Article 1: Parkinson Disease
Theresa A. Zesiewicz, MD, FAAN. Continuum (Minneap Minn). 2019; 25 (4 Movement Disorders):896–918.
PURPOSE OF REVIEW
Parkinson disease is a common neurodegenerative disorder that affects millions of people worldwide. Important advances in the treatment, etiology, and the pathogenesis of Parkinson disease have been made in the past 50 years. This article provides a review of thecurrent understanding of Parkinson disease, including the epidemiology, phenomenology, and treatment options.
Parkinson disease is nowrecognized to be a heterogeneouscondition marked by both motor and nonmotor symptoms. It is composed of preclinical, prodromal, and clinical phases. New medications with improved ease of administration have been approved for its treatment. Innovative surgical therapies for Parkinson disease may be used when motor symptoms persist despite optimal medical management.
Parkinson disease is a complex, heterogeneous neurodegenerativedisorder. Considerable progress has been made in its treatment modalities, both pharmacologic and surgical. While its cure remains elusive, exciting new research advances are on the horizon.
- A renaissance of therapeutic options for Parkinson disease have occurred in the last 50 years. Levodopa remains the gold standard for treatment of Parkinson disease, but dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyltransferase inhibitors, and surgical procedures have greatly expanded the therapeuticoptions.
- Parkinson disease affects millions of people worldwide, and its prevalence increasesgreatly with advancing age.
- Clinical features of Parkinson disease include tremor, rigidity, akinesia (or bradykinesia), and posturalinstability. Nonmotor symptoms are commonly experienced by patients and often negatively impact quality of life. Premotor symptoms include constipation, anosmia, rapid eye movement sleep disorder, and depression.
- The diagnosis of Parkinson disease is made clinically. Red flags for atypical parkinsonism include severe dysautonomia, early-onset hallucinations and dementia, freezing, postural instability, and lack of response to levodopa. Red flags for atypical parkinsonism also include early speech difficulties and imbalance, poor response to levodopa, and symmetrical symptoms.
- Parkinson disease may be divided into preclinical, prodromal, and clinical phases. Patients generally experience good response to levodopa for several years following their diagnosis.
- Parkinson disease is characterized by the loss of dopaminergic neurons and the presence of Lewy bodies containing the misfolded protein α-synuclein.
- Parkinson disease remains a clinical diagnosis. Neuroimaging techniques such as dopamine transporter single-photon emission computed tomography are helpful in differentiating between essential tremor and tremor from parkinsoniansyndromes.
- Clinical rating scales and patient diaries are helpful inmonitoring disease progression and are useful tools in clinical research trials.
- While levodopa is the gold standard in the treatment of Parkinson disease, it is nowavailable in several formulations that may provide ease of administration and improved efficacy. Other available medications are dopamineagonists, catechol-O-methyltransferase inhibitors, monoamine oxidase type B inhibitors, an N-methyl-D-aspartate antagonist, and anticholinergic medications.
- Patients with Parkinson disease should be offered dopaminergic treatment when their symptoms are bothersome. Patients with Parkinson disease should be encouraged to exercise, as long as it is performed safely.
- The aim of Parkinson disease treatment is to optimize on time and reduce off time while minimizing troublesome levodopainduced dyskinesia. Treatment of levodopa induced dyskinesia requires identifying its occurrence in relation to levodopa dosing.
- Surgical treatment of Parkinson disease was developed for patients who, despite medication optimization, experience motor symptoms that cannot be satisfactorily ameliorated by medication.
Article 2: Progressive Supranuclear Palsy, Corticobasal Degeneration, and Multiple System Atrophy
Paul Greene, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):919–935.
PURPOSE OF REVIEW
Patients who have parkinsonian features, especially without tremor, that are not responsive to levodopa, usually have one of these three major neurodegenerative disorders rather than Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). Each of these disorders eventually develops signs and symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at disease onset. Although these conditions are not generally treatable, it is still important to correctly diagnose the condition as soon as possible.
In recent years, it has been increasingly recognized that thesymptoms of these diseases do not accurately predict the pathology, and the pathology does not accurately predict the clinical syndrome. Despite this, interest has grown in treating these diseases by targetingmisfolded tau (in thecase of PSP and CBD) and misfolded α-synuclein (in the case of MSA).
Knowledge of the characteristic signs and symptoms of PSP, MSA, and CBD are essential in diagnosing and managing patients who have atypical parkinsonian syndromes.
- Patients with parkinsonian features who do not improve with levodopa usually do not have idiopathic Parkinsondisease and often have either progressive supranuclear palsy, multiple system atrophy, or corticobasal degeneration.
- Progressive supranuclear palsy is a likely diagnosis in patients with parkinsonian features and earlydevelopment of a supranuclear palsy.
- Some patients with progressive supranuclear palsy do not develop a supranuclear palsy until later in the course of the disease. Early features that suggest progressive supranuclear palsy are an angry or puzzled look, growling speech, early development of dysphagia, and a broad-based gait with abducted arms.
