Non-Parkinsonian Movement Disorders E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: NIP- Neurology in Practice
• Sprache: Englisch

Seitenzahl: 494

Veröffentlichungsjahr: 2017

Beschreibung

A clinical ‘in the office’ or ‘at the bedside’ guide to effective patient care for neurologists in practice and in training 

• Each presentation includes practical descriptions of phenomenology, and key clinical information from the history and neurological examination that guide the physician to the correct diagnosis, and treatment options
• Throughout the book Science Revisited highlights remind clinicians of the scientific anchors related to each  disorder, and Evidence at a Glance boxes summarise clinical trial evidence-based review information 
• Numerous video clips in every chapter demonstrate different movement disorders to aid diagnosis 
• Unique learning tools, Tips and Tricks and Caution Warning boxes, give useful hints on improving outcomes and preventing errors 

Leseprobe

NEUROLOGY IN PRACTICE:

SERIES EDITORS: ROBERT A. GROSS, DEPARTMENT OF NEUROLOGY, UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA

JONATHAN W. MINK, DEPARTMENT OF NEUROLOGY, UNIVERSITY OF ROCHESTER MEDICAL CENTER, ROCHESTER, NY, USA

Non‐Parkinsonian Movement Disorders

EDITED BY

Deborah A. Hall, MD, PhD

Department of Neurological SciencesSection of Movement DisordersRush University Medical Center, ChicagoIllinois, USA

Brandon R. Barton, MD, MS

Department of Neurological SciencesSection of Movement DisordersRush University Medical Center;

Neurology SectionJesse Brown VA Medical CenterChicago, Illinois, USA

This edition first published 2017, © 2017 by John Wiley & Sons, Ltd.

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Library of Congress Cataloging‐in‐Publication Data

Names: Hall, Deborah A., editor. | Barton, Brandon R., editor.Title: Non‐Parkinsonian movement disorders / edited by Deborah A. Hall and Brandon R. Barton.Description: Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2016. | Includes bibliographical references and index.Identifiers: LCCN 2016023027 | ISBN 9781118473924 (Paperback) | ISBN 9781118474068 (Adobe PDF) | ISBN 9781118474051 (epub)Subjects: | MESH: Movement Disorders–diagnosis | Diagnosis, Differential | Diagnostic Techniques, NeurologicalClassification: LCC RC376.5 | NLM WL 390 | DDC 616.8/3–dc23LC record available at https://lccn.loc.gov/2016023027

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Background cover image: iStockphoto.com

List of Contributors

Pinky Agarwal MDMovement Disorders CenterEvergreen Health Neuroscience InstituteKirkland, WA

Brandon R. Barton MD, MSDepartment of Neurological SciencesSection of Movement DisordersRush University Medical Center;Neurology SectionJesse Brown VA Medical CenterChicago, IL

Nina Browner MDNational Parkinson Foundation Center of ExcellenceUniversity of North CarolinaChapel Hill, NC

Daniel Burdick MDMovement Disorders CenterEvergreen Health Neuroscience InstituteKirkland, WA

Florence C. F. Chang MBBS, FRACPNeurology DepartmentWestmead HospitalWentworthville, NSW

Khashayar Dashtipour MD, PhDDepartment of Neurology, Movement DisordersLoma Linda University School of MedicineLoma Linda, CA

Rohit Dhall MBBS, MSPHParkinson’s Institute and Clinical CenterSunnyvale, CA

Alberto J. Espay MD, MScGardner Center for Parkinson’s Disease and Movement DisordersDepartment of NeurologyUniversity of CincinnatiCincinnati, OH

Steven J. Frucht MDMount Sinai Medical CenterNY

Janice Fuentes MDDepartment of Neurology, Movement DisordersLoma Linda University School of MedicineLoma Linda, CA

Deborah A. Hall MD, PhDDepartment of Neurological SciencesSection of Movement DisordersRush University Medical CenterChicago, IL

Samantha Holden MDUniversity of Colorado School of Medicine, Aurora, Colorado, USA

Un Jung Kang MDDepartment of NeurologyColumbia University Medical CenterNY

Olga Klepitskaya MDDepartment of NeurologySchool of Medicine, University of ColoradoAurora, CO

Jeff Kraakevik MDAssistant ProfessorOregon Health and Science UniversityPortland, OR

Stephanie Lessig MDDepartment of NeurosciencesUniversity of California San DiegoLa Jolla, CA

Shyamal H. Mehta MD, PhDDepartment of NeurologyMovement Disorders DivisionMayo ClinicPhoenix, AZ

Ifeoma Nwaneri MDReston Hospital CenterSpringfield, VA

Gian Pal MD, MSDepartment of Neurological SciencesSection of Movement DisordersRush University Medical CenterChicago, IL

Kathleen L. Poston MD, MSDepartment of Neurology and Neurological SciencesStanford UniversityStanford, CA

Michael Rotstein MDTel Aviv Sourasky Medical CenterTel Aviv, Israel

Bernadette Schoneburg MDNorthshore Medical GroupGlenview, IL

Lauren Schrock MDUniversity of UtahDepartment of NeurologySalt Lake City, UT

David Shprecher DO, MScCleo Roberts Center, Banner Sun HealthResearch Institute in Sun City, AZ

Christina L. Vaughan MD, MSHospice and Palliative Medicine ProgramUniversity of California San Diego/Scripps HealthLa Jolla, CA

Aleksandar Videnovic MDDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBoston, MA

Padmaja Vittal MD, MSNorthwestern Medicine Regional Medical GroupWinfield, IL

Tao Xie MD, PhDDepartment of NeurologyUniversity of Chicago Medical CenterChicago, IL

S. Elizabeth Zauber MDDepartment of NeurologyIndiana University School of MedicineIndianapolis, IN

Series Foreword

The genesis for this book series started with the proposition that, increasingly, physicians want direct, useful information to help them in clinical care. Textbooks, while comprehensive, are useful primarily as detailed reference works but pose challenges for uses at the point of care. By contrast, more outline‐type references often leave out the “hows and whys”—pathophysiology, pharmacology—that form the basis of management decisions. Our goal for this series is to present books, covering most areas of neurology, that provide enough background information to allow the reader to feel comfortable, but not so much as to be overwhelming, and to associate that with practical advice from experts about care, combining the growing evidence base with best practices.

