October 31, 2008 — In this case record professor Metwally discusses a case presented with the clinical diagnosis of congenital syringomyelia with Arnold Chiari malformation. The case is presented in downloadable PDF format.
A 30 years old female patient presented clinically with gradual progressive atrophy of the small muscles of the both hands, Bilateral C5,C6 segmental hypoalgesia.
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Syringomyelia is a chronic disorder involving the spinal cord or the medulla or both. Pathologically it is characterized by the development of cavitations and gliosis within these structures. When cavitations and gliosis extend to the medulla (bulb), the term syringobulbia is applicable. (The x ray room) (Print this case report)
The present term “syringomyelia” was devised by ollivier in 1837 from the two Greek words “to become hollow” and “marrow”. This term was intended to describe any cavitation in the spinal cord including even the central canal which had not been recognized as a normally occurring structure until stifling described it in 1859. [1]
In order to understand the pathogenesis of congenital syringomyelia it is necessary to understand the dynamics of the CSF flow in the central canal of the spinal cord and the surrounding subarachnoid spaces.
The bulk flow of the CSF follows a downward route behind the spinal cord and posterior to the dentate ligament from the cervical region and down to the lumber region and then upward in front of the spinal cord to the basilar cisterns. Pressure waves are generated by the distension and the collapse of the cerebrovascular and the spinovascular beds and are felt to be responsible for the CSF pulsation. As in case of the blood, the propagation of the pulse waves is independent of and much faster than the blood velocity. Also the propagation of the CSF pulse wave is much more rapid than the actual CSF movement.
The CSF down flow, which occur behind the spinal cord, begins during systole and ceases during diastole and is of 10 times greater volumetric magnitude than the ventricular pulse.
The ventricular CSF pulse wave is generated by the pulsation of the choroid plexus in the lateral ventricles which then escapes through the foramen of magendi into the subarachnoid spaces and is progressively damped as it passes down behind the spinal cord through the foramen magnum; in this way the central canal of the spinal cord is bypassed and is not subjected to the ventricular fluid pulse wave and is left behind as a potentially distensible vestigial structure.
Around 30% of the CSF is formed in the central canal of the spinal cord and flow upward by the milking action of the CSF pressure waves that are transmitted to the walls of the spinal cord. These pressure waves are thought to be caused by engorgement of the spinal venous plexus and are most marked during coughing, straining and other valsalvas effect producing maneuver. [1]
Slide show 1. Case radiology
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References
Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]
October 31, 2008 — In this case record professor Metwally discusses a case presented with the clinical diagnosis of spinal dysraphism. The case is presented in downloadable PDF format.
11 years old male patient presented clinically with shortness of the left leg, scoliosis, pes cavus and penetrating deep ulcer in the sole of the left leg. Examination of the back revealed lumbosacral hypertrichosis.
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The spinal cord is formed by invagination of a tube of ectoderm, around which the mesoderm and scleroderm close to form the meninges and vertebral column. This process when interrupted before completion, results in malformations ranging from minor radiological abnormalities to those incompatible with life.
The general term for these malformations is dysraphism. In order of severity, the grades of dysraphism are:-
1- Overt spinal dysraphism
2- Occult spinal dysraphism
Congenital spinal anomalies have been classified into three broad categories – 1) Open spinal dysraphism 2) Occult spinal dysraphism and 3) Caudal spinal anomalies. Occult spinal dysraphism refers to a heterogenous group of disorders in which the neural tissue lies deep to an intact skin cover. Open dysraphism is characterized by exposed neural tissue and the condition is clinically evident at birth. In caudal spinal anomalies, the clinical picture is dominated by anorectal, urogenital and lower limb anomalies [1]. Occult spinal dysraphism, tend to be overlooked at birth. The manifestations become apparent later in life due to either cutaneous stigmata or slowly progressing neurological signs [1]. Imaging is essential to diagnose and characterize these lesions.
Embryology
By the 17th post-ovulation day, the notochord forms in the midline of the embryo. The ectoderm overlying the notochord is induced to form the neuroectoderm. The neuroectoderm folds and dissociates from the superficial ectoderm in a process termed primary neurulation. This process explains the formation of most of the spinal cord. The distal conus and the filum terminale develop as a result of canalization and retrogressive differentiation or secondary neurulation.