- A minority of patients with the pathology of progressive supranuclear palsy may have signs and symptoms suggesting a variety of conditions, including corticobasal degeneration and, rarely, idiopathic Parkinson disease, primary progressive aphasia, cerebellar ataxia, frontotemporal dementia, and primary lateral sclerosis.
- Other pathologies may produce signs and symptoms suggestive of progressive supranuclear palsy, including Alzheimer disease, some frontotemporal dementias, Whipple disease, Niemann-Pick disease type C, and Gaucher disease.
- The pathology of progressive supranuclear palsy is characterized by deposits of 4-repeat tau in astrocytes and oligodendroglia in multiple regions of the basal ganglia and cortex of the brain.
- Preliminary studies of agents that interfere with the formation or spread of misfolded tau are being conducted with the hope of stopping or slowing the progression of progressive supranuclear palsy.
- The clinical hallmarks of classic corticobasal degeneration are parkinsonism combined with unilateral dystonia, myoclonus, and cortical deficits such as apraxia, cortical sensory loss, and alien limb phenomenon.
- As in progressive supranuclear palsy, the pathology of corticobasal degeneration also involves widespread deposition of 4-repeat tau but also includes asymmetric cortical atrophy and neuronal, oligodendroglial, and astrocytic deposits distinct from the deposits in progressive supranuclear palsy.
- As with progressive supranuclear palsy, multiple pathologies may mimic the signs and symptoms of corticobasal degeneration, including progressive supranuclear palsy, Alzheimer disease, Pick disease, and Creutzfeldt-Jakob disease. When this happens, it is known as corticobasal syndrome. Similarly, the pathology of corticobasal degeneration may present as progressive supranuclear palsy, primary nonfluent aphasia, Alzheimer disease, and other conditions.
- Middle-aged patients presenting with parkinsonism, autonomic insufficiency, and ataxia usually have multiple system atrophy. However, many patients with multiple system atrophy may initially only have symptoms in one or two of these categories, making the correct diagnosis more difficult. The development of laryngeal stridor is a strong clue that the diagnosis is multiple system atrophy.
- Unlike progressive supranuclear palsy and corticobasal degeneration, multiple system atrophy is a synucleinopathy, not a tauopathy. This may have implications for future treatments.
- Like progressive supranuclear palsy and corticobasal degeneration, there are widespread pathologic abnormalities in multiple systematrophy, but the characteristic inclusions contain α-synuclein, not tau. The first identified abnormality was a glial cytoplasmic inclusion containing α-synuclein, but neuronal inclusions havealso been identified. Rarely, Lewy bodies are found in multiple system atrophy.
- There has been an intensive search for genetic risk factors for these conditions. Some candidate genes have been identified, but this has not currently led to any therapeutic innovations. Some genes have been identified thatoccasionally produce one of these syndromes, but those, so far, have been responsible for only a small percentage of known cases.
- The typical features of progressive supranuclear palsy (supranuclear palsy), corticobasal degeneration (cortical myoclonus and other focal cortical deficits), and multiple system atrophy (autonomic failure and ataxia) suggest the correct diagnosis but do not achieve both sensitivity and specificity.
- Some symptoms of progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophycan be treated, such as constipation; blepharospasm and other dystonias (with botulinum toxin injections); orthostasis; depression; pain; pseudobulbar affect; and other symptoms.
Article 3: Tics and Tourette Syndrome
Harvey S. Singer, MD, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):936–958.
PURPOSE OF REVIEW
The purpose of this article is to present current information on the phenomenology, epidemiology, comorbidities, and pathophysiology of tic disorders and discuss therapy options. It is hoped that a greater understanding of each of these components will provide physicians and caregivers with the necessary information to deliverthoughtful and optimal care to affected individuals.
Recent advances include the finding that Tourette syndrome is likely due to a combination of several different genes, both low-effect and larger-effect variants, plus environmental factors. Pathophysiologically, increasing evidence supports involvement of the cortical–basal ganglia–thalamocortical circuit; however, the primary location and neurotransmitter remain controversial. Behavioral therapy is first-line treatment, and pharmacotherapy is based on tic severity. Several newer therapeutic agents are under investigation (eg, valbenazine, deutetrabenazine, cannabinoids), and deep brain stimulation is apromising therapy.
Tics, defined as sudden, rapid, recurrent, nonrhythmic motormovements or vocalizations, are essential components of Tourette syndrome. Although some tics may be mild, others can cause significant psychosocial, physical, and functional difficulties that affect daily activities. In addition to tics, most affected individuals have coexisting neuropsychological difficulties (attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety, mood disorder, disruptive behaviors, schizotypal traits, suicidal behavior, personality disorder, antisocial activities, and sleep disorders) that can further impact social and academic activities or employment.
- Tics have several characteristics that are useful in identifying their presence, including precipitating factors, a waxing and waning pattern, admixture of new and old tics, a premonitory urge thatresolveswhen the tic is done, reduction when engrossed, and variable severity.
