Christopher Stephen

• MB ChB, FRCP
• Assistant Professor at Massachusetts General Hospital

A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologi...

Background and objectives Dystonia is the third most common movement disorder. Motor and non-motor manifestations of dystonia may impact Health Related Quality of Life (HRQoL), with lower HRQoL scores compared to the healthy population. People with generalized dystonia report worse HRQoL scores (vs. people with focal distributions). Social determin...

Background The Patient‐Reported Outcome Measure of Ataxia (PROM‐Ataxia) has been validated cross‐sectionally but not longitudinally. Objective We aimed to validate PROM‐Ataxia as a measure of patient experience of disease over time, examine overall and domain‐specific progression, and test convergent validity with other clinical outcome assessment...

Objective Frequent and objective assessment of ataxia severity is essential for tracking disease progression and evaluating the effectiveness of potential treatments. Wearable-based assessments have emerged as a promising solution. However, existing methods rely on inertial data features directly correlated with subjective and coarse clinician-eval...

Late-Onset GM2-Gangliosidoses (LOGG) are rare, neurodegenerative lysosomal disorders that include late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) subtypes. Cerebellar atrophy is common, even in the absence of clinical ataxia, particularly in LOTS. Recent reports have also described brainstem atrophy in LOTS. We assessed brainstem substructu...

Abnormal eye movements occur early in the course of disease in many ataxias. However, clinical assessments of oculomotor function lack precision, limiting sensitivity for measuring progression and the ability to detect subtle early signs. Quantitative assessment of eye movements during everyday behaviors such as reading has potential to overcome th...

Background Language impairment is common in progressive supranuclear palsy (PSP) and is often overlooked due to the severity of the motor symptoms. We investigated whether language can be used to predict PSP prognosis. Methods One hundred‐forty‐six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV‐8E12) clinical tria...

Quantitative analysis of human behavior is critical for objective characterization of neurological phenotypes, early detection of neurodegenerative diseases, and development of more sensitive measures of disease progression to support clinical trials and translation of new therapies into clinical practice. Sophisticated computational modeling can s...

Background The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed. Objectives To evaluate the MoCA as an outcome measure in PSP clinical trials. Methods Cognitive data from 162 participants in the placebo arm of the Biogen PASSP...

A significant barrier to developing disease-modifying therapies for spinocerebellar ataxias (SCAs) and multiple system atrophy of the cerebellar type (MSA-C) is the scarcity of tools to sensitively measure disease progression in clinical trials. Wearable sensors worn continuously during natural behavior at home have the potential to produce ecologi...

Background Brain imaging studies investigating grey matter in functional neurological disorder (FND) have used univariate approaches to report group-level differences compared with healthy controls (HCs). However, these findings have limited translatability because they do not differentiate patients from controls at the individual-level. Methods 1...

Background Adrenomyeloneuropathy (AMN) is a neurodegenerative disease phenotype of X-linked adrenoleukodystrophy (ALD), resulting in progressive myeloneuropathy causing spastic paraparesis, sensory ataxia, and bowel/bladder symptoms. We conducted a retrospective cohort study using two large administrative databases to characterize mortality and the...

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential cl...

italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Objective : Objective, sensitive, and meaningful disease assessments are critical to support clinical trials and clinical care. Speech changes are one of the earliest and most evident manifestations of cerebellar ataxias. This work aims to develop mode...

Definitive diagnosis of multiple system atrophy of the cerebellar type (MSA-C) is challenging. We hypothesized that rates of change of pons and middle cerebellar peduncle diameters on MRI would be unique to MSA-C and serve as diagnostic biomarkers. We defined the normative data for anterior–posterior pons and transverse middle cerebellar peduncle d...

Background Genetic prion diseases, including Gerstmann‐Sträussler‐Scheinker disease (GSS), are extremely rare, fatal neurodegenerative disorders, often associated with progressive ataxia and cognitive/neuropsychiatric symptoms. GSS typically presents as a rapidly progressive cerebellar ataxia, associated with cognitive decline. Late‐onset cases are...