Our series will encompass various aspects of neurology, with topics and the specific content chosen to be accessible and useful.

Chapters cover critical information that will inform the reader of the disease processes and mechanisms as a prelude to treatment planning. Algorithms and guidelines are presented, when appropriate. “Tips and Tricks” boxes provide expert suggestions, while other boxes present cautions and warnings to avoid pitfalls. Finally, we provide “Science Revisited” sections that review the most important and relevant science background material, and references and further reading sections that guide the reader to additional material.

Our thanks, appreciation, and respect go out to our editors and their contributors, who conceived and refined the content for each volume, assuring a high‐quality, practical approach to neurological conditions and their treatment.

Our thanks also go to our mentors and students (past, present, and future), who have challenged and delighted us; to our book editors and their contributors, who were willing to take on additional work for an educational goal; and to our original publisher, Martin Sugden, for his ideas and support, for wonderful discussions and commiseration over baseball and soccer teams that might not quite have lived up to expectations. And thanks, too, to Claire Bonnett, our current publisher, for her efforts to bring this volume forward.

This volume represents the end of our series. As readers will recognize, neurology encompasses far more than we have presented; still, we hope that the high points encompassed by these books will serve well.

We have dedicated the series to Marsha, Jake, and Dan, and to Janet, Laura, and David. And also to Steven R. Schwid, MD, our friend and colleague, whose ideas helped shape this project and whose humor brightened our lives; but he could not complete this goal with us. Our thanks to them are undiminished.

Robert A. GrossJonathan W. MinkRochester, NY, USA

Foreword

Non‐Parkinsonian Movement Disorders, edited by my colleagues, Drs. Brandon Barton and Deborah Hall, is a new entry in the larger series, Neurology in Practice and an immediate compendium of the Parkinsonian Movement Disorders. The topics covered in this volume provide the practicing neurologist, psychiatrist, and primary care health professional with expert reviews that cover both hypokinetic and hyperkinetic disorders. Hypokinetic disorders discussed include stiff‐person syndrome, catatonia, and catalepsy as well as a variety of stiff‐muscle conditions. For the hyperkinetic disorders, the editors have assembled a group of expert authors to cover tremors, myoclonus, tics, chorea, dystonia, and involuntary movements due to toxins and drugs. Importantly, because neurological disorders can be both out‐patient and in‐patient consultations, a chapter on ICU movement disorders emergencies is included, and an important chapter on the knotty and complex problem of psychogenic movement disorders that focuses on a variety of functional movements, both consciously and unconsciously generated.

Each presentation is anchored in very practical descriptions of phenomenology, key clinical information from the history and neurological examination that guide the physician to the correct diagnosis and treatment options. The text is enriched with tables and figures and a number of unique learning tools not found in other books on this topic. These tools include special boxed “Tips and Tricks” and “Caution” warnings that can help prevent errors. Besides the focus on practical clinical medicine, the authors provide two special highlights in each chapter, “Science Revisited” to remind clinicians of the scientific anchors related to the disorders and “Evidence at a Glance” where clinical trial evidence‐based review information is provided. All these special additions allow a reader to study the full text, but also to retrieve rapidly needed key points.

With a long career devoted to the treatment of movement disorders, research, and education, I laud the editors and their recruited authors in providing the medical community with an accessible and accurate book with a unique format. In a busy environment, this text serves as a very solid neurological work with the essentials delivered in a succinct and highly readable format.

Because a movement disorders diagnosis always starts with accurate visual identification, a very strong advantage of this text is the video material that accompanies each chapter. The elegant examples assembled are well synchronized with the text materials and allow the reader to study very good examples of the disorders under consideration. I suggest that readers start a chapter with a short examination of the video materials, so as to be clear on the type of movement under discussion, then read the text, finally returning to the videos for a focused re‐examination of the details of the carefully prepared examples. With this emphasis on the key role of expert visual recognition in movement disorders, the words of the celebrated nineteenth‐century neurologist, Jean‐Martin Charcot, resonate, and I offer this citation as the reader embarks on the very pleasant road of reading this volume:

Let someone say of a doctor that he really knows his physiology or anatomy, that he is dynamic—these are not real compliments; but if you say he is an observer, a man who knows how to see, this is perhaps the greatest compliment one can make (Charcot, 1888, Leçons du mardi).

