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Background and purpose Postconcussive vestibular and ocular motor symptoms are common and contribute to longer recovery. The Vestibular/Ocular Motor Screening (VOMS) is used to detect such symptoms, but a VOMS performed at rest may miss symptoms that are only provoked by exertion. Supervised exercise challenges (SECs) have been shown to detect concussion-related symptoms provoked by physical exertion. The purpose of this study was to determine whether athletes undergoing an SEC will exhibit greater symptom provocation with the VOMS compared to a VOMS performed at rest prior to an SEC. Methods Thirty-six athletes (58.3% male) between ages 10 and 18 years and within 30 days of concussion were included. All participants completed VOMS assessments at rest and immediately after an SEC. VOMS total symptom score increases were calculated for both pre- and post-SEC assessments compared using Wilcoxon ranked sum tests. The frequencies of positive assessments for each VOMS item were compared using McNemar's test. Results There were significant increases in post-SEC symptom provocation scores compared with pre-SEC scores for all VOMS items. The post-SEC VOMS identified 29 participants (80.6%) as positive in at least 1 VOMS item compared with 21 participants (58.3%) identified as positive pre-SEC (P = 0.008). For all VOMS items, the post-SEC VOMS identified participants who were previously negative on a pre-SEC VOMS but became positive after the SEC. Discussion and conclusions An SEC performed prior to a VOMS assessment may increase the detection of vestibular and ocular motor symptoms that may be missed if the VOMS was performed only at rest.Video Abstract available for more insight from the authors (see the Video Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A342).

Context Supervised exercise challenges (SECs) have been shown to be safe and beneficial in the early symptomatic period after concussion. Thus far, most in-clinic SECs studied have included a form of basic aerobic exercise only. An SEC that also includes dynamic forms of exercise mimics all steps of a standard return-to-play progression and may enhance the detection of concussion symptoms to guide in-clinic management decisions. Objective To determine whether an SEC that includes a dynamic SEC (DSEC) uncovered symptoms that would not have been identified by an SEC involving an aerobic SEC (ASEC) alone in adolescent patients with sport-related concussion. Design Retrospective case series. Setting Multidisciplinary sport concussion clinic at a tertiary care center. Patients or Other Participants A total of 65 adolescent athletes (mean age = 14.9 ± 2.0 years, 72.3% males) who underwent an in-clinic SEC within 30 days of concussion. Main Outcome Measure(s) Presence of pre-exercise symptoms and symptom provocation during the SEC were recorded, with exercise-provoked symptoms categorized as occurring during ASEC or DSEC. Results Of the total patient sample, 69.2% (n = 45/65) experienced symptom provocation at some point during the SEC. Symptoms were provoked in 20 patients during the ASEC, whereas 25 completed the ASEC without symptom provocation before becoming symptomatic during the subsequent DSEC and 20 completed the SEC without any symptom provocation. Of the 65 patients in the total sample, 46 were asymptomatic immediately before the SEC. Of these previously asymptomatic patients, 23.9% (n = 11/46) experienced symptom provocation during the ASEC, and an additional 37.0% (n = 17/46) remained asymptomatic during the ASEC but then developed symptoms during the DSEC. Conclusions The ASEC alone may not detect symptom provocation in a significant proportion of concussion patients who otherwise would develop symptoms during a DSEC.