- Tics can be highly variable and fluctuate, and an individual’s tic repertoire evolves over time.
- The diagnosis of a tic disorder is based on historical features and observation of the tics; no definitivediagnostic laboratory test has yet been established.
- Simple tics are relatively common in childhood, with reports of prevalence (the number of cases in thepopulation at a given time) being 6% to 12% (range of 4% to 24%).
- Most individuals with Tourette syndrome have at least one comorbid/coexisting neuropsychological problem.
- Coexisting neuropsychological issues add a significant additional burden to patients with Tourette syndrome or chronic motor or vocal tic disorder.
- Tourette syndrome is currently classified as a polygenic inherited disorder, suggesting that a combination of a variety of genes (some common, some with a loweffect or rare, and others having a larger effect) and environmental factors are all involved in its transmission.
- The existence of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections(PANDAS) and its proposed therapy are extremely controversial.
- A series of parallel cortical–basal ganglia–thalamocortical circuits provide a framework for understanding the pathophysiology of tics and associated behaviors.
- Identification of the true primary site of anatomic abnormality in Tourette syndrome remains an area of active discussion.
- It is important to recognize that within a multitransmitter interconnected system, a successful pharmacotherapy does not necessarily indicate that the primary neurotransmitter abnormality is being targeted.
- The establishment of an effective therapeutic plan for Tourette syndrome and tics requires careful initialassessment of tics, determining the presence of co-occurring issues, and clarifying the resulting impairment of each issue.
- The first step in treatment of Tourette syndrome is education of the patient, his/her family, and the school or workplace about the diagnosis, its potential coexisting issues, and indications for therapy.
- Specific criteria for initiating behavioral or pharmacologic ticsuppressing therapy include the presence of psychosocial problems, tic-induced musculoskeletal/physical difficulties, and disruption of classroom/work settings.
- Various practice guidelines have suggested that habit reversal training, more specifically Comprehensive Behavioral Intervention for Tics (CBIT) should be the first-line intervention for tics.
- In general, a two-tiered approach to the use of pharmacotherapy is recommended for treating tics, with use of tier 1 medications for milder tics and use of tier 2medications reserved for more difficult to control symptoms.
- Deep brain stimulation is a stereotactic treatment that has significant potential for the treatment of tics.
Article 4: Tremor
Elan D. Louis, MD, MS, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):959–975.
PURPOSE OF REVIEW
Tremor may be defined as an involuntary movement that is rhythmic (ie, regularly recurrent) and oscillatory (ie, rotating around a central plane) and may manifest in a variety of ways; accordingly, tremor has a rich clinical phenomenology. Consequently, the diagnosis of tremor disorders can be challenging, and misdiagnoses are common. The goal of this article is to provide the reader with straightforward approaches to the diagnosis and treatment of tremors.
Focused ultrasound thalamotomy of the ventral intermediate nucleus of the thalamus is an emerging and promising therapy for the treatment of essential tremor.
The evaluation should start with a detailed tremor history followed by a focused neurologic examination, which should attend to the many subtleties of tremor phenomenology. Among other things, the history and examination are used to establish whether the primary tremor is an action tremor (ie, postural, kinetic, or intention tremor) or a resting tremor. The clinician should then formulate two sets of diagnoses: disorders in which action tremor is the predominant tremor versus those in which resting tremor is the predominant tremor. Among the most common of the former type are essential tremor, enhanced physiologic tremor, drug-induced tremor, dystonic tremor, primary writing tremor, orthostatic tremor, and cerebellar tremor. Parkinson disease is the most commondisorder of resting tremor. This article details the clinical features of each of these disorders, as well as those of additional tremor disorders. Thediagnosis of tremor disorders is challenging. The approach to evaluating apatientwith a tremor involves a history and a neurologic examination that is focused on the nuances of tremor phenomenology, which are numerous.
- Tremors are involuntary movements that are both rhythmic and oscillatory.
- An initial step in evaluating patients with tremor is to determine whether the tremor is primarily present at rest or with activity.
- The key feature of essential tremor is kinetic tremor.
- The kinetic tremor of essential tremor is typically slightly asymmetric.
- Approximately one-half of patients with essential tremor exhibit intention tremor during the fingernose-finger maneuver.
- The postural tremor in essential tremor is generally out of phase; this can create a seesaw effect when thepatients’ arms are held in the wing-beat position.
- Resting tremor may occur in patients with severe or long-standing essential tremor, but it is restricted to the arms.
- Neck tremor is several times more common in women with essential tremor than in men with essential tremor.
- Neck tremor is always pathologic. It is not a feature of enhanced physiologic tremor.
- Although limb tremor may be present, head tremor should not be a feature of drug-induced action tremor.
- The tremor in dystonia may be neither rhythmic nor oscillatory.
- Dystonic head tremor often persists after the patient lies on his or her back; this is generally not true of essential tremor.
- Primary writing tremor is a tremor that occurs mainly while writing but not during other tasks that involve the hands.
- In some cases, orthostatic tremor may be heard when a stethoscope is placed over the affected leg; the tremormakes a sound like a distant helicopter.