Christopher G. Goetz, MD, Chicago, IL, USA, 2016

About the Companion Website

This book is accompanied by a companion website:

www.wiley.com/go/hall/non‐parkinsonian_movement_disorders

The website includes:

Videos

1Approach to Movement Disorders

Deborah A. Hall, MD, PhD1 and Brandon R. Barton, MD, MS1,2

1Department of Neurological Sciences, Section of Movement Disorders, Rush University Medical Center, Chicago, Illinois, USA

2Department of Neurological Sciences, Rush University Medical Center; Neurology Section, Jesse Brown VA Medical Center, Chicago, Illinois, USA

Introduction

Patients with movement disorders typically present with a change in their overall pattern of movements: this may represent an increase of movement (hyperkinetic), decrease (hypo‐ or akinetic), uncoordinated movement (ataxia), or a combination of the aforementioned. The initial task is to properly categorize the appearance or “phenomenology” of the movement disorder, as this is the essential step to guide the clinician in developing a differential diagnosis and treatment plan. Given recent advances in neurology, the majority of movement disorder patients are candidates for treatment, such as medication, physical therapy, or surgical interventions.

The first part of this book provides a short chapter on non‐parkinsonian hypokinetic movement disorders; parkinsonian disorders are covered in another volume in this series. The second part includes hyperkinetic disorders. Part three includes various syndromes that do not fit into the other categories or that overlap between categories. Broader chapters in part four, on genetics, neuroimaging, rating scales, and videotaping suggestions, are intended to serve as clinician resources.

This introductory chapter provides an approach that will facilitate the evaluation of a movement disorder patient. The phenomenological categorization of the most common movement disorders falls into seven major categories: parkinsonism, tremor, dystonia, myoclonus, chorea, ataxia, and tics. Most of the commonly encountered disorders can be classified into one of these categories, but given the breadth of the diseases in the field, there are many unusual or rare types of movement that may not be easily categorized or may be consistent with more than one phenomenological category. A thorough history and examination are essential to defining the phenomenology. Home videotapes of the patient may also be useful if the movements are intermittent, variable, or not seen clearly in the office. Laboratory testing and imaging are necessary in some movement disorders, but are less helpful in many circumstances given that the disorders are diagnosed mainly on history and examination.

History

Start by asking six questions in the history.

1. Can you describe the movements?

Patients will usually be able to describe a decrease or increase (or both) in their overall movement from baseline, although often hyperkinetic aspects of abnormal movements can overshadow the hypokinetic movements from the patient’s perspective. Hypokinetic movement disorders, also termed bradykinesia (slowed movement) or akinesia (loss of movement) are characterized by an overall decrease in the speed or amplitude of movement in any area of the body. Signs and symptoms could include decreased facial expression, slowed speech, reduced dexterity of the extremities, decreased arm swing, and slowed walking speed. Hyperkinetic movement disorders, also generally termed dyskinesia (abnormal movements), are characterized by an increase in baseline movements. Hyperkinetic movement disorders have highly variable manifestations, ranging from increased eye closure to arm flailing to jerking of the legs. Lastly, patients may complain of a change in the character of voluntary movements, such as becoming clumsy or unsteady with walking, which may be seen in ataxic disorders.

Certain features of abnormal movements are very important to elicit in the patient’s description. Defining the conditions under which the movement occurs, such as with rest or with action, is necessary for accurate diagnosis and categorization of tremor. An ability to suppress the movement or an increase in the movement with suggestion are features common to tics. Specific triggers of the movements, especially with certain tasks, may be reported in dystonic disorders or paroxysmal movement disorders. Myoclonus can be triggered by startle. Asking about worsening of the disorder or improvement with certain foods or alcohol can narrow the differential diagnosis in forms of dystonia, myoclonus, or tremor disorders. A history of falls, especially the temporal course, is helpful in disorders that affect gait and balance, as falls are seen earlier or more frequently in some disorders as opposed to others.

2. When did the movements start and how have they changed over time?

Most movement disorders are subacute or chronic in nature. An acute onset is less common and may signify a secondary movement disorder related to an underlying inciting event, such as a stroke or medication change. Acute onset of movement disorders at maximal severity is also commonly seen in functional movement disorders, where patients will often present to emergency departments from the start. Most hypokinetic, hyperkinetic, and ataxic movement disorders will slowly worsen over time. Disorders that improve over time are less common; for example, tic disorders will typically improve from childhood into adolescence and adulthood. Static movement disorders may occur with birth injury or some dystonic disorders.

3. Are the movements continuous or intermittent?

Although many movement disorders start out as intermittent or suppressible, they tend to become more continuous or constant when they progress over time. The rest tremor seen in parkinsonian disorders is a classic example, where the tremor starts intermittently in a limb before becoming more regular and spreading to other limbs. Early on, this type of tremor can be sometimes voluntarily suppressed or decreased with movement, but later the tremor is continuous. Episodic movement disorders are much less common. Paroxysmal disorders, which are typically choreic or dystonic in nature, can many times be diagnosed by history alone if specific triggers such as sudden movements cause the disorder to occur. Functional (psychogenic) movement disorders are also frequently episodic. The circumstances under which the movement occurs can be particularly helpful. For example, restless legs syndrome worsens at night when the patient is laying down.

4. Is there a family history?

All modes of inheritance patterns are seen in movement disorders and the genetic basis of these disorders is rapidly being discovered. It is not sufficient to inquire only about the particular movement disorder seen in the patient, since broadening the questioning to other biological family members may yield additional important clues. For example, patients with grandchildren with intellectual disabilities may be at risk for fragile X‐associated disorders. Tic patients may have associated diagnoses in the family, such as attention deficit hyperactivity disorder.

5. Are there other medical illnesses?

The majority of movement disorders are restricted to the nervous system, but systemic organ involvement may provide diagnostic clues. For example, patients with underlying cancers may be at risk for paraneoplastic disorders and iron deficiency anemia or diabetes may predispose to restless legs syndrome. The presence of cardiomyopathy is associated with Friedreich ataxia or mitochondrial disorders. Enlargement of visceral organs (spleen, liver) may suggest a lysosomal storage disease.