OVERT SPINAL DYSRAPHISM
Simple Spina Bifida
It is a bony defect, without herniation of meninges or nervous tissue. It occurs most commonly at the lumbosacral and first cervical levels. It is frequently asymptomatic incidental finding, but in appropriate clinical picture, should alert to the possibility of an underlying malformation of the neuraxis.
Meningocele and meningomyelocele
This refers to protrusion of meninges and nervous tissue, it occurs most frequently near the foramen magnum, and in the lumbosacral region, the thoracolumbar junction is another common site. A posterior defect and widening of the spinal canal are common associated abnormalities.
Two specific types of meningoceles without a posterior defect may be encountered:
Anterior sacral meningocele:
Presents no external stigmata, and is usually discovered accidentally. The sacrum is hypoplastic with a defect in its anterior wall which is easily overlooked on plain films. Contrast medium may passes into the lesion slowly and delayed filming is necessary.
Lateral meningocele:
It commonly occurs in the dorsal spine and protrudes through an intervertebral foramen. Lateral meningoceles are frequently encountered in patients with neurofibromatosis.
Slide show 1. Case radiology
Click here to download the case record in PDF format (606 KB)
Click here to download the short case version of this case record in PDF format (114 K)
References
Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]
October 31, 2008 — In this edition of “talking psychiatry” publication Professor Metwally discusses schizophrenia in mentally retarded patients. This topic is presented in downloadable PDF format.
Click here to download this topic (Schizophrenia in mentally retarded patients) in PDF format (80 KB)
Studies that have been published in the review period have advanced understanding of the epidemiology, presentation, assessment, suspected neuropathology, genetics and treatment of, and service issues relating to, schizophrenia spectrum disorders in people with intellectual disabilities. The number of published studies investigating schizophrenia spectrum disorders in people with intellectual disabilities continues to increase slowly. The evidence base, however, needs to be strengthened, particularly by randomized controlled trials in pharmacotherapy, psychosocial interventions and service delivery.
The evidence base regarding schizophrenia spectrum disorders (SSDs) in people with intellectual disabilities has been limited. This review considers the most recent studies in this area with an emphasis on those published from January 2005 to April 2008. These studies were identified from a MEDLINE literature search using the key terms of schizophrenia, psychosis, disabilities and mental retardation. Wherever possible, this review will focus on SSDs rather than on nonspecified psychosis, but in people with intellectual disabilities it is often more difficult to diagnose the former, particularly as the level of intellectual disabilities increases. Thus, many studies pertain to the less specific diagnosis of ‘psychosis’ rather than SSDs; so, these will also be considered here. The term intellectual disabilities will be used, even though many of the studies cited use other terminologies such as mental retardation and learning disabilities.
Epidemiology
Turner[1] suggested that the point prevalence of SSDs in intellectual disabilities was at least 3%, and this figure has been widely accepted in the literature. A lower point prevalence of psychosis of 1.3% has been recently reported in those with intellectual disabilities in a sample of more than 42 000 people living at home or in cared accommodation across Australia.[2] The interviewers for the survey were, however, not medically trained and mental disorders were identified by self-report, both of which would have increased the risk of nondetection of SSDs and nonaffective psychosis in the sample.
Accurate determination of prevalence rates of SSDs in people with intellectual disabilities is complicated by many diagnostic problems. These problems include distinguishing true hallucinations from developmentally appropriate behaviours such as self-talk and talking to imaginary friends. Pickard and Paschos[3] have explored this difficulty, and offered pointers towards the differentiation of pseudohallucinations and true hallucinations, in their report of two patients with intellectual disabilities who had been previously considered as having an SSD but were eventually diagnosed with personality disorders.
Most of the research literature on SSDs and nonaffective psychosis in intellectual disabilities has focused on people with mild intellectual disabilities. As intellectual disabilities become more severe, there has been conflicting opinion on whether rates of SSDs are higher or lower. Two recent studies[4,5] have found higher incidences of SSDs/psychosis in those with mild or moderate intellectual disabilities compared with those with more severe intellectual disabilities. It, however, remains unclear whether these findings reflect true prevalence rates or they merely reflect the problems in the detection of SSDs and psychosis in people with more severe intellectual disabilities. Cowley et al.[4] also found higher prevalence of SSDs with older age, in contrast with an earlier study,[6] and also lower prevalence rates of SSDs in white participants compared with nonwhites.