- The clinical phenomenology of tremor of cerebellar origin is heterogeneous, and it extends beyond that ofintention tremor to include postural tremor, kinetic tremor, resting tremor, and orthostatic tremor.
- Rubral tremor is strikingly asymmetric, and it has resting, postural, and kinetic components.
- Psychogenic tremors often have an abrupt onset.
- Wing-beat tremor is considered a classic tremor in Wilson disease, but it is not the most common type of tremor in that disease.
- Although intention tremor is common in patients with fragile X tremor-ataxia syndrome, kinetic, postural, and resting tremorsmay also occur.
- The resting tremor in Parkinson disease is generally asymmetric.
- In contrast to essential tremor, the jaw tremor of Parkinson disease is more often noted when the patient’s mouth is closed and relaxed rather than while the patient is speaking.
Article 5: The Dystonias
H. A. Jinnah, MD, PhD. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):976–1000.
PURPOSE OF REVIEW
This article provides a summary of the state of the art in the diagnosis, classification, etiologies, and treatment of dystonia.
Although many different clinicalmanifestations of dystoniahave been recognized for decades, it is only in the past 5 years that a broadly accepted approach has emerged for classifying them into specific subgroups. The new classification system aids clinical recognition and diagnosis by focusing on key clinical features that help distinguish the many subtypes. In the past few years, major advances have been made inthe discovery of new genes as well advances in our understanding of the biological processes involved. These advances have led to major changes in strategies for diagnosis of the inherited dystonias. An emerging trend is to move away from heavy reliance on the phenotype to target diagnostic testing toward a broader approach that involves large gene panels or whole exome sequencing.
The dystonias are a large family of phenotypically andetiologically diverse disorders. The diagnosis of these disorders depends on clinical recognition of characteristic clinical features. Symptomatic treatments are useful for all forms of dystonia and include oral medications, botulinum toxins, and surgical procedures. Determination of etiology is becoming increasingly important because the number ofdisorders is growing and more specific and sometimes disease-modifying therapies now exist.
- Dystonic movements are not always slow; they can be rapid or jerky, or resemble tremor.
- Dystonic movements tend to be patterned, not random.
- Dystonic movements are often triggered or worsened by voluntary muscle activity.
- Identification of a geste antagoniste (sensory trick) can be a very helpful clue because it is unique to dystonia and is important to ask patients about.
- The history and examination of patients with dystonia should focus on four areas: body region affected, age at onset, temporal features, and ancillary neurologic problems.
- For the most common focal dystonias that emerge after 40 years of age, laboratory investigations are usually not needed.
- For any dystonia that emerges in a child or young adult, laboratory investigations are guided by the history and examination.
- For almost all classic inherited dystonic disorders in children, late-onset cases or less severe cases are known to occur in adults.
- Elucidating etiology is important because specific treatments are available for several types of dystonia.
- Isolated dystonia may be the initial manifestation for neurologic disorders typically associated with more complex syndromes.
- More than 100 known causes for dystonia exist.
- Genetic forms of dystonia should be referred to by the name of the gene, not the DYT locus name.
- Dystonia results from dysfunction of a motor network that includes the basal ganglia, cerebellum, and sensorimotor cortex.
- All children and young adults with unexplained dystonia must have a trial of levodopa to rule outdopa-responsive dystonia.
- Carbamazepine and related anticonvulsant medications may be remarkably effective at very low doses in patients with paroxysmal kinesigenic dyskinesia.
- When treating dystonia, it is important to customize both the dose and the interval between doses for optimal benefits with botulinum toxin.
- Botulinum toxins are the treatment of first choice for focal and segmental dystonias and sometimes the most discomforting aspects in generalized dystonias.
- Deep brain stimulation is the most commonly offered surgical treatment for dystonia although ablative procedures may be appropriate in some cases.
- Selection of patients with dystonia for surgical intervention should be done by experienced multidisciplinary teams.
- Focused ultrasound is becoming more popular for ablative surgery in patients with dystonia although experience is still limited.
Article 6: Chorea
Pichet Termsarasab, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1001–1035.
PURPOSE OF REVIEW
This article provides an overview of the approach to chorea in clinical practice, beginning with a discussion of the phenomenologic features of chorea and how to differentiate it from other movement disorders. The diagnostic approach, clinical features of important acquired and genetic choreas, and therapeutic principles are also discussed. Practical clinical points and caveats are included.
C9orf72 disease is the most common Huntington disease phenocopy, according to studies in the European population. Anti-IgLON5 disease can present with chorea. The role of immunotherapies in Sydenhamchorea has increased, and further clinical studiesmay be useful. Benign hereditary chorea is a syndrome or phenotype due to mutations in several genes, including NKX2-1, ADCY5, GNAO1, PDE10A. New-generation presynaptic dopamine-depleting agents provide more options for symptomatic treatment of chorea with fewer adverse effects. Deep brain stimulation has been performed in several choreic disorders, but features other than chorea and the neurodegenerative nature should be taken intoconsideration. Studies on genetic interventions for Huntington disease are ongoing.