6. Have the movements been treated in the past and what was the response to treatment?

A response to dopamine medications may facilitate diagnosis of dopa‐response dystonia. Paroxysmal movement disorders may be exquisitely responsive to antiepileptic medications. Other substances may improve movements, such as the improvement of essential tremor, essential myoclonus, and myoclonus‐dystonia with alcohol.

Examination

Depending on the movement disorder, abnormal movements may be present in focal or contiguous areas of the body or may be generalized. By determining the location and phenomenology of the movement, most patients can be placed into one of seven distinct patterns of abnormal movement.

Parkinsonism

The main features of parkinsonism are tremor at rest, bradykinesia or akinesia, rigidity, loss of postural reflexes, flexed posture, and freezing. Parkinsonism, in particular, Parkinson disease, is the most common disorder seen in movement disorder clinics and is covered by another volume of this series.

Tremor

This pattern is typically rhythmical and oscillatory and may affect more than one body part. Tremor should be classified on examination by the conditions under which it is activated: at rest, with posture, or with action. Tremor may be present in multiple conditions, for example, essential tremor, which is frequently seen with posture and action or intention. Tremors may also be task specific, such as the dystonic tremor of writer’s cramp.

Chorea

Choreic movement is random in nature and is purposeless, non‐rhythmic, and unsustained. It may appear to flow from one body part to another. Huntington disease is a frequent cause of chorea and manifests with brief, irregular movements. Chorea can be suppressed or camouflaged. It can be accompanied by “negative chorea” or motor impersistence.

Dystonia

In dystonia, agonist and antagonist muscles contract simultaneously causing twisting movements that are frequently sustained. The speed of the movement is variable and when sustained, can lead to abnormal postures and contractures. Dystonia is typically worsened with action, sometimes only occurring with specific actions. It can be classified by location, age of onset, and etiology, and the classification system has recently been revised.

Myoclonus

This pattern consists of brief, sudden, typically irregular jerks from muscle contraction. Myoclonus may be synchronized and triggered by action or startle. Negative myoclonus is caused by inhibition of the muscles, with the classic example being asterixis. Myoclonus can be rhythmic or oscillatory and occur in various parts of the body, either focally or generally.

Tics

Tics are abnormal movements (motor) or sounds (phonic) that are abrupt, usually transient, and can be simple or complex. Tics can vary over time and can be accompanied by an uncomfortable urge or feeling. Tics may be suppressible, although severe tics may be continuous. Gilles de la Tourette syndrome is characterized by the presence of both motor and phonic tics, present for more than one year, with young onset.

Ataxia

Lack of coordination of movement distinguishes ataxia from other movement disorders. The pattern of ataxic movement varies, but may include clumsy limb movements (dysmetria), dysarthria, ataxic eye findings such as abnormal pursuit, and uncoordinated walking. Kinetic tremor can also accompany ataxic signs. Ataxia can be localized to the peripheral or central nervous system so a thorough sensory and vestibular examination is necessary in these patients.

Other patterns of movements

There are several other types of abnormal movements that, despite being distinctly recognizable, do not fit well into the preceding patterns. These include stiff‐muscles, akathetic movements, myokymia, paroxysmal dyskinesias, restless legs, and stereotypy. In addition, some movement disorders have more than one pattern of movement, such as in the myoclonus‐dystonia disorders. Functional movement disorders frequently do not fit well into the above‐described patterns, but caution must be maintained, since many unusual movement disorders can be labeled functional.

Diagnostic testing

Accurate description of the phenomenology of the abnormal movements as a result of the history and examination is the first and most fundamental step in diagnosis of movement disorders. Additional diagnostic testing is not warranted in many situations, for example, in the classic appearance of Tourette syndrome. However, there are some studies that may enhance or confirm clinical diagnosis. For example, laboratory studies can be useful particularly with tremor. Abnormalities of the thyroid, evidenced by elevated or low thyroid stimulating hormone (TSH), may cause or worsen tremor. Wilson disease, diagnosed by abnormal copper levels (in serum and/or urine), low ceruloplasmin, and the presence of Kaiser–Fleischer rings; should be considered in younger patients who present with bizarre tremors or other unusual movement patterns/combinations.

Genetic testing is available for many movement disorders and is driven by family history, age of the patient, and financial resources. For the more rare movement disorders, such as the inherited ataxias and Huntington disease, it may be the only testing that can give a definitive diagnosis. For individuals who are considering family planning, it may be necessary that genetic testing be accompanied by genetic counseling.

Neurophysiological assessment may be helpful in myoclonus, where myoclonic jerks show brief electromyography (EMG) bursts of 10–50 milliseconds. Rhythmicity in tremor can be demonstrated on EMG, but this is not frequently ordered by clinicians when evaluating a patient with tremor. Electromyography may also be helpful therapeutically in dystonic patients when used in conjunction with botulinum toxin treatment. Nerve conduction studies may be used to evaluate ataxic individuals for sensory abnormalities in peripheral nerves.

Imaging can be valuable in movement disorders that do not fit classic patterns or presentations. The most common movement disorders typically show normal basal ganglia structures on routine imaging, as in essential tremor, and dystonia. However, patients with movement disorders that are localized to one side of the body, that have abrupt stroke‐like onset, or that include ataxia should be imaged with computed tomography or preferably, magnetic resonance imaging. Atrophy of specific structures, such as the striatum in Huntington disease, or the cerebellum in degenerative ataxias, may support the clinical diagnosis. Functional or nuclear medicine imaging is playing an increasingly important role in diagnostics.