OBJECTIVEPrevious studies have shown that clinically asymptomatic high-acceleration head impacts (HHIs) may be associated with neuronal and axonal injury, as measured by advanced imaging and biomarkers. Unfortunately, these methods of measurement are time-consuming, invasive, and costly. A quick noninvasive measurement tool is needed to aid studies of head injury and its biological impact. Quantitative pupillometry is a potential objective, rapid, noninvasive measurement tool that may be used to assess the neurological effects of HHIs. In this study, the authors investigated the effect of HHIs on pupillary metrics, as measured using a pupillometer, in the absence of a diagnosed concussion.METHODSA prospective observational cohort study involving 18 high school football athletes was performed. These athletes were monitored for both the frequency and magnitude of head impacts that they sustained throughout a playing season by using the Head Impact Telemetry System. An HHI was defined as an impact exceeding 95g linear acceleration and 3760 rad/sec2 rotational acceleration. Pupillary assessments were performed at baseline, midseason, after occurrence of an HHI, and at the end of the season by using the NeurOptics NPi-200 pupillometer. The Sport Concussion Assessment Tool, 5th Edition (SCAT5), was also used at each time point. Comparisons of data obtained at the various time points were calculated using a repeated-measures analysis of variance and a t-test.RESULTSSeven athletes sustained HHIs without a related diagnosed concussion. Following these HHIs, the athletes demonstrated decreases in pupil dilation velocity (mean difference 0.139 mm/sec; p = 0.048), percent change in pupil diameter (mean difference 3.643%; p = 0.002), and maximum constriction velocity (mean difference 0.744 mm/sec; p = 0.010), compared to measurements obtained at the athletes’ own midseason evaluations. No significant changes occurred between the SCAT5 subtest scores calculated at midseason and those after a high impact, although the effect sizes (Cohen’s d) on individual components ranged from 0.41 to 0.65.CONCLUSIONSMeasurable changes in pupil response were demonstrated following an HHI. These results suggest that clinically asymptomatic HHIs may affect brain reflex pathways, reflecting a biological injury previously seen when more invasive methods were applied.

Concussions after a head injury among children continues to be a substantial public health concern. An increasing number of concussions are being managed initially by primary care physicians. The diagnosis of concussion remains a clinical diagnosis despite the availability of ancillary tests such as computerized neuropsychological testing, advanced imaging, and blood biomarkers. Clinically, overlooking other injuries and comorbidities may lead to prolonged recovery for the patient. Addressing concussions in a multidisciplinary approach may help in reducing recovery time for patients. Retirement from sport in the pediatric population remains a controversial issue lacking evidenced-based studies.

We investigated sex-based differences in the presence and severity of aggregated symptom indicators as well as individual concussion symptoms.Materials and Methods: A cross-sectional examination of sex differences in symptoms reported by adolescents upon initial concussion evaluation at a concussion clinic. Nine hundred and eighty-six adolescents completed the Sport Concussion Assessment Tool (SCAT5) symptom checklist. Chi-square and Mann-Whitney U tests were used for differences in the presence and severity of symptoms, respectively. Sex differences in global indices of symptom distress were compared.Results: Females endorsed more symptoms (Female: Median (M)=15, Interquartile range (IQR):9-18 vs. Male: M=11, IQR: 6-15, p

ObjectiveTo assess the safety of supervised exercise (SE) in acute sport related concussion (SRC), and explore its influence on recovery.BackgroundPrevious guidelines for the management of SRC have suggested complete physical and cognitive rest until asymptomatic, while he 2017 Berlin consensus statement now suggests return to light activity after 24–48 hours. The influence of early exercise on recovery following SRC remains unclear, and there is little evidence regarding its safety or efficacy.Design/methodsRetrospective chart review of 124 patients with SRC who presented to a university sports neurology clinic within 30 days of injury between September 2016 and January 2017. Symptomatic patients who initiated SE within 16 days of injury were compared to those who did not undergo SE or initiated SE later than post-injury day 16 using Cox regression. The regression model controlled for multiple covariates including age, sex, history of previous concussions, injury severity, relevant co-morbidities, and other treatments received.ResultsNo serious adverse events were observed in the early SE group. Furthermore, early SE was associated with earlier return to sport (hazard ratio = 2.35, p = 0.030), and the early SE group had fewer days from SRC until clearance for return to sport (mean 26.5 ± 11.2 days vs 35.1 ± 26.5 days, p = 0.020). There also was a non-significant trend toward fewer asymptomatic days in the early SE compared to non-early SE groups (mean 16.7 ± 7.1 days vs 22.4 ± 22.5 days, p = 0.054).ConclusionEarly SE performed in the acute symptomatic stage of SRC was safe and was associated with earlier return to sport.