Clinical features remain crucial in guiding the differentialdiagnosis and appropriate investigations in chorea. Given the complexity of most choreic disorders, treating only the chorea is not sufficient. A comprehensive and multidisciplinary approach is required.
- Randomness is the key phenomenologic feature of chorea.
- Chorea with quick velocities may look jerky, resembling myoclonic jerks.
- Chorea in one of three body distributions (hemichorea, orobuccolingual involvement, and forehead chorea) can serve as a clue to narrow down the differential diagnoses.
- Structural lesions and systemic disorders (such as nonketotic hyperglycemia and polycythemia vera) can cause hemichorea.
- Sydenham chorea can present with hemichorea or very asymmetric involvement.
- The time course can help classify chorea into acquired and genetic etiologies.
- Age group and known prevalence are very important diagnostic clues in chorea.
- The most common acquired chorea in children is Sydenham chorea.
- The most common genetic chorea in adults is Huntington disease, followed by C9orf72 disease and spinocerebellar ataxia type 17.
- The most common genetic chorea in children is benign hereditary chorea.
- A negative family history does not exclude genetic causes of chorea.
- Huntington disease–like 2 is almost exclusively seen in patients with African ancestry.
- Autoimmune chorea should be included in the differential diagnoses of chorea with a subacute temporal profile.
- Neuropsychiatric features such as irritability, attention deficit hyperactivity disorder, and obsessivecompulsive behavior can be seen in Sydenham chorea.
- It is important to search for an underlying etiology in hormonal-related chorea, including chorea gravidarum and estrogen-induced chorea.
- Nonmotor features in Huntington disease are often more debilitating than chorea itself.
- Chorea is gradually replaced by parkinsonian features in later stages of Huntington disease; thus, the treatment regimen requires revision periodically.
- Delayed initiation of saccades is a hallmark eye movement abnormality in Huntington disease.
- Senile chorea should not be used as a diagnosis, and an underlying etiology should be sought.
- Children with Huntington disease typically do not present with chorea but rather parkinsonism, dystonia, and seizures.
- Age at onset in Huntington disease is determined by the number of CAG repeats, genetic modifiers, and environmental factors.
- Genetic counseling should be considered before ordering genetic testing for Huntington disease.
- Autosomal recessive ataxia syndromes can present with a variety of hyperkinetic movement disorders, including chorea.
- In addition to chorea-acanthocytosis and McLeod syndrome, acanthocytes can also be seen in 10% of Huntington disease–like 2 and pantothenate kinase–associated neurodegeneration as well as abetalipoproteinemia and aceruloplasminemia.
- Patients with McLeod syndrome can benefit from cardiac surveillance and autologous blood transfusion.
- Caudate atrophy is not specific to Huntington disease and can also be seen in other disorders, such aschorea-acanthocytosis and Huntington disease–like 2.
- Benign hereditary chorea syndromes can be due to multiple mutations; the classic benign hereditary chorea is due to NKX2-1 (TITF) mutations. Some patients with NKX2-1–related benign hereditary chorea can paradoxically respond to levodopa.
- Patients with choreic disorders can benefit from a multidisciplinary approach. Associated features and comorbidities, such as cognitive and neuropsychiatric features, should be taken into consideration when treating chorea. Mild and nonbothersome chorea does not require treatment. Immunotherapies are treatment options in Sydenham chorea.
- The main pharmacologic targets of chorea are dopaminergic synapses, either at presynaptic orpostsynaptic sites.
Article 7: Ataxia
Sheng-Han Kuo, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1036–1054.
PURPOSE OF REVIEW
This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellarataxia.
Recent advances in genetics have led to the identificationof novel genetic causes for ataxia and a more comprehensive understanding of the biological pathways critical for normal cerebellar function.When these molecular pathways become dysfunctional, patients develop cerebellar ataxia. In addition, several ongoing clinical trials for Friedreich ataxia and spinocerebellar ataxia will likely result in novel symptomatic and disease-modifying therapies for ataxia. Antisense oligonucleotides for spinocerebellar ataxias associated with CAG repeat expansions might be a promising therapeutic strategy.
Cerebellar ataxias include heterogeneous disorders affecting cerebellar function, leading to ataxic symptoms. Step-by-step diagnosticworkups with genetic investigations are likely to reveal the underlying causes of ataxia. Some disease-specific therapies for ataxia exist, such as vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke encephalopathy, highlighting the importance of recognizing these forms of ataxia. Finally, genetic diagnosis for patients with ataxia will accelerate clinical trials for disease-modifying therapy and will have prognostic value and implications for family planning for these patients.
- Determining the etiology of cerebellar ataxia iscomplex; however, step-by-step approaches can streamline the diagnostic workflow.
- Key questions regarding difficulty running, trouble walking in high heels or barefoot on the beach, andveering toward one side can be helpful in identifying the subtle gait abnormality associated with ataxia.