Tsakanikos et al.[7] found that patients with intellectual disabilities and autism referred to a service in southeast London were not more likely to have psychosis compared with those with intellectual disabilities but without autism. It is, however, again difficult to be sure that these results reflect true comorbidity rates. The authors list many of the methodological problems they encountered, including the crudeness of the screening tool Psychiatric Assessment for Adults with Developmental Disabilities (PAS-ADD) Checklist, in detecting possible psychosis and the rating clinicians being potentially biased by the existing diagnoses. It should also be noted that those individuals with autism tended to have moderate or severe intellectual disability in which it is often extremely difficult to make a clear-cut diagnosis of SSD or even nonspecified psychosis. This may have thus resulted in the apparent lack of association between autism and psychosis.
In a study by Deb et al.,[8] it has been reported that those with schizophrenia and intellectual disabilities were more likely to have epilepsy compared with those with typical intelligence and with schizophrenia. Cowley et al.,[4] however, found that individuals with epilepsy and intellectual disabilities had a lower incidence of schizophrenia than those with intellectual disabilities but without epilepsy. In this study, the level of intellectual disabilities again may have been a confounding factor, as the prevalence of epilepsy increases in more severe intellectual disabilities.[9] Matsuura et al.[10] investigated the prevalence, psychopathology and cognitive functioning associated with psychotic disorders among 336 adult patients with epilepsy and mild or moderate intellectual disabilities in a Japanese multicentre study. They found a higher prevalence of psychotic disorders among patients with intellectual disabilities than among those with normal intelligence. Psychotic symptoms were, however, similar in presentation in patients with epilepsy with and without intellectual disabilities. The authors noted difficulties in distinguishing psychotic symptoms due to epilepsy from those due to schizophrenia.
Click here to download this topic (Schizophrenia in mentally retarded patients) in PDF format (80 KB)
References
Turner TH. Schizophrenia and mental handicap: an historical review, with implications for further research. Psychol Med 1989; 19:301-314.
White P, Chant D, Edwards N, et al. Prevalence of intellectual disability and comorbid mental illness in an Australian community sample. Aust N Z J Psychiatry 2005; 39:395-400.
Pickard M, Paschos D. Pseudohallucinations in people with intellectual disabilities: two case reports. Ment Health Asp Dev Disabil 2005; 8: 91-93.
Cowley A, Holt G, Bouras N, et al. Descriptive psychopathology in people with mental retardation. J Nerv Ment Dis 2004; 192:232-237.
Holden B, Gitleson JP. The association between severity of intellectual disability and psychiatric symptomatology. J Intellect Disabil Res 2004; 48:556-562.
Cooper SA. Epidemiology of psychiatric disorders in elderly compared with younger adults with learning disabilities. Br J Psychiatry 1997; 170: 375-380.
Tsakanikos E, Costello H, Holt G, et al. Psychopathology in adults with autism and intellectual disability. J Autism Dev Disorders (in press).
Deb S, Thomas M, Bright C. Mental disorder in adults with intellectual disability. Prevalence of functional psychiatric illness among a communitybased population aged between 16 and 64 years. J Intellect Disabil Res 2001; 45:495-505.
Bowley C, Kerr M. Epilepsy and intellectual disability. J Intellect Disabil Res 2000; 44:529-543.
Matsuura M, Adachi N, Muramatsu R, et al. Intellectual disability and psychotic disorders of adult epilepsy. Epilepsia 2005; 46 (Suppl 1):11-14.
October 30, 2008 — Dystonias are defined as sustained muscle contractions, often causing twisting movements or abnormal postures with variable age of onset and anatomic distribution. Dystonia secondary to another neurologic condition or exogenous insult may produce other abnormal movements or neurologic signs
Video 1. Dystonias are defined as sustained muscle contractions, often causing twisting movements or abnormal postures.