Concussion represents the immediate and transient symptoms of a mild traumatic brain injury (TBI),1 and is defined as a clinical syndrome of biomechanically induced alteration of brain function.2 The term “concussion” is often used interchangeably with “mild traumatic brain injury.”1

OBJECTIVE To examine the factor structure of the Sport Concussion Assessment Tool-5 (SCAT5) symptom scale in adolescents on their initial presentation to a concussion clinic within the typical recovery period after concussion (ie

Purpose To examine interrelationships among Vestibular/Ocular-Motor Screen (VOMS) items and to characterize the recovery of VOMS performance in a sample of adolescents treated with vestibular physical therapy (VPT) after concussion. Methods Seventy-seven patients with concussion and 77 participants without concussion completed the study. Adolescents with concussion received an individualized VPT intervention consisting of targeted exercises for gaze stability, postural stability, ocular-motor control, habituation, and aerobic activities. The exercises were performed during a weekly clinic visit and via a home exercise program. Results Except for near-point convergence distance, all VOMS items were significantly interrelated. Over the course of VPT, significant improvements in VOMS performance were observed, and discharge scores were similar to scores observed in adolescents without concussion. Conclusions The VOMS measured moderately related functions and captured changes over the course of VPT. Clinicians should consider the contextual risk of "false positive" in their interpretation of VOMS.

Rationale and Objectives Infectious encephalitis is a relatively common cause of morbidity and mortality. Treatment of infectious encephalitis with antiviral medication can be highly effective when administered promptly. Clinical mimics of encephalitis arise from a broad range of pathologic processes, including toxic, metabolic, neoplastic, autoimmune, and cardiovascular etiologies. These mimics need to be rapidly differentiated from infectious encephalitis to appropriately manage the correct etiology; however, the many overlapping signs of these various entities present a challenge to accurate diagnosis. A systematic approach that considers both the clinical manifestations and the imaging findings of infectious encephalitis and its mimics can contribute to more accurate and timely diagnosis. Materials and Methods Following an institutional review board approval, a health insurance portability and accountability act (HIPAA)-compliant search of our institutional imaging database (teaching files) was conducted to generate a list of adult and pediatric patients who presented between January 1, 1995 and October 10, 2013 for imaging to evaluate possible cases of encephalitis. Pertinent medical records, including clinical notes as well as surgical and pathology reports, were reviewed and correlated with imaging findings. Clinical and imaging findings were combined to generate useful flowcharts designed to assist in distinguishing infectious encephalitis from its mimics. Key imaging features were reviewed and were placed in the context of the provided flowcharts. Results Four flowcharts were presented based on the primary anatomic site of imaging abnormality: group 1: temporal lobe; group 2: cerebral cortex; group 3: deep gray matter; and group 4: white matter. An approach that combines features on clinical presentation was then detailed. Imaging examples were used to demonstrate similarities and key differences. Conclusions Early recognition of infectious encephalitis is critical, but can be quite complex due to diverse pathologies and overlapping features. Synthesis of both the clinical and imaging features of infectious encephalitis and its mimics is critical to a timely and accurate diagnosis. The use of the flowcharts presented in this article can further enable both clinicians and radiologists to more confidently differentiate encephalitis from its mimics and improve patient care.