Treatment

The majority of treatment options in movement disorders are symptomatic, not curative. However, in a few circumstances, early intervention of treatable forms of movement disorders may be curative or halt the progression of the disease. While rare, such conditions should be considered in patients with particular disease profiles; examples include patients with young onset tremor, dystonia or parkinsonism (Wilson disease), or fluctuating dystonic and parkinsonian features (dopa‐responsive dystonia).

The approach described in this chapter offers a straightforward approach to evaluating a movement disorder patient. Questions about the movements, course, family history, medical illnesses, and medication response will help the clinician with the evaluation. Correctly describing the phenomenology is key to narrowing the list of diagnostic possibilities and guides the need for additional testing. The subsequent chapters will fill in the details, and with this framework, the reader will gain an ease of diagnosis and treatment of movement disorders.

Further Readings

Fahn S, Jankovic J, Hallett M.

Principles and Practice of Movement Disorders

, 2nd ed. Philadelphia: Saunders, 2007.

Fernandez HH, Rodriguez RL, Skidmore FM, Okun MS.

A Practical Approach to Movement Disorders: Diagnosis, Medical and Surgical Management

. New York: Demos Medical Publishing, 2007.

Part 1Hypokinetic

2Hypokinetic (Non‐Parkinsonian) Movement Disorders

Shyamal H. Mehta, MD, PhD1 and Alberto J. Espay, MD, MSc2

1Department of Neurology, Movement Disorders Division, Mayo Clinic, Phoenix, Arizona, USA

2Gardner Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA

Introduction

Movement disorders can be broadly classified into two categories, based on the presence of excess movement or a deficiency of movement. Hyperkinetic movements involve the presence of excessive involuntary movements that may manifest as tremor, chorea‐ballism, myoclonus, and tics, among other disorders. Hypokinetic movements show paucity of movement and are described with terms such as bradykinesia (slowness of movement) or akinesia (absence or extreme poverty of movement). The most common form of hypokinetic disorders are the parkinsonian syndromes, including idiopathic Parkinson Disease (PD), atypical parkinsonism, (multiple system atrophy, corticobasal syndrome, progressive supranuclear palsy, etc.), and secondary causes of parkinsonism (midbrain tumors, paraneoplastic disorders, etc.). These topics are covered in another book in this series. A different category of slowness comes from disorders that affect motor function to the extent of rendering it “parkinsonian” but that cannot be explained by traditional impairments in the basal ganglia circuitry. This chapter focuses on the non‐parkinsonian causes of hypokinetic movement disorders, which may not be traditionally included in the differential diagnosis of parkinsonism.

This chapter aims to highlight some of the important and treatable causes of non‐parkinsonian hypokinetic syndromes such as stiff person syndrome, primary lateral sclerosis, catatonia and psychomotor depression, hypothyroidism, and normal pressure hydrocephalus. These, along with other general causes, which can result in paucity or absence of movement, are listed in Table 2.1.

Table 2.1 Non‐parkinsonian causes of hypokinesia

Stiff‐person syndrome and related disorders

Primary lateral sclerosis (PLM)

Catatonia

Neuromuscular causes: hypothyroidism, Brody syndrome, myotonia

Akinetic mutism

Sequelae of vascular events (affecting anterior cerebral artery distribution)

Structural lesions: tumors, hydrocephalus, traumatic brain injury

Post‐infectious: Creutzfeldt–Jakob disease, post‐encephalitic parkinsonism

Functional or psychogenic slowness

Stiff‐person syndrome (SPS)

Moersch and Woltman described “stiff man syndrome” in 1956 in 14 patients who had progressively fluctuating rigidity and painful spasms affecting the muscles of the back and abdomen. An association between SPS and DM was established in the late 1980s; however, only a few of the originally reported patients had concomitant diabetes mellitus (DM). Solimena and colleagues later reported the presence of anti‐glutamic acid decarboxylase (anti‐GAD) antibodies in patients with SPS and DM. Since GAD is the rate‐limiting enzyme for the synthesis of GABA, the major inhibitory neurotransmitter, in the central nervous system, GABAergic depletion at the cortical and spinal interneuronal level is central to the pathogenesis of SPS.

About 80% of SPS patients have a high titer of anti‐GAD antibodies detectable in the serum or CSF. GAD is synthesized in the presynaptic GABAergic neurons in both the central nervous system and in the islet of Langerhans β‐cells of the pancreas, hence the association with DM. There are two GAD isoforms—GAD65 and GAD67—but it is GAD65 that has been implicated in both SPS and DM. The GAD antibodies recognize different regions (epitopes) of the GAD molecule. The GAD antibodies in type 1 DM recognize the carboxy‐terminal end or the center of the GAD molecule, while in SPS they recognize the amino‐terminal fragment of GAD. Even though GAD antibodies are the most common antibodies associated with SPS, other proteins, both pre‐ and post‐synaptic, in the GABAergic neuron have been implicated in the etiology of SPS or its variants (Box 2.1).

