Management of CLN1 Disease: International Clinical Consensus.

BACKGROUND: CLN1 disease (neuronal ceroid lipofuscinosis type 1) is a rare, genetic, neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase 1 (PPT1) enzyme deficiency. Clinical features include developmental delay, psychomotor regression, seizures, ataxia, movement disorders, visual impairment, and early death. In general, the later the age at symptom onset, the more protracted the disease course. We sought to evaluate current evidence and to develop expert practice consensus to support clinicians who have not previously encountered patients with this rare disease. METHODS: We searched the literature for guidelines and evidence to support clinical practice recommendations. We surveyed CLN1 disease experts and caregivers regarding their experiences and recommendations, and a meeting of experts was conducted to ascertain points of consensus and clinical practice differences. RESULTS: We found a limited evidence base for treatment and no clinical management guidelines specific to CLN1 disease. Fifteen CLN1 disease experts and 39 caregivers responded to the surveys, and 14 experts met to develop consensus-based recommendations. The resulting management recommendations are uniquely informed by family perspectives, due to the inclusion of caregiver and advocate perspectives. A family-centered approach is supported, and individualized, multidisciplinary care is emphasized in the recommendations. Ascertainment of the specific CLN1 disease phenotype (infantile-, late infantile-, juvenile-, or adult-onset) is of key importance in informing the anticipated clinical course, prognosis, and care needs. Goals and strategies should be periodically reevaluated and adapted to patients' current needs, with a primary aim of optimizing patient and family quality of life.

The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson's disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with DBS worldwide, have delayed regulatory agency approval (e.g., FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry.

Experience, knowledge, and opinions about childhood genetic testing in Batten disease.

BACKGROUND AND OBJECTIVES: Policies for genetic testing in children (GTIC) focus on medical or psychosocial benefit to the child, discouraging or prohibiting carrier testing, and advising caution regarding pre-symptomatic diagnosis if no treatment exists. This study sought to understand parents' perspectives on these issues and determine their experiences and knowledge related to genetic testing for Batten disease - a set of inherited neurodegenerative diseases of childhood onset for which no disease modifying therapies yet exist. METHODS: Parents of children with Batten disease completed a survey of their knowledge of genetics, experience with genetic testing, and opinions regarding GTIC. RESULTS: 54% had sought genetic testing for non-affected family members, including predictive diagnosis of healthy, at-risk children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain GTIC. CONCLUSIONS: Parents of children with an inherited disease are knowledgeable about genetics and wish to establish predictive or carrier status of at-risk children.

Tic disorders.

PURPOSE OF REVIEW: Primary tic disorders are complex, multifactorial disorders in which tics are accompanied by other sensory features and an array of comorbid behavioral disorders. Secondary tics are proportionally much less frequent, but their etiology is diverse. This review aims to guide clinicians in the recognition of the phenomenology, pathophysiology, and treatment of these disorders. RECENT FINDINGS: Advances include greater phenomenologic insights, particularly of nonmotor (sensory) features; increased knowledge of disease mechanisms, particularly coming from neuropsychological, functional imaging, pathologic, and animal model studies; growing evidence on the efficacy of alpha-2 agonists and the newer generation of dopamine-modulating agents; and recent strides in the evaluation of cognitive-behavioral therapy and deep brain stimulation surgery. SUMMARY: The correct diagnostic approach to tic disorders requires accurate historical gathering, a thorough neurologic examination, and detailed definition of the patient's psychopathologic profile. Treatment should always begin with individualized psychoeducational strategies. Although pharmacologic treatments remain beneficial for most patients, cognitive-behavioral treatments have thus far shown promising efficacy. Deep brain stimulation surgery should still be limited to adult patients refractory to pharmacotherapy and cognitive-behavioral therapy.

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

Definition and classification of negative motor signs in childhood.

In this report we describe the outcome of a consensus meeting that occurred at the National Institutes of Health in Bethesda, Maryland, March 12 through 14, 2005. The meeting brought together 39 specialists from multiple clinical and research disciplines including developmental pediatrics, neurology, neurosurgery, orthopedic surgery, physical therapy, occupational therapy, physical medicine and rehabilitation, neurophysiology, muscle physiology, motor control, and biomechanics. The purpose of the meeting was to establish terminology and definitions for 4 aspects of motor disorders that occur in children: weakness, reduced selective motor control, ataxia, and deficits of praxis. The purpose of the definitions is to assist communication between clinicians, select homogeneous groups of children for clinical research trials, facilitate the development of rating scales to assess improvement or deterioration with time, and eventually to better match individual children with specific therapies. "Weakness" is defined as the inability to generate normal voluntary force in a muscle or normal voluntary torque about a joint. "Reduced selective motor control" is defined as the impaired ability to isolate the activation of muscles in a selected pattern in response to demands of a voluntary posture or movement. "Ataxia" is defined as an inability to generate a normal or expected voluntary movement trajectory that cannot be attributed to weakness or involuntary muscle activity about the affected joints. "Apraxia" is defined as an impairment in the ability to accomplish previously learned and performed complex motor actions that is not explained by ataxia, reduced selective motor control, weakness, or involuntary motor activity. "Developmental dyspraxia" is defined as a failure to have ever acquired the ability to perform age-appropriate complex motor actions that is not explained by the presence of inadequate demonstration or practice, ataxia, reduced selective motor control, weakness, or involuntary motor activity.

Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome.

In response to recent publicity regarding the potential use of deep brain stimulation (DBS) for reducing tic severity in Tourette's syndrome (TS), the Tourette Syndrome Association convened a group of TS and DBS experts to develop recommendations to guide the early use and potential clinical trials of DBS for TS and other tic disorders. The goals of these recommendations are to ensure that all surgical candidates are (1) fully informed about the risks, benefits, and alternative treatments available; (2) receive a comprehensive evaluation before surgery to ensure that DBS is clearly the appropriate clinical treatment choice; and (3) that early clinical experience will be documented publicly to facilitate rational decision-making for both clinical care and future clinical trials.

Microinfusion of antineuronal antibodies into rodent striatum: failure to differentiate between elevated and low titers.

An autoimmune-mediated mechanism has been proposed for several pediatric movement disorders. In a three-center (Brown, Yale, and Johns Hopkins) collaborative effort, serum antineuronal antibodies (ANAb) were measured by use of ELISA or immunohistochemical techniques on 35 children (mean age 11.4 years) with Tourette syndrome, attention deficit hyperactivity disorder, and/or obsessive compulsive disorder. Eight sera, 4 containing the highest and 4 the lowest levels of ANAb, were identified at each institution. Selected sera (total of 9 with elevated and 7 with low ANAb) were re-encoded and sent to each center for infusion into the ventrolateral striatum of 16 male Sprague-Dawley rats. Animals were observed for behavioral abnormalities for 3 days before the start of infusion, during infusion on days 2-4, and for 2 days after infusion. Combined stereotypy scores increased after antibody infusion, but there was no significant effect based on serum titer (p=0.85). Scores differed among centers, but analyses based on individual institutional data again failed to show an effect based on elevated or low ANAb values (Brown, p=0.95; Yale and Johns Hopkins, p=0.81). Post hoc studies with sham surgery and infusion of phosphate-buffered saline support suggestions of nonspecific behavioral effects unrelated to antibody titer. This report emphasizes that any conclusions about antibody-mediated movement disorders that are based upon results from the rodent infusion model must be considered with caution.

Effects of pallidotomy and levodopa on walking and reaching movements in Parkinson's disease.

We examined the effects of levodopa and unilateral pallidotomy on quantitative measures of walking and reaching in Parkinson's disease (PD). We also compared quantitative measures of movement with standard clinical rating scales. We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 10 people with PD. Subjects were tested after withholding PD medications for at least 8 hours and again 30 to 45 minutes after taking the first morning dose of levodopa. They were studied in this manner before unilateral pallidotomy and then 3.5 to 10 months after surgery. The UPDRS motor subscale was performed in each state. Kinematic data were collected as subjects reached to a target and walked. The UPDRS motor subscale ratings were similar to those reported in the literature: pallidotomy improved the overall motor score and the contralateral bradykinesia + rigidity score, but not the gait + posture score. In contrast, kinematic measures demonstrated that levodopa and pallidotomy had different effects on walking and reaching speed. Both treatments improved walking speed, and the effect was additive. Levodopa improved reaching speed before pallidotomy but did not improve it as much after pallidotomy. Additionally, pallidotomy had inconsistent effects on reaching; some subjects were faster and others were slower. The subjects who initially reached more slowly improved after pallidotomy; the subjects who initially reached more normally (faster) worsened after pallidotomy. On the basis of our results, we speculate that basal ganglia output pathways that control walking and reaching may be distinct, such that bilateral projections to the pedunculopontine area influence walking, whereas ipsilateral thalamocortical projections influence reaching.

Progressive myoclonus in a child with a deep cerebellar mass.

Myoclonus is often associated with pathology of the cerebellum. However, the site of neurons responsible for the generation of myoclonus in cerebellar disease is not known. The authors report a young child with myoclonus associated with a ganglioglioma in the region of the deep cerebellar white matter and cerebellar nuclei. They hypothesize that abnormal paroxysmal discharge of neurons in the cerebellar nuclei can generate myoclonus.