BACKGROUND: Adrenomyeloneuropathy (AMN) is a neurodegenerative disease phenotype of X-linked adrenoleukodystrophy (ALD), resulting in progressive myeloneuropathy causing spastic paraparesis, sensory ataxia, and bowel/bladder symptoms. We conducted a retrospective cohort study using two large administrative databases to characterize mortality and th...

Objective Late‐onset GM2 gangliosidosis (LOGG) subtypes late‐onset Tay‐Sachs (LOTS) and Sandhoff disease (LOSD) are ultra‐rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We...

Dysarthria is a common manifestation across cerebellar ataxias leading to impairments in communication, reduced social connections, and decreased quality of life. While dysarthria symptoms may be present in other neurological conditions, ataxic dysarthria is a perceptually distinct motor speech disorder, with the most prominent characteristics bein...

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dyston...

Objective Objective, sensitive, and meaningful disease assessments are critical to support clinical trials and clinical care. Speech changes are one of the earliest and most evident manifestations of cerebellar ataxias. The purpose of this work is to develop models that can accurately identify and quantify these abnormalities. Methods We use deep...

Dystonia is the third most common movement disorder, characterized by abnormal, frequently twisting postures related to co-contraction of agonist and antagonist muscles. Diagnosis is challenging. We provide a comprehensive appraisal of the epidemiology and an approach to the phenomenology and classification of dystonia, based on the clinical charac...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults. It is well-established that CADASIL results in neurocognitive dysfunction and mood disturbance. There is also cumulative evidence that CADASIL patients are more susceptible to ischemi...

Novel disease-modifying therapies are being evaluated in spinocerebellar ataxias and multiple system atrophy. Clinician-performed disease rating scales are relatively insensitive for measuring disease change over time, resulting in large and long clinical trials. We tested the hypothesis that sensors worn continuously at home during natural behavio...

Dystonia is a common movement disorder involving abnormal, often twisting postures and is a challenging condition to diagnose as we present here in a comprehensive overview. The pathophysiology of dystonia involves abnormalities in brain motor networks, sensorimotor integration, and maladaptive cortical plasticity in the context of genetic factors....

The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient’s wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the...

Purpose of review: This article discusses the most recent findings regarding the diagnosis, classification, and management of genetic and idiopathic dystonia. Recent findings: A new approach to classifying dystonia has been created with the aim to increase the recognition and diagnosis of dystonia. Molecular biology and genetic studies have iden...

Late-onset GM2 gangliosidosis (LOGG) is an ultra-rare neurological disease with motor, cognitive and psychiatric manifestations. It is caused by mutations in the HEXA or HEXB genes. Although cerebellar structural and metabolic impairments have been established, global brain functional impairments in this disease remain unknown. In this first functi...

Magnetic resonance spectroscopy (MRS) and functional MRI (fMRI), related through common biophysical bases, provide complementary information about brain function. The link between MRS and fMRI measures is of interest, especially in the ultra-rare, metabolic disease late-onset GM2 gangliosidosis (LOGG). Imaging studies on LOGG have been few and far...

Background and purpose: Motor functional neurological disorder is a prevalent and costly condition at the intersection of neurology and psychiatry that is diagnosed using positive "rule-in" signs. Physical therapy is a first-line treatment and consensus recommendations exist to guide clinical care. Nonetheless, optimal outpatient treatment of adul...

Digital assessments enable objective measurements of ataxia severity and provide informative features that expand upon the information obtained during a clinical examination. In this study, we demonstrate the feasibility of using finger tapping videos to distinguish participants with Ataxia (N = 169) from participants with parkinsonism (N = 78) and...

Objective /Background: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD. Patients/Methods We admi...

Objective: Assessment of motor severity in cerebellar ataxia is critical for monitoring disease progression and evaluating the effectiveness of therapeutic interventions. Though wearable sensors have been used to monitor gait tasks in order to enable frequent assessment, existing solutions only estimate gait performance severity rather than compre...