Box 2.1 Autoimmune antibodies in SPS and variants

Presynaptic:

GAD and amphiphysin

Postsynaptic:

GABA‐A receptor associated protein, glycine and gephyrin

Clinical features

SPS disease is sporadic in nature, affecting women more often than men (in a recent series ~ 70% patients were women). Although the age of onset is variable, most of the afflicted adults are between 29 to 59 years of age. Symptoms start slowly and insidiously with episodic aching and stiffness of the axial musculature (paraspinal and abdominal muscles). Symptoms are usually symmetric and progress to involve the proximal muscles in all four extremities (Video 2.1). Typically the distal limb and facial muscles are spared. Patients have a characteristic hyperlordosis of the spine, which makes it very difficult for them to bend over to touch their toes. The hyperlordosis persists even when they are laying down. The rigidity and stiffness may fluctuate on an hour‐to‐hour or daily basis. If it affects the neck, patients should be counseled not to drive until adequately treated, as it may significantly limit their ability to turn their heads.

Superimposed on the stiffness, patients also have intermittent severe spasms. These can be precipitated by various triggers, such as loud noise, sudden movement, touch, stress, and fatigue. Spasms usually last for minutes and abate once the offending stimuli are removed. However, during the spasms, patients can experience significant pain. The spasms can be variable in magnitude and severity, may occur in rapid succession, leading to a “spasmodic storm,” and can be severe enough to cause fracture of the long bones.

The fear of precipitating the spasms causes patients to have anxiety and task‐related phobias. More than 50% of patients fear open spaces. The presence of phobias, excessive startle, and exacerbation of symptoms when emotionally upset many times leads to an erroneous diagnosis of a functional or psychogenic disorder and, unfortunately, delays proper treatment.

Electromyography (EMG) studies show the presence of continuous motor unit activity at rest without any abnormality in the motor unit morphology. Reflex‐induced spasms are short‐latency (<80 ms), stereotyped motor responses to nerve stimulation. These are expressed as one or more hypersynchronous bursts of EMG activity followed by short pauses and then slow cessation.

Diagnosis of SPS variants and related conditions

SPS is a clinical diagnosis. Dalakas and colleagues have outlined criteria, which can assist the clinician in making the diagnosis (Box 2.2). However, there are patients who do not meet all of these criteria or have other additional features: they are often categorized as SPS variants, which we describe below (Box 2.3).

Box 2.2 Guidelines for diagnosis of SPS—Dalakas criteria

Stiffness in axial muscles (abdominal and thoracolumbar) leading to hyperlordosis of the spine

Superimposed painful spasms precipitated by sudden noise, stress, or tactile stimuli

Confirmation of the continuous motor unit activity in agonist and antagonist muscles by electromyography

Absence of other neurological findings that could explain the stiffness

Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot, or radioimmunoassay

Response to benzodiazepines

*

* Not part of Dalakas's criteria, but commonly included in the diagnostic criteria.

Box 2.3 SPS variants and associated conditions

Stiff‐person plus syndrome

Stiff‐limb syndrome

Paraneoplastic SPS

Progressive encephalomyelitis with rigidity and myoclonus (PERM)

Progressive encephalomyelitis with rigidity and myoclonus

Progressive encephalomyelitis with rigidity and myoclonus (PERM) variant of SPS (formerly, “stiff‐person plus syndrome”) is a rare paraneoplastic disorder characterized by brainstem (cranial nerve) signs, long tract signs from spinal cord involvement, and myoclonus, in addition to the typical SPS signs/symptoms. Patients with PERM have symptoms atypical for SPS and poor response to medications. Imaging may show white matter hyperintensities in the brain and/or spinal cord. CSF studies show lymphocytic pleocytosis, elevated IgG, and oligoclonal bands. Recently, antibodies to glycine receptors have been detected in patients with PERM in addition to amphiphysin and GAD antibodies.

Stiff‐limb syndrome

Some patients have focal onset of rigidity, affecting a single limb. This is descriptively termed “stiff‐limb syndrome (SLS).” In this SPS variant, the symptoms remain most severe in the presenting limb, although eventually axial muscles may be affected as well. However, spread to other areas is less common. Patients with stiff‐limb syndrome are often anti‐GAD‐antibody negative, and in general, anti‐GAD antibodies are less common in SLS as compared to SPS (15% vs. 88%). Also patients with SLS may not adequately respond to GABAergic medications such as benzodiazepines, which are very beneficial in classic SPS. Successful treatment with botulinum toxin type A has been reported, since the symptoms of SLS are focal in nature as compared to SPS.

Paraneoplastic SPS

SPS of paraneoplastic etiology (ca. 5% of the SPS patients) predominantly affects the neck and arms as opposed to the typical lower‐body‐predominant distribution of SPS. It is associated with malignancies of the breast, colon, lung, thymus, and Hodgkin’s lymphoma. The antibodies involved are amphiphysin and gephyrin. If these antibodies are positive, a high degree of clinical suspicion for a covert malignancy is warranted.

Treatment

Benzodiazepines form the mainstay of treatment in SPS. Diazepam (10–100 mg/d) and clonazepam (4–6 mg/d) both have been used with considerable success. Patients tend to stabilize clinically and are able to function on this regimen, but they may continue to experience disability from residual stiffness. Baclofen, a GABAB receptor agonist, is the second drug of choice. Oral doses up to 100 mg/d and intrathecal pump infusion have been used. A practical approach is to use a combination of diazepam and baclofen, allowing lower doses than may be possible with each drug alone. Anticonvulsants that augment GABAergic transmission, such as valproic acid, gabapentin, vigabatrin, and levetiracetam, have been successfully used in selected cases.