General Considerations
Dystonia is a form of abnormal motor control characterized by relatively sustained and directional muscle contractions that produce abnormal postures or twisting and repetitive movements. The movements are usually longer in duration than those seen in other movement disorders (such as chorea or myoclonus), involve the co-contraction of agonist and antagonist muscles, and tend to be repetitive, or patterned, consistently involving the same muscle groups; Dystonia is often aggravated by voluntary movement. In action dystonia, the dystonic movements are elicited only with voluntary movement. “When dystonia is evinced only with particular actions, it is called task-specific dystonia; examples include writer’s cramp and the embouchure dystonia of woodwind and brass musicians. Activation of dystonic movements by actions in remote parts of the body is called overflow; examples include leg dystonia while writing or axial dystonia with talking. Dystonia that is suppressed by voluntary activity is called paradoxical dystonia; for example, talking or chewing may suppress dystonia involving facial and oromandibular muscles (also known as Meige syndrome).
Factors chat tend to exacerbate dystonia include fatigue and emotional stress, and the movements usually decrease with relaxation or sleep. Many patients discover a tactile or proprioceptive sensory trick (geste antagonists} that minimizes the dystonia; for example, a patient with cervical dystonia may touch the chin. Severe dystonia is less likely to respond to these maneuvers, and joint contractures can occur when dystonia is long-standing.
Classification
Dystonia is classified by anatomic distribution, by age of onset, and by etiology (Table 1).
Table 1. Classification of dystonia.
Anatomic Distribution
Focal
Cervical dystonia
Blepharospasm
Spasmodic dysphonia
Oromandibular dystonia
Writer’s cramp
Segmental
Meige syndrome
Craniocervical dystonia
Multifocal
Hemidystonia
Generalized
Age of Onset
Early (<26y)
Late (>26 years)
Etiology
Primary (idiopathic) dystonia
Secondary
Inherited
Dystonia-plus
Degenerative diseases
Complex or unknown etiology
Parkinson disease and other parkinsonisms.
Symptomatic of exogenous or environmental cause
Dystonic phenomenology in another movement disorder
Anatomic distribution
In focal dystonia, Abnormal movements involve a single body region, whereas segmental dystonia affects two or more contiguous body parts. In multifocal dystonia, two or more noncontiguous body areas are involved. Hemidystonia, affecting one side of the body, is suggestive of a secondary dystonia. Generalized dystonia involves the legs (or one leg and the trunk) plus at least one other area of the body.
Cervical dystonia is the most common of the focal dystonias. Various combinations of neck muscles may be involved to produce abnormal head positions, including horizontal turning (torticollis), tilting (laterocollis), flexion (anterocollis), or extension (retrocollis). Repetitive jerking of the head may resemble tremor, but can usually be distinguished by its directional preponderance. Approximately 75% of patients complain of neck pain.
Less common than cervical dystonia are the dystonias that involve cranial muscles. Blepharospasm causes contraction of the orbicularis oculi; mild cases are characterized by increased rate and flurries of blinking, whereas more severely affected patients have visual impairment due to sustained forceful eye closure.
Spasmodic dysphonia results from dystonia of the vocal cords; abnormal adduction, which causes a strained,strangled voice, is more common than abduction, in which the voice sounds whispering and breathy. In oromandibular dystonia there is abnormal activity in lower facial, tongue, jaw, and pharyngeal muscles that may interfere with speaking or swallowing.
Brachial dystonia is a form of focal dystonia that may be primarily, or only, present with writing (so-called writer’s cramp); it is probably more common than is usually recognized. In about 15% of patients there is spread from the dominant to the contralateral arm, ac which point it is considered segmental bibrachial dystonia. Other segmental dystonias involve the cranial muscles (eg, Meige syndrome), sometimes in combination with neck muscles (cranial-cervical dystonia).
Age of onset
Age of onset is an important prognostic consideration, because patients with onset of dystonia in childhood or adolescence are likely co progress to generalized or multifocal dystonia, especially when the dystonia initially involves the leg.
Aetiology
Classification of a patient’s dystonia by etiology is useful for prognosis, for guiding therapy, and for genetic counseling.
In primary dystonia, which may be familial or sporadic, no associated neurologic abnormalities (eg, dementia, ocular abnormalities, ataxia, spasticity, or paresis) are present. (An exception is tremor resembling essential tremor, which appears to be increased in patients with primary dystonia, especially those with cervical dystonia.)