- Patients with ataxia can have a variety of eye movement abnormalities, including nystagmus, hypermetric or hypometric saccades, and ophthalmoplegia.
- The gait abnormality associated with cerebellar ataxia can change over the course of the disease.
- After establishing the signs of cerebellar ataxia, look for other neurologic signs (eg, tremor, dystonia, parkinsonism, motor neuron signs) as clues to the cause of ataxia.
- Laboratory evaluation can be helpful in identifying nutritional and immunologic causes of cerebellar ataxia.
- Aside from cerebellar atrophy, specific changes on MRI associated with different forms of cerebellar ataxia can provide important diagnostic clues.
- The spinocerebellar ataxia nomenclature relates to the autosomal dominant causes of ataxia.
- Autosomal recessive ataxia can be divided into three categories: (1) cerebellar ataxia with predominant sensory neuronopathy, (2) cerebellar ataxia with sensorimotor axonal neuropathy, and (3) cerebellar ataxia without sensory neuropathy.
- Fragile X tremor-ataxia syndrome is the most common cause of X-linked ataxia.
- The first approach to the genetics of ataxia is to investigate for repeat expansions, which are the common causes of autosomal dominant, recessive, and X-linked ataxia.
- Patients with multiple system atrophy can have cerebellar ataxia, parkinsonism, autonomic dysfunction, and pyramidal signs.
Article 8: Myoclonus
John N. Caviness, MD, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1055–1080.
PURPOSE OF REVIEW
This article offers clinicians a strategic approach for making sense of a symptom complex that contains myoclonus. The article presents an evaluation strategy that highly leverages the two major classification schemes of myoclonus. The goal of this article is to link evaluation strategy with diagnosis and treatment of myoclonus.
The growth of medical literature has helped better define myoclonus etiologies. Physiologic study of myoclonus types and etiologies with electrophysiologic testing has provided greater clarity to the pathophysiology of the myoclonus in various diseases. Although studies have been limited, the role of newer treatment agents and methods has made progress.
Myoclonus has hundreds of different etiologies. Classification is necessary to evaluate myoclonus efficiently and pragmatically. The classification of myoclonus etiology, which is grouped by different clinical presentations, helps determine the etiology and treatment of the myoclonus. The classification of myoclonus physiology using electrophysiologic test results helps determine the pathophysiology of the myoclonus and can be used to strategize symptomatic treatment approaches. Both basic ancillary testing (including EEG and imaging) and more comprehensive testing may be necessary. Treatment of the underlying etiology is the ideal approach. However, if such treatment is not possible or is delayed, symptomatic treatment guided by the myoclonus physiology should be considered. More controlled study of myoclonus treatment is needed. Further research on myoclonus generation mechanisms should shed light on future treatment possibilities.
- The brief, lightninglike muscle contraction defines it as myoclonus.
- Myoclonus is a symptom or sign, not a diagnosis. It occurs in multiple diseases and conditions.
- Evaluation for myoclonus begins with a comprehensive history and neurologic examination that allows the clinical presentation classification into a physiologic, essential, epileptic, or symptomatic category.
- EEG should be the initial electrophysiologic testing for myoclonus without a determined etiology.
- Cortical myoclonus physiology is best defined by brief (<50 ms) EMG discharges and a focal EEG correlating with the myoclonus. Enlarged cortical somatosensory evoked potential wave, abnormal long-latency EMG reflex, and increased corticomuscular coherence are supportive but not confirmatory.
- Cortical-subcortical myoclonus physiology is best defined by generalized epileptiform discharges that occur with the myoclonus. It most commonly takes the form of EEG generalized spike-and-wave discharges.
- Subcortical-nonsegmental myoclonus physiology is defined by one of two patterns: (1) initiation from the brainstem or spinal cord followed by simultaneous rostral and caudal EMG recruitment or (2) multifocal myoclonus EMG discharges. Both patterns show EMG discharges of more than 100 ms.
- Segmental myoclonus physiology is defined by low-frequency rhythmic myoclonus EMG discharges that persist almost continuously, with more than 100 ms duration EMG discharges confined to a few contiguous muscle segments.
- Peripheral myoclonus physiology is defined by a highly variable myoclonus EMG discharge duration confined to a specific root, plexus, or peripheral nerve.
- Physiologic myoclonus is a normal phenomenon. Education and reassurance are usually the best treatments.
- Essential myoclonus is pathologic but chronic with little or no disability. It is not common.
- Epileptic myoclonus etiologies are chronic seizure disorders that have myoclonus as a prominent phenomenon.
- Symptomatic myoclonus is secondary to another disorder, neurologic or non-neurologic. Multiple other symptoms and signs are usually present or tied to definable pathology.
- A determined etiology for themyoclonus will allow the clinician to determine whether the underlying myoclonus cause is treatable or curable.
- If treatment of the etiology of myoclonus is not possible or is delayed, then symptomatic treatment should be considered if overall improvement is possible when weighing potential side effects.