Functional movement disorders (FMDs) are a diagnostic and treatment challenge and can be particularly debilitating conditions, even more so than their “organic” movement disorder counterparts. FMDs may represent the most common movement disorders emergency encountered by neurologists, as these patients frequently present acutely, with an unclear di...

Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for ob...

Objective To explore the use of wearable sensors for objective measurement of motor impairment in spinocerebellar ataxia (SCA) patients during clinical assessments of gait and balance.Methods In total, 14 patients with genetically confirmed SCA (mean age 61.6 ± 8.6 years) and 4 healthy controls (mean age 49.0 ± 16.4 years) were recruited through th...

Background Non-motor symptoms are common in Parkinson’s disease (PD) and some, including hyposmia, constipation, and REM sleep behavior disorder, often precede the clinical diagnosis. Objective To assess the relation between combinations of non-motor features and presence of PD among women. Methods A nested case-control study was conducted among...

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick di...

Background: Gait and balance difficulties are among the most common clinical manifestations in adults with X-linked adrenoleukodystrophy, but little is known about the contributions of sensory loss, motor dysfunction, and postural control to gait dysfunction and fall risk. Objective: To quantify gait and balance deficits in both males and females w...

Objective: Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). Methods: We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who...

Objective: Functional dystonia (FD) is a disabling and diagnostically challenging functional movement disorder (FMD). We sought to identify historical predictors of FD vs. other primary dystonias (ODs) and develop a practical prediction algorithm to guide neurologists. Methods: 1475 consecutive new patient medical records were reviewed at an adu...

Background Despite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing access to genetic testing may be limited in clinical practice. Objectives To assess worldwide access to genetic tests for movement disorders and factors impacting their utilization. Methods The Rare Movement D...

Dystonia is a common movement disorder, involving sustained muscle contractions, often resulting in twisting and repetitive movements and abnormal postures. Dystonia may be primary, as the sole feature (isolated) or in combination with other movement disorders (combined dystonia), or as one feature of another neurological process (secondary dystoni...

Background: Cervical dystonia (CD) is a rare disorder, and health care providers might be unfamiliar with its presentation, thus leading to delay in the initial diagnosis. The lack of awareness displays the need to highlight the clinical features and treatment in cervical dystonia. In our cohort, we have identified an earlier age of onset in men, d...

Eye movements are disrupted in many neurodegenerative diseases and are frequent and early features in conditions affecting the cerebellum. Characterizing eye movements is important for diagnosis and may be useful for tracking disease progression and response to therapies. Assessments are limited as they require an in-person evaluation by a neurolog...

Importance There is limited information about health care use and costs in patients with functional neurological disorders (FNDs). Objective To assess US emergency department (ED) and inpatient use and charges for FNDs. Design, Setting, and Participants This economic evaluation used Healthcare Cost and Utilization Project data to assess all-payer...

Functional neurological (conversion) disorder (FND) is a prevalent and disabling condition at the intersection of neurology and psychiatry. Advances have been made in elucidating an emerging pathophysiology for motor FND, as well as in identifying evidenced-based physiotherapy and psychotherapy treatments. Despite these gains, important elements of...

Background X‐linked dystonia parkinsonism (XDP) is a rare disorder characterized by adult‐onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism. Gait impairment is common. Methods Case series of 4 XDP patients with a unique gait disorder. Results The patients displayed a characteristic gait disorder...

Background: Functional neurological disorder (FND) is a prevalent neuropsychiatric condition characterized by sensorimotor difficulties. Patients with FND at times report that sensory experiences trigger and/or exacerbate their symptoms. Sensory processing difficulties are also commonly reported in other psychiatric disorders frequently comorbid i...

