36, intermediate = 27- 35, and non-expanded 39). Pair-wise analyses compared individual behavioral items of the UHDRS. Results: Of the 983 participants analyzed, 50 (5.2%) had an intermediate repeat expansion, 346 (35.1%) were expanded, and 587 (59.7%) were non-expanded. Like those with an expanded allele, participants with an intermediate expansion scored high on the UHDRS measure of apathy.Low self esteem/guilt and irritability were also increased in the intermediate repeat group, and approached the gene expanded group in this regard. Conclusions: In a cohort of individuals at-risk for HD, those with an intermediate CAGn expansion were motorically, cognitively and functionally similar to those without the gene expansion. However, they exhibited apathy and a tendency towards other behavioral abnormalities comparable to the gene expanded group. Though traditionally considered non-pathologic, the intermediate repeat length may manifest as a distinctly behavioral phenotype. Future studies in larger populations of individuals with intermediate CAGn expansions are needed to confirm these findings. Supported by: Huntington Study Group. Disclosure: Dr. Killoran has nothing to disclose. Dr. Biglan has received personal compensation for activities with Lundbeck and Theravance Inc as a consultant. Dr. Biglan received research support from Presbyterian Home of Central New York, Susquehana Nursing and Rehabilitation Center, Marvell Inc, and Google. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc. Dr. Eberly has nothing to disclose. Dr. Kayson has nothing to disclose. Dr. Oakes has received personal compensation in an editorial capacity for the journal "Lifetime Data Analysis". Dr. Young has received royalty payments from Novartis. Dr. Young has received research support from Novartis. Dr. Shoulson has received personal compensation for activities with AstraZeneca, Keryx Pharmaceuticals, Jazz Pharmaceuticals, Neurogen Corp, Alexa Molecular Delivery Corp, Nouvel Pharma, Novartis, and Westat. Dr. Shoulson has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Shoulson has received research support from NIH, NHGRI, NINDS, Cephalon, Inc., Pharmacia and Upjohn, Inc. (Pfizer), Parallel Group, and Prestwick Pharmaceuticals, Inc.