- Symptomatic treatment best aligns with the myoclonus physiology classification. An agent that suppresses a specific myoclonus physiology can potentially do that for all myoclonus cases with that common physiology.
- Cortical myoclonus treatments are also antiseizure agents and are able to reduce the hyperexcitability of the cortex resulting in suppression of cortical myoclonus.
- Subcortical myoclonus agents operate at the subcortical movement areas such as the basal ganglia and brainstem.
- Deep brain stimulation has been used successfully for the myoclonus-dystonia syndrome.
- Botulinum toxin injections have been used for segmental and peripheral myoclonus.
Article 9: Tardive Syndromes
Joseph H. Friedman, MD, FAAN, FANA. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1081–1098.
PURPOSE OF REVIEW
This article reviews the history, nosology, clinical features, epidemiology, and treatment of tardive syndromes.
The major advance in the field of tardive syndromes has been the development and US Food and Drug Administration (FDA) approval of two vesicular monoamine transporter type 2 inhibitors, valbenazine and deutetrabenazine, for treating tardive syndromes. These medications are derivatives of tetrabenazine and reduce dyskinetic movements by reducing dopamine stimulation. Treatment is not curative, and the medications reduce, or “mask,” symptoms but presumablywithout adding to the long-term risk of increased involuntary movements believed to accrue from suppressive treatment with dopamine receptor–blocking drugs. A confounding advance has been the accumulation of data finding that second-generation antipsychotics, also known as atypical antipsychotics, may not be safer than first-generation antipsychotics in causing tardive syndromes. The public health risk of tardive syndromes may actually have increased as some second-generation antipsychotics, widely promoted to both doctors and patients, are increasingly used asantidepressants.
Tardive syndromes remain a public health risk. Second-generationantipsychotics have not been proven to have less risk than first-generation drugs in causing tardive syndromes and are nevertheless being used more widely to treat depression, bipolar disease, and insomnia. Symptomatic treatment for tardive syndromes is available, although expensive.
- The relationship between tardive dyskinesia and antipsychotics took several years to establish and was initially thought to be rare.
- All definitions of tardive dyskinesia or tardive syndromes require at least several weeks exposure to a drug preceding the development of a new movement disorder that persists for several weeks while on the drug, or off the drug, and is not better explained by an alternative etiology.
- There are several different tardive syndromes. Dyskinesia and stereotypies are very similar, while akathisia and dystonia are very different. The others are rare. Patients may have more than one syndrome. It is important to note that patients often have more than one tardive syndrome.
- While widely believed to represent dopamine supersensitivity, the pathophysiology of tardive syndromes remains unknown, and no explanation explains the variety of tardive syndromes.
- Tardive syndromes remain a major problem for patients treated with dopamine receptor–blocking drugs. While there are data to suggest that second-generation antipsychotics are less likely to cause a tardive syndrome than first-generation antipsychotics, these data are not convincing, and the largest study performed to answer this question did not find a difference.
- Deutetrabenazine and valbenazine are approved treatments for tardive syndromes, and probably work best for nondystonic disorders. Replacing the neuroleptic with clozapine at a dose to treat the psychosis may be very helpful, especially for dystonic syndromes.
- Botulinumtoxin is likely to be helpful for all focal dystonias, including tardive dystonias. Deep brain stimulation, with globus pallidus interna as the target, may be helpful for dystonic or choreoathetoid tardive disorders.
Article 10: Movement Disorders in Children
Toni S. Pearson, MBBS; Roser Pons, MD. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1099–1120.
PURPOSE OF REVIEW
This article provides an overview of the clinical features and disorders associated with movement disorders in childhood. This article discusses movement disorder phenomena and their clinical presentation in infants and children and presents a diagnostic approach to suspected genetic disorders with a focus on treatable conditions.
Technologic advances inmolecular genetic testing over thepast decade continue to lead to the discovery of new diseases. This article discusses the clinical presentation and early experience with treatment for several recently described genetic forms of infantile-onset and childhood-onset dystonia and chorea.
The clinical spectrum of pediatric movement disorders is broad and heterogeneous, ranging from acute or transient self-limited conditions to conditions that cause profound lifelong motor disability. Most movement disorders in childhood are chronic, and the large number of rare, genetic conditions associated with pediatricmovement disorders can pose a significant diagnostic challenge. Recognition of distinctive diagnostic clues in the history and examination can facilitate the diagnosis of potentially treatable disorders.
- Many causes of childhood ataxia exist that may be broadly divided into acute, intermittent, and chronic categories.
- Myoclonus can be physiologic (hypnic myoclonus), or it can be the manifestation of a broad range of systemic disorders and metabolic derangements.
- Parkinsonism in children differs from parkinsonism in adults, often manifesting as bradykinesia/hypokinesia, dystonia, and axial hypotonia; tremor is often absent.
- Neonates, infants, and toddlers may manifest with a number of benign and transient movement disorders such as myoclonus, dystonia, or tremor; development is normal, and treatment is not required.
- The most common etiologies underlying acute movement disorders in a previously healthy child are autoimmune, drug-induced, and psychogenic.