Primary dystonia is distinguished from the secondary dystonias by the absence of signs other than dystonia as well as by the absence of an identified exogenous cause or brain degeneration. The secondary dystonias include (1) the inherited dystonia-plus syndromes, which are similar to primary dystonia in that there is no evidence of brain degeneration but signs other than dystonia are present (specifically myoclonus and parkinsonism); (2) inherited neurologic conditions associated with neuron degeneration (eg, Huntington disease, Wilson disease, and spinocerebellar ataxias); (3) dystonia associated with Parkinson disease and other parkinsonisms; and (4) dystonia resulting from environmental causes (eg, exposure to neuroleptic agents, stroke). Finally, dystonia may occur as a feature of other movement disorders, such as tic disorders and paroxysmal dyskinesias.
Most primary dystonias are focal or segmental in distribution, with onset in adulthood. About 10% of patients with primary dystonia have generalized dystonia, usually starring in childhood or adolescence (early onset). A major cause of early-onset primary dystonia is mutation of the gene DYTl located on the long arm of chromosome 9 (9q34.1). This generic subclass of primary dystonia is called Oppenheim dystonia (formerly dystonia, musculorum deformans). DYTl dystonia has a mean age of onset of 12.5 years, and in 94% of cases begins in a limb. It tends to progress to generalized dystonia; as previously mentioned, the probability of generalization is related to age and site of onset. The DYTl gene codes for torsinA, a heat-shock protein that binds ATP; in DYTl dystonia, deletion of a GAG triplet from this gene results in loss of a glutamic acid residue from torsinA. This deletion is especially common in the Ashkenazi Jewish population, where its prevalence is 1 in 2000 people. It is inherited in an autosomal-dominant fashion with penetrance of 30%. Less common familial primary dystonias that have been mapped include DYT6 (autosomal dominant dystonia with a wide range of disability in Mennonite and Amish families), DYT7 (autosomal dominant fecal dystonia in a northwestern German family), and DYT13 (autosomal-dominance craniocervicobrachial dystonia in an Italian family).
The dystonia-plus syndromes include dopa-responsive dystonia, rapid-onset dystonia-parkinsonism, and myoclonus-dystonia. Perhaps the most important to recognize, because it is treated effectively with levodopa, is dopa-responsive dystonia, also called Segaiwa disease. In patients with this form of dystonia, gait dysfunction (often appearing stiff-legged or spastic) begins in early or mid-childhood, and symptoms worsen as the day progresses and improve with sleep. Parkinsonism, including rigidity, bradykinesia, flexed posture, and loss of postural reflexes, may be prominent, making juvenile parkinsonism an important differential diagnosis. Dopa-responsive dystonia has also been misdiagnosed as cerebral palsy. Girls are affected more often man boys. Onset in adulthood is uncommon; in adult patients the disorder may present as focal dystonia or parkinsonism. Most cases of dopa-responsive dystonia are caused by heterozygous mutations in the GTP-cyclohydrolase I (GCHI) gene located at 14q22.1 (DYT5); many different mutations have been identified, making genetic testing complex and expensive. The mutations severely impair the activity of GHH1, which catalyzes the rate-limiting step in the synthesis of tetrahydrobiopterin, a necessary cofactor for tyrosine hydroxylase; tyrosine hydroxylase in turn converts tyrosine to levodopa. Inheritance is autosomal dominant, with reduced penetrance that appears co be sex influenced (ie, higher in girls). Although the dystonia can improve dramatically with anticholinergic medications such as trihexyphenidyl, a trial of oral levodopa therapy at low doses (usually no more than 300–400 mg/day) is useful for diagnosis as well as for treatment. Additional support for the diagnosis can be obtained from a phenylalanine-loading test, in which blood levels of phenylalanine remain elevated for a prolonged period, because tetrahydrobiopterin has a role as a cofactor for phenylalanine hydroxylase as well as tyrosine hydroxylase. Measurement of biopterin metabolices in cerebrospinal fluid may also aid in diagnosis.
In addition to classic dopa-responsive dystonia resulting from heterozygous GCH1 mutations, variants of the disorder may result from homozygous or compound heterozygous mutations in GCH1, in genes for other enzymes involved in pterin metabolism, and in genes encoding tyrosine hydroxylase. Patients with these defects are often more severely affected clinically, and features stemming from deficiency of norepinephrine and serotonin may predominate.
Another rare dystonia-plus syndrome is rapid-onset dystonia-parkinsonism, in which there is sudden onset of dystonia and parkinsonism during adolescence or early adulthood progressing over hours to weeks, after which the symptoms usually stabilize. Inheritance is autosomal dominant and maps to 19ql3 (DYT12). Recently the gene was identified; it codes for Na/K ATPase e3, a catalytic subunit of the sodium-potassium pump.