Cervical musculoskeletal and neuromuscular attributes, which may vary between men and women, influence an individual's capacity to stabilize the head.To examine sex differences in cervical musculoskeletal and neuromuscular attributes and their impact on head stability. The secondary objective was to examine the effects of anticipation and preload on head kinematics.Thirty-four (20 men, 14 women) recreationally active adult athletes completed a perturbation protocol with anticipation and preloading conditions in this descriptive cross-sectional study. We assessed the neuromuscular response of the sternocleidomastoid to perturbation and head kinematics. We measured neck girth, sternocleidomastoid physiological cross-sectional area, and isometric strength.Women had smaller neck girth, smaller sternocleidomastoid physiological cross-sectional area, and lower isometric strength than men. Women had greater baseline electromyography (EMG) amplitude and greater peak EMG response than men. There were no sex differences in sternocleidomastoid onset latency or head kinematics. Women had a greater increase in baseline EMG amplitude after preloading and anticipated conditions. Preloading attenuated sex differences in muscle onset latency. Across the sexes, there was a significant main effect of anticipation on head kinematics.Men and women used different strategies to stabilize the head, and responded differently to the preloading and anticipation conditions.

Copper is a required cofactor for enzymes in critical metabolic pathways. Mutations in copper metabolism genes or abnormalities in copper metabolism result in disease from copper excess or deficiency. Wilson disease (WD) is an autosomal-recessive disease caused by mutations in the ATP7B gene which encodes a copper-transporting ATPase. Over 500 different WD mutations throughout the ATP7B gene have been described, most of which are missense mutations. Mutations in both ATP7B alleles result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic WD include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Misdiagnosis and delay in treatment are clinically relevant because untreated WD progresses to hepatic failure or severe neurologic disability and death. Treatment can prevent and cure WD. Mutations in a second, closely related copper-transporting ATPase, ATP7A, cause a spectrum of copper deficiency disorders that include Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy. Two important, nongenetic causes of copper deficiency myeloneuropathy are copper deficiency following gastric bypass or due to excess zinc ingestion, both of which can cause a myeloneuropathy similar to vitamin B12 deficiency. Copper deficiency following gastric bypass is preventable, and identification and elimination of the excess zinc source, most commonly dental cream, can result in recovery.

Background The majority of studies examining the role of cervical muscles on head-neck kinematics focused on musculoskeletal attributes (e.g. strength). Cervical neuromuscular response to perturbation may represent a divergent construct that has not been examined under various perturbation conditions. This study examined the association between cervical musculoskeletal attributes and cervical neuromuscular response of the sternocleidomastoid (SCM) to perturbation. Furthermore, this study examined the effect of anticipation and preload on the SCM neuromuscular response. Methods Nineteen participants completed measurement of SCM muscle size, cervical flexion maximal voluntary isometric contraction, and the neuromuscular response of the SCM to cervical perturbation. Cervical perturbation was delivered by dropping a 1.59 kg mass from a loading apparatus. The impulsive load was delivered under four conditions: (1) Anticipated perturbation with no preload (A-NP), (2) Unanticipated perturbation with no preload (U-NP), (3) Anticipated perturbation with preload (A-P), and (4) Unanticipated perturbation with preload (U-P). Results None of the cervical musculoskeletal attributes were correlated with the SCM cervical neuromuscular response. This study demonstrated significant effect of preloading and anticipation on baseline EMG amplitude and EMG onset latency for the SCM. Furthermore, there was a significant effect of preloading on average EMG response amplitude for the SCM. Discussion The findings of this study indicate that cervical neuromuscular response of the SCM is different from musculoskeletal attributes and is influenced by perturbation conditions. These findings provide conceptual support to examine the neuromuscular response of the SCM in mitigating head-neck kinematics.