- In a child with a dyskinetic cerebral palsy phenotype, absent risk factors for perinatal brain injury, and normal brain MRI, investigation for an underlying genetic disorder should be considered. Some genetic disorders have disease-specific treatment that improves symptoms and developmental outcome.
- The primary monoamine neurotransmitter disorders comprise defects of enzymes, cofactors, and transporters involved in the metabolism and homeostasis of the catecholamines and serotonin.
- In biogenic amine disorders, neuroimaging is usually normal, and diagnosis is confirmed with the analysis of monoamine neurotransmitter metabolites and pterins in CSF and with molecular analysis.
- The epileptic-dyskinetic encephalopathies are a heterogeneous group of disorders that are associated with a spectrum of movement disorders, most frequently chorea, but also dystonia and stereotypies.
- Huntington disease in childhood often presents with an akinetic-rigid syndrome rather than chorea.
- Myoclonus-dystonia is a rare genetic movement disorder characterized by a combination of nonepileptic myoclonic jerks and dystonia.
- Myoclonus-dystonia is compatible with an active and normal life span; however, some patients have a progressive course leading to considerable disability. Treatment is usually disappointing.
- Progressive myoclonic epilepsy is characterized by action myoclonus, epileptic seizures, and progressive neurologic decline. The majority of genes involved in progressive myoclonic epilepsy encode lysosomal proteins and are inherited in an autosomal recessive pattern. The largest group of progressive myoclonic epilepsies are the neuronal ceroid lipofuscinosis.
- Juvenile parkinsonism refers to hereditary conditions with onset before the age of 21 years that clinically resemble Parkinson disease but with different histopathologic characteristics.
- In juvenile parkinsonism disease, progression is slower than in idiopathic Parkinson disease. Patients have a marked response to levodopa, although dyskinesias and motor fluctuations occur early.
- The classic genetic paroxysmal dyskinesias may be clinically distinguished from one another by the episode triggers, episode duration, and the presence or absence of interictal neurologic features.
Article 11: Psychogenic (Functional) Movement Disorders
Mary Ann Thenganatt, MD; Joseph Jankovic, MD, FAAN. Continuum (Minneap Minn). August 2019; 25 (4 Movement Disorders):1121–1140.
PURPOSE OF REVIEW
This article reviews a practical approach to psychogenic movement disorders to help neurologists identify and manage this complex group of disorders.
Psychogenic movement disorders, also referred to as functional movement disorders, describe a group of disorders that includes tremor, dystonia, myoclonus, parkinsonism, speech and gait disturbances, and other movement disorders that are incongruent with patterns of pathophysiologic (organic) disease. The diagnosis is based on positive clinical features that include variability, inconsistency, suggestibility, distractibility, suppressibility, and other supporting information. While psychogenic movement disorders are often associated with psychological and physical stressors, the underlying pathophysiology is not fully understood. Although insight-oriented behavioral and pharmacologic therapies are helpful, a multidisciplinary approach led by a neurologist, but also including psychiatrists and physical, occupational, and speech therapists, is needed for optimal outcomes.
The diagnosis of psychogenic movement disorders is based on clinical features identified on neurologic examination, and neurophysiologic and imaging studies can provide supporting information.
- Early diagnosis of a psychogenic movement disorder is important as longer duration of symptoms is associated with poor outcome.
- Diagnosis of a psychogenic movement disorder is based on positive signs and symptoms and isnot a diagnosis of exclusion.
- Psychogenic movement disorders are typically sudden in onset and rapidly progress to severe disability.
- In patients with psychogenic tremor, variability of tremor frequency and direction is common, as well as suggestibility, distractibility, and entrainability.
- Total body tremor is a typical manifestation of psychogenic tremor, including a bobbing of the head and trunk.
- A rapid-onset fixed dystonia is the typical phenotype of psychogenic dystonia.
- A clinical diagnosis of propriospinal myoclonus is unreliable, and more than 50% of cases are psychogenic.
- Psychogenic gait often presents as slowness and buckling at the knees, dramatic compensatory measures, and improvement with minimal support.
- Psychogenic parkinsonism often coexists with organic parkinsonism.
- Psychogenic facial spasms are typically tonic contractions of the lower face with ipsilateral platysma contraction and downward deviation of the lip.
- Psychogenic tics typically lack a premonitory urge, suppressibility, and often lack a family or childhood history of tics.
- Psychogenic paroxysmal dyskinesias have variable duration and phenomenology and often have atypical triggers.
- The neurologist’s role involves explaining the diagnosis, providing educational information, coordinating treatment and providing neurologic follow-up to patients diagnosed with psychogenic movement disorders.
- Patients with psychogenic movement disorders may benefit from psychotherapy and psychotropic medications to treat depression and anxiety.
- Specialized physical therapy focusing on motor retraining can be helpful for patients with psychogenic movement disorders.
- Functional MRI studies have demonstrated impaired self-agency and dysfunctional emotional processing in patients with psychogenic movement disorders.