Given the immunologic etiology of SPS, immunomodulatory therapy has also been considered. Anecdotal reports and a placebo‐controlled trial with intravenous immunoglobulin (IVIg) have yielded promising results, and IVIg is the preferred immunotherapeutic option. Reports of benefit with plasmapheresis are also reported. Treatment with prednisone and other immunosuppressive agents are less promising. However, there are increasing reports of rituximab (a B‐cell depleting monoclonal antibody) being successfully used in the treatment of benzodiazepine‐refractory SPS and to treat the PERM variant. Treatment of paraneoplastic SPS also requires addressing the underlying malignancy. Botulinum toxin injections can be considered for targeted areas (paraspinal or thigh muscles) or in an affected extremity in stiff‐limb syndrome, to supplement oral medications.

Primary lateral sclerosis

Primary lateral sclerosis (PLS) was a term coined in the nineteenth century by Erb to describe a disorder characterized by “spinobulbar” spasticity exclusively due to upper motor neuron degeneration. Some patients with PLS eventually develop lower motor neuron signs, meeting criteria for amyotrophic lateral sclerosis (ALS). Lower‐extremity onset and slow progression increase confidence in the diagnosis of PLS and decrease the likelihood of later evolution into ALS. PLS affects equally both genders. The age of onset ranges from 30s to late 60s (Box 2.4). Although it is a sporadic disease with no family history in affected individuals, a rare hereditary variant affecting infants and children has been identified, called juvenile PLS. Mutations in the amyotrophic lateral sclerosis 2 (ALS2) gene coding for the protein Alsin or a loss of function mutation in ERLIN2 gene (which codes for endoplasmic reticulum lipid raft protein that plays a role in ER associated degradation pathway) have been implicated in the etiology of juvenile PLS.

Box 2.4 Criteria for diagnosis of primary lateral sclerosis—Pringle criteria

Adult onset

Spastic quadriparesis, spastic dysarthria, hyperreflexia, and bilateral Babinski signs with or without pseudobulbar affect for at least three years

Absence of lower motor neuron signs

Preservation of higher cognitive functions

Magnetic resonance imaging demonstrates atrophy of the precentral gyrus

Negative spinal cord MRI (to exclude cervical myelopathy)

Negative family history

Negative CSF studies (to exclude inflammatory, autoimmune and paraneoplastic processes)

PLS typically manifests with slowly progressive, lower extremity pain, weakness and spasticity (Video 2.2). Less commonly, upper extremity or bulbar symptoms can be presenting features. The spastic paresis tends to progress in a cephalad fashion to involve the axial musculature and upper extremities, eventually involving the bulbar musculature causing dysarthria and dysphagia. A diagnosis of PLS should not be made at the initial onset of symptoms unless at least three years have elapsed with slowly progressive upper motor neuron signs, in the absence of other motor, extrapyramidal, or cognitive impairments. Lower extremity onset, very slow progression, and absence of lower motor neuron signs at five years increases the diagnostic certainty of PLS.

Nerve conduction studies are normal in PLS and electromyography (EMG) studies may be normal or show mild denervation changes in the distal muscles (in stark contrast to ALS). However, repeat biannual testing for at least five years should be done to monitor for development of lower motor neuron involvement. MRI of the cervical spine is mandatory to exclude cervical myelopathy, which is the main PLS mimic. CSF studies may be considered to exclude inflammatory, post‐infectious, or autoimmune encephalomyelopathies.

The treatment for PLS is symptomatic. Muscle relaxants (e.g., baclofen, tizanidine, and cyclobenzaprine) or benzodiazepines (diazepam or clonazepam) may help alleviate the spasticity. When oral medications do not provide adequate relief, intrathecal baclofen may be considered. Treatment of other comorbid infections such as respiratory tract and urinary tract infections are necessary to prevent exacerbation of spasticity. Physical therapy for muscle strengthening and stretching exercises may be beneficial. Physical therapy assessments of gait and balance and speech therapy evaluations of swallowing are crucial in tailoring management to minimize these complications. In later stages, when breathing is affected, non‐invasive ventilatory support may be necessary. With appropriate care, the median survival of PLS of 20 years and is significantly longer than ALS.

Catatonia

Dr. Karl Kahlbaum (1828–1899) first described catatonia in his monograph published in 1874, wherein he published case histories of 28 patients with catatonic episodes. Catatonia is a syndrome of excessive motor inhibition associated with disorders of mood, behavior, or thought. It is commonly encountered in the psychiatric inpatient setting, especially in patients with schizophrenia (Box 2.5). Although catatonia is not typically categorized as a movement disorder, it is characteristic for its extreme poverty of movement (akinetic form) and can sometimes be difficult to distinguish from parkinsonism. Other presentations include hyperexcitable and malignant forms associated with the neuroleptic malignant syndrome (NMS). The common signs in catatonia include mutism or echo phenomena (echolalia, echopraxia) cataplectic posturing, waxy flexibility, negativism, and staring (Video 2.3). Variable features include stereotypy, mannerisms, and automatic obedience. Catatonia may also occur in special populations such as children with developmental and neurological disorders, especially those with autism and related disorders, as well as geriatric patients with severe depression. Some other causes of catatonia include post‐encephalitic parkinsonism, tacrolimus neurotoxicity in organ transplant patients, anti‐NMDA receptor antibody‐mediated encephalitis, post anoxic brain injury, and as a part of neurobehavioral disorders such as autism and Tourette’s syndrome.