OBJECTIVEThe authors of recent concussion guidelines have sought to form a consensus on injury management, but it is unclear if they have been effective in conveying this information to the public. Many parents and athletes obtain medical recommendations via the Internet. This review is aimed at evaluating consistency between online resources and published guideline statements in postconcussion return-to-play (RTP) decisions.METHODSFive websites were selected through a Google search for RTP after concussion, including a federal government institution (Centers for Disease Control and Prevention) website, a national high school association (National Federation of State High School Associations) website, a popular nationally recognized medical website for patients (WebMD), a popular parent-driven website for parents of children who participate in sports (MomsTeam), and the website of a private concussion clinic (Sports Concussion Institute), along with a university hospital website (University of Michigan Medicine). Eight specific items from the Zurich Sport Concussion Consensus Statement 2012 were used as the gold standard for RTP recommendations. Three independent reviewers graded each website for each of the 8 recommendations (A = states guideline recommendations appropriately; B = mentions guideline recommendation; C = does not mention guideline recommendation; F = makes inappropriate recommendation).RESULTSA grade of A was assigned for 45.8% of the recommendations, B for 25.0%, C for 25.0%, and F for 4.2%. All the websites were assigned an A grade for the recommendation of no RTP on the day of injury. Only 1 website (WebMD) mentioned medication usage in conjunction with the Zurich statement, and only 2 websites (Sports Concussion Institute and University of Michigan Medicine) mentioned appropriate management of persistent symptoms. None of these websites commented correctly on all 8 guideline recommendations.CONCLUSIONSOnline resources are inconsistent in relaying guideline recommendations for RTP and provide a potential source of confusion in the management of concussion for athletes and their parents, which can result in inappropriate RTP decisions.

ObjectiveTo understand which exercises provoke symptoms, as well as the type and frequency of symptoms, during supervised exercise (SE) following concussion, and to better understand how to interpret and utilize findings during SE.BackgroundExercise is increasingly used in the management of sport-related concussion, and SE has been shown to be associated with faster clearance to return to sport. However, the optimal use of exercise following concussion is not known, and findings during SE have not been studied.Design/MethodsThis study is a retrospective review of patients seen at a sport concussion clinic. Participants were concussed athletes under age 18 who underwent SE within 30 days of concussion. A typical SE session began with a basic cardiovascular exercise followed by dynamic exercise challenges. Data recorded included exercise type, pre-exercise symptoms, symptom exacerbation scores, and maximum heart rate during exercise. A symptom was considered provoked if a new symptom developed or if an existing symptom increased by ≥3 points on a 10 point scale. Outcome measures were referral to vestibular physical therapy and the number of days from concussion until clearance for return to sport. Data were analyzed using two-sample t tests, linear and logistic regression models.Results66.2% of patients experienced symptom provocation during SE. Symptom provocation did not occur until the dynamic challenge portion of the workout in 55.6% of those symptomatic. Dizziness was the most common symptom (48.5%), and medicine ball exercises (50.0%) the most common provoking exercise. Dizziness provoked during SE predicted referral to vestibular physical therapy (OR 5.90, p = 0.015). Provocation of symptoms during basic cardiovascular exercises predicted a greater number of days until clearance for return to sport (p = 0.015).ConclusionsSymptom provocation during SE provides useful information in return to play decision making, guidance for physical thearpy treatments, and prognostication of recovery time following concussion.

ObjectiveTo determine if completion of a symptom free return to play progression (RTPP) was associated with a symptom free return to sport. A secondary analysis investigated symptom free return to sports participation following supervised exercise.BackgroundThe current consensus statement on concussion in sport recommends a graded return-to-sport strategy but there is limited data on the utility of this approach.Methods200 sequential clinic patients with physician-diagnosed concussion sustained during sport participation were contacted by phone following completion of care from a University-associated Sports Neurology clinic. A survey about their success in returning to their sport was administered. Standardized data elements were extracted from the medical records and analyzed. The study was approved by the university of Michigan Institutional Review Board.ResultsThe survey was completed on 61 (31%) patients. Of these, 57 (93%) returned to sport participation without symptom reoccurrence. Of those who returned to sport 41 (80%) returned to sport without symptom reoccurrence within 2 weeks of completed clinical care. 53 (87%) completed a RTPP and 49 (92%) of those completing a RTPP returned to sport without symptom reoccurrence. Completing a RTPP, compared to those not completing a RTPP, was significantly associated with return to sport participation without symptom reoccurrence (p = 0.0000001). Of those surveyed, 32 (52%) underwent supervised exercise (SE) as part of their clinical care. Completing SE, as compared to those not undergoing SE, was significantly associated with return to sport participation without symptom reoccurrence (p = 0.017).ConclusionsOur results support recommendations for utilizing graded return-to-sport strategy demonstrating that 92% of those completing a RTPP successfully returned to sport. Our data also suggest that completion of SE was a predictor of symptom free return to sport and can be incorporated in to return to play decision making.