‘Stroke mimics: Transient focal neurological events’ explores the important stroke-like symptoms that are due to non-cerebrovascular causes. Stroke mimics account for up to 31% of code stroke presentations, and up to 60% of potential TIAs. The most common stroke mimics are seizures, migrainous auras, and functional neurological disorders. Making an...

Objective: A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features. Methods: Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of...

Background: Objective assessments of movement impairment are needed to support clinical trials and facilitate diagnosis. The objective of the current study was to determine if a rapid web-based computer mouse test (Hevelius) could detect and accurately measure ataxia and parkinsonism. Methods: Ninety-five ataxia, 46 parkinsonism, and 29 control...

Objective: Despite promising research and consensus recommendations on the important therapeutic role of physical therapy for motor functional neurological disorder (FND), little is known about the feasibility and potential efficacy of implementing physical therapy for this population in a U.S.-based outpatient program. Given health care system di...

Oculomotor abnormalities are common in the spinocerebellar ataxias (SCAs). In studies of SCAs 1, 2, 3, and 6, eye movement abnormalities correlate with disease severity. Oculomotor abnormalities may be the sole motor manifestation of early and/or premanifest disease; however, not all ataxia rating scales include oculomotor assessment. We sought to...

Background ATP1A3 mutations cause a wide clinical spectrum, and are one of the “commoner rare diseases”. Methods Case series of four patients with ATP1A3 mutations Results The patients displayed characteristic episodes of dystonic arm posturing, involving a dystonic, flexed arm held in front of the body, or held close to the body but with the han...

Purpose of review In this review, we present the multidisciplinary approach to the management of the many neurological, medical, social, and emotional issues facing patients with cerebellar ataxia. Recent findings Our holistic approach to treatment, developed over the past 25 years in the Massachusetts General Hospital Ataxia Unit, is centered on...

Functional neurological disorders (FND) are complex and prevalent neuropsychiatric conditions. Importantly, some patients with FND develop acute onset symptoms requiring emergency department (ED) evaluations. Historically, FND was a “rule-out” diagnosis, making assessment and management in the ED difficult. While the rapid triage of potential neuro...

Background Several non-motor features may individually contribute to identify prodromal Parkinson’s disease (PD), but little is known on how they interact. Methods We conducted a case–control study nested within the Health Professionals Follow-up Study in a large cohort of men age 40–75 at recruitment in 1986. Cases (n=120) had confirmed PD, were...

Objective To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features. Methods A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and...

Background There is increasing evidence that the effects of Huntington's disease (HD) extend beyond the central nervous system. In particular, significant cardiac dysfunction has been described in transgenic mouse models and suggested in symptomatic patients, in whom cardiac involvement could provide an independent risk for sudden cardiac death. M...

Background Motor functional neurologic disorders (FND) — previously termed ‘hysteria′ and later ‘conversion disorder′ — are exceedingly common and frequently encountered in the acute hospital setting. Despite their high prevalence, patients with motor FND can be challenging to accurately diagnose and effectively manage. To date, there is limited gu...

The most common temporary focal neurological events are transient ischemic attacks, migrainous accompaniments, seizures, and functional psychogenic episode.

Despite advancements in the assessment and management of functional neurological disorder (FND), the feasibility of implementing a new standard of care remains unclear. Chart reviews were performed for 100 patients with motor FND to investigate factors related to treatment adherence and clinical improvement over an average follow-up of 7 months. Of...

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis o...

Spontaneous intracranial hypotension typically results from a spontaneous cerebrospinal fluid (CSF) leak.1 ,2 Symptoms include orthostatic headache and meningism without a recent dural puncture,2 and may be associated with distant and trivial trauma.3 The diagnosis may be made clinically by the typical headache and supported by pachymeningeal enhan...

Pulmonary amyloidosis in the setting of Sjogren syndrome is rare. It most commonly presents in form of multinodular disease with or without cysts formation. Amyloid plaques may also deposit in the airway submucosa, causing airway narrowing; the condition referred as "tracheobronchial amyloidosis" (TBA). Patients with this condition most commonly pr...

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging after mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distr...