Box 2.5 causes of catatonia

Psychiatric Illness: schizophrenia, depression, obsessive‐compulsive disease

Drugs—dopamine receptor blocking drugs (antipsychotics and some antiemetics), selective serotonin reuptake inhibitors

Post‐encephalitic parkinsonism

Tacrolimus‐induced neurotoxicity in solid organ transplant patients

Anti‐NMDA receptor antibody‐mediated encephalitis

Some neurodevelopmental diseases such as autism and Tourette syndrome

Post‐anoxic brain injury

Treatment of catatonia should be done in concert with a psychiatrist. Identification of the syndrome and the underlying cause is key to its successful treatment. The motor manifestations of catatonia syndrome are exquisitely responsive to benzodiazepines and barbiturates. In fact, symptomatic improvement after the acute administration of a challenge with lorazepam is used as a confirmatory test of the diagnosis. Lorazepam 1–2 mg is administered sublingually or intramuscularly. If this is ineffective, it should be repeated again in three hours and then again in another three hours as an adequate treatment trial. Higher doses (4–12 mg/d) are rarely necessary. Also the presence of catatonia can increase the risk of NMS if antipsychotics are introduced prior to treatment of catatonia. Antipsychotics can be safely introduced once the patients are ambulatory and catatonia is resolved. There are data to support the use of electroconvulsive therapy (ECT) for the treatment of catatonia, regardless of various psychiatric disorders and organic causes, if symptoms do not improve with benzodiazepines.

Neuromuscular causes of hypokinesia

Hypothyroidism

Hypothyroidism is common in the elderly, affecting 5–20% of women and 3–8% of men. Common causes include autoimmune thyroiditis, previous thyroid surgery, and radioiodine therapy. Medications such as amiodarone and lithium, among others, can also cause hypothyroidism. Some of the common clinical signs, which can be mistaken for signs of PD, include changes in voice, fatigue, weakness/slowness of the extremities, and constipation. In addition, patients can have “hung‐up” reflexes (delayed relaxation of the deep tendon reflexes) in hypothyroidism, which are not seen in PD. Hence screening and testing for thyroid dysfunction should always be done in elderly patients, especially if there are other signs or symptoms which might be atypical for PD.

Brody syndrome

This is an autosomal recessive, male‐predominant disorder associated with impaired calcium uptake by the sarcoplasmic reticulum (Science Revisited). The characteristic clinical feature involves chronic difficulty in performing sustained muscular activities due to an exercise‐induced failure in relaxation. A task may be feasible to perform initially, but with continued effort, significant slowing to the point of movement cessation occurs, requiring a period of rest for the movement to be restored. This may give the false appearance of bradykinesia, although amplitude decrement is not appreciated. Clinical exam reveals normal strength with single effort, normal sensation, normal deep tendon reflexes, and the absence of percussion myotonia. EMG shows electrical silence in a contracted muscle after exercise. Dantrolene sodium and calcium channel blockers, such as verapamil and nifedipine, have been used successfully in the treatment of Brody syndrome.

SCIENCE REVISITED

Genetics of Brody disease and syndrome

Brody disease—rare inherited myopathy due to mutations in ATP2A1 gene (ATPase, Ca++ transporting, cardiac muscle, fast twitch 1) causing reduced sarcoplasmic reticulum Ca2+ ATPase (SERCA1) enzyme activity. Low SERCA1 activity leads to slow entrance of calcium ions into the sarcoplasmic reticulum, thus delaying muscle relaxation and causing muscle cramps.

Brody syndrome—similar phenotype except for prominent myalgias. Reduced SERCA1 enzyme activity occurs in the absence of ATP2A1 gene mutations.

Myotonia

Myotonia is the delayed relaxation of skeletal muscle fibers after voluntary muscle contraction. It manifests as painless muscle stiffness immediately on initiating activity. Patients may have difficulty relaxing their tight grip after a handshake or opening their eyes after tight eye closure, giving the appearance of slowness of movement. Percussion of the thenar eminence with a reflex hammer results in prolonged adduction or opposition of the thumb (percussion myotonia). Myotonia improves after repeated effort and exercise (the “warm‐up phenomenon”). EMG reveals motor unit potentials with a characteristic waxing and waning pattern—similar to the sound of a dive‐bomber or motorcycle.

The two major categories of myotonia are dystrophic and non‐dystrophic. Myotonic dystrophy is a common muscular dystrophy, involving progressive muscle weakness, myotonic discharges and multi‐organ involvement. There are two genetically distinct types, both of which are autosomal dominant (Science Revisited). Adult‐onset myotonic dystrophy type 1 is characterized by muscle weakness, myotonia, cataracts, cardiac conduction defects (a significant cause of early mortality), insulin resistance, male hypogonadism, and frontal baldness. In contrast, signs and symptoms in myotonic dystrophy type 2 can be variable, and myotonia may or may not be present. Muscle weakness in type 2 disease begins at a later stage than type 1, the clinical course is more favorable, and life expectancy is almost normal since fewer patients with type 2 disease have severe cardiac complications. However, myalgias can be quite severe in type 2 disease and patients may need round‐the‐clock pain medications.

SCIENCE REVISITED

Genetics of myotonic dystrophy

Type 1

Type 2

Inheritance

Autosomal Dominant

Autosomal Dominant

Chromosome

19Q13.3

3Q21.3

Abnormal Gene

Dystrophia‐Myotonica Protein Kinase (

DMPK

)

Zinc‐Finger‐Protein‐9 Gene (

ZNF9

)

Expansion

CTG Trinucleotide Repeat Expansion

CCTG Tetranucleotide Repeat Expansion

Anticipation

Common

Rare

Other disorders with clinical and electrical myotonia or paramyotonia include myotonia congenita: Becker and Thomsen, which are responsive to acetazolamide, paramyotonia congenita (sodium or chloride channelopathies) (Box 2.6