As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective.

Importance Chronic traumatic encephalopathy (CTE) refers to pathologic changes that have been found in some individuals with a history of repetitive traumatic impact to the head (hereinafter referred to as head trauma). These changes cannot be assessed during the clinical evaluation of a living patient. Observations The neuropathologic features, taxonomy, history, role of biomarkers in diagnosis, and existing criteria of CTE are reviewed. Previous criteria have been proposed to approach the living patient; however, a unified, specific approach is needed for the practicing clinician. We propose a new diagnostic construct for the clinical syndrome associated with repetitive exposure to head trauma: traumatic encephalopathy syndrome. This clinical paradigm will provide the framework for a diagnosis of probable, possible, and unlikely traumatic encephalopathy syndrome, with included discussion regarding the minimum exposure, nature of the clinical course, and additional clinical features needed for diagnosis. Conclusions and Relevance While prospective longitudinal studies are ongoing to further elucidate the association of exposure to head trauma, clinical features, and the development of pathologic changes, a corresponding clinical construct for diagnosis is necessary.

The triad of leukoencephalopathy, cerebral calcifications, and ysts (LCC) represents a very rare, and distinct clinico-radiologic ntity of unknown etiology, first described in children by Labrune t al. [1] in 1996. The onset ranges from infancy to adults 1–5], with varying clinical presentations including a combinaion of mild cognitive dysfunction or normal intelligence, seizures, erebellar, pyramidal and extrapyramidal signs. The disorder s characterized by diffusely progressive basal ganglia, brain tem and subcortical white matter calcifications, cerebellar, and upratentorial parenchymal cysts, as well as diffusely abnormal 2-weighted sequences on MRI [1–4]. The white matter abnoralities were described as a leukoencephalopathy rather than demyelinating process (leukodystrophy) [2]. Histopathologic xamination reveals angiomatous-like blood vessels, gliosis, and eaded, corkscrew-shaped intracytoplasmic inclusions typically ssociated with highly gliotic tissue surrounding cysts and vascuar malformations (Rosenthal fiber formation) in the white matter 1,3,4]. Complications are typically a consequence of mass effect ncluding cerebral edema leading to intracranial hypertension, apilledema, syringomyelia and eventually tonsillar herniation [4].

Parkinson's disease (PD) is a significant neurodegenerative disease of the elderly, affecting 1 to 2% of those over 60 years of age. The disorder is characterized by resting tremor, bradykinesia, rigidity, postural instability, and pathologically by alpha-synuclein-positive Lewy bodies. For most, the etiology is unknown and it is likely due to a multifactorial interaction of genes and the environment. In a minority, a clear environmental, toxic, or genetic etiology is determined. Six genes have been identified to cause diseases often indistinguishable from sporadic PD. Although accounting for only 1 to 3% of PD, the identification of single genes that cause PD clearly indicate that PD can have solely genetic causes. In addition to single-gene mutations, large familial aggregation and twin studies demonstrate a modest genetic component in idiopathic PD.

FDG (fluorodeoxyglucose) PET (positron emission tomography) is a useful tool in the clinical workup of patients being evaluated for dementing illnesses. It is particularly effective at differentiating primary neurodegenerative diseases such as Alzheimer disease from alternative considerations including frontotemporal dementia. We present the case of a patient with peripartum antibody-mediated voltage-gated potassium channel encephalitis whose FDG PET findings were suggestive of frontotemporal dementia-like disorder. Voltage-gated potassium channel antibody-mediated encephalitis is an increasingly described clinical phenomenon whose presentation may mimic primary neurodegenerative diseases.

Wilson disease patients present with any of several neurologic phenotypes, and their treated outcomes vary widely. Our goal was to determine whether presenting clinical features of neurologic Wilson disease (WD) predict longer term neurologic outcomes in patients receiving anticopper treatment.Patients enrolled in four WD treatment trials received a standardized neurologic examination at trial enrollment and then at pre-specified intervals following anticopper therapy, initially with tetrathiomolybdate or trientine and then with zinc. The examination scored patients' motor signs, including tremor, rigidity, dystonia, dyarthria, and gait. The Total Score was obtained by summing these subscores. Eighty-six patients were included in our analysis, with a mean follow-up of 34.7 months. Retrospectively, the analysis compared scaled and unscaled sign subscores at enrollment and follow-up with change in the Total Score, using a generalized estimating equations approach.In the primary analysis, improvement in the Total Score was best predicted by sign subscores for tremor (beta -0.7, p = 0.006), gait abnormalities (beta -3.7, p 0.001), and speech (beta = -1.3, p = 0.05). Dystonia (beta = 1.8, p 0.001) and facial expression (beta = 1.9, p = 0.03) were associated with worsening Total Score. Of the motor signs followed individually, dystonia proved most resistant to treatment.This is the first large-scale prospectively acquired study assessing prognostic significance of specific neurologic signs in WD. Our data support the historical observations that tremor is a favorable prognostic sign while dystonia is relatively refractory to treatment in WD.

It has become clear that serum "free" copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance-if they worsen neurologically as often happens with penicillamine or trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than trientine. In the trientine arm of study 2, mean free copper levels actually went up during trientine therapy. The 5 patients who neurologically worsened on trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way "away from food" tetrathiomolybdate was given.

Background: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to trientine for the initial therapy of neurologic Wilson's disease.

Background Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurodegenerative disorder caused by 27-sterol hydroxylase (CYP27) deficiency. Objective To describe clinical features and results of genetic analysis in a family with CTX. Design Case report. Setting University hospital. Subjects A 54-year-old woman with CTX, her family members, and 115 white control subjects. Main Outcome Measures Results of clinical evaluation and magnetic resonance imaging of the brain in the affected subject; results of mutation analysis of the CYP27 coding sequence in the patient, her parents, and the control subjects. Results The proband and her affected sibling had classic features of CTX, including presenile cataracts, tendon xanthomas, diarrhea, and a complex neurodegenerative disorder. They were somewhat atypical, however, because their cataracts were congenital, cognitive impairment had been noted in childhood, and the white matter involvement was more severe than usual. The proband was shown to be homozygous for CYP27 mutation R362C. Similar analysis of 115 control subjects identified 1 subject who was a heterozygous carrier for this same CYP27 mutation. Conclusions The prevalence of CTX due to CYP27 mutation R362C alone is approximately 1 per 50 000 among white individuals. Although the disorder is rare, this incidence is substantially greater than previously recognized. Greater awareness of CTX is important because specific treatment is available.

Objective: To compare tetrathiomolybdate and trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. Design:A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received50mgofzinc2timesperday.Patientswerehospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. Setting: A university hospital referral setting. Patients:Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Intervention:Treatment with either trientine plus zinc or tetrathiomolybdate plus zinc. Main Outcome Measures: Neurologic function was assessed by semiquantitative neurologic and speech examinations.Drugadverseeventswereevaluatedbyblood cell counts and biochemical measures. Results: Six of 23 patients in the trientine arm and 1 of 25patientsinthetetrathiomolybdatearmunderwentneurologic deterioration (P.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving trientine had an adverse effect of anemia.Fourpatientsreceivingtrientinediedduringfollow-up, 3 having shown initial neurologic deterioration.Neurologicandspeechrecoveryduringa3-yearfollow-up period were quite good. Conclusion:Tetrathiomolybdate is a better choice than trientine for preserving neurologic function in patients who present with neurologic disease. ClinicalTrials.gov Identifier: NCT00004339