Myoclonus-dystonia (DYTl 1) is a dystonia-plus syndrome with prominent myoclonic jerks, usually affecting the arms and trunk more than the legs. Inheritance is autosomal dominant, and many patients have a mutation in the E-sarcoglyc in gene on chromosome 7q21. The symptoms characteristically respond to alcohol, and alcoholism (as well as other psychiatric disorders) may coexist.
Although the causes of secondary dystonia are numerous, patients with primary dystonia significancy outnumber those with secondary dystonia. Nevertheless, it is important to identify patients with secondary dystonia, because treatment of the underlying condition may be warranted.
Factors that raise the likelihood that dystonia is secondary include history of a potentially causative insult (eg, perinatal injury, stroke, encephalitis, head trauma or peripheral trauma, brain tumor, exposure to neurotoxic agents); abnormalities in the neurologic examination (including hemidystonia), neuroimaging, or laboratory evaluation; onset of dystonia at rest rather than action; early onset of cranial dystonia or late onset of leg dystonia; and evidence that the dystonia is psychogenic.
A common cause of secondary dystonia is exposure to drugs (hat block dopamine receptors; neuroleptic agents used in psychiatric practice and antiemetics are most frequently responsible. dystonia may occur soon after initiation of therapy (acute dystonic reaction) or after prolonged treatment (tardive dystonia). (These disorders are discussed in more detail later in this chapter under Tardive Dyskinesia and Drug-induced Movement Disorders.) Exogenous causes also include injury to the central nervous system (especially the basal ganglia and thalamus) or peripheral nervous system; dystonia can be a feature of complex regional pain syndrome. It is also relatively common for dystonia to emerge through psychogenic mechanisms; features that suggest a nonorganic etiology include movements chat vary over time, disappearance with distraction, give-way weakness, and sensory findings that do not conform co a physiologically plausible pattern.
Inherited degenerative diseases that can cause dystonia include many autosomal-dominant and autosomal-recessive conditions, X-linked dominant and recessive conditions, and mitochondrial defects. As previously mentioned, these diseases usually do not cause pure dystonia. Wilson disease is an important consideration, because it requires early treatment. It results from mutations in the ATP7B gene on chromosome 13 chat produce a defect in copper metabolism, leading to the insidious development of neurologic, psychiatric, or hepatic dysfunction. Inheritance is autosomal recessive; over 200 different mutations have been reported, making genetic testing impractical. When onset is in childhood, Wilson disease usually presents with hepatic dysfunction, but neurologic presentation is most typical in adult-onset disease. Dystonia can be generalized, segmental, or multifocal, but cranial involvement is characteristic; Wilson’s original 1912 monograph highlighted the typical “sardonic” smile. Other common neurologic abnormalities include tremor (classically “wing-beating”), dysarthria, dysphagia, drooling, ataxia, and dementia. In addition to brain and liver involvement (cirrhosis, acute hepatitis), systemic findings can involve the eye, heart, kidney, bones, joints, glands, and muscles.
Rarer hereditary-degenerative causes of dystonia Include other autosomal-recessive Inborn errors of metabolism, such as Niemann-Pick type C, neuronal ceroid lipofuscinosis, GM, and GM, gangliosidoses, glutaric academia, and methylmalonic aciduria. Formerly called Hallervorden-Spatz disease, pantothenate kinase-associated neurodegeneration is an autosomal-recessive disease chat results in abnormal deposition of iron in the basal ganglia, producing childhood onset of dystonia, spasticity, seizures, and dementia. Lubag (DYT3) is an X-linked recessive dystonia-parkinsonism affecting male Filipinos. Usual onset is in adulthood, with cranial or generalized dystonia; parkinsonism may co-occur or develop later. The course tends to be progressive. The deafness-dystonia (Mohr Tranebjaerg) syndrome is a X-linked recessive condition associated with mutation in the DDP1 gene. The spinocerrbellar ataxias (especially SCA3 [Machado-Joseph disease, SCA2, and SCA17) can be associated with dystonia, as can dentatorubropallidoluysian atrophy.
Pathogenesis
Many cases of secondary dystonia are associated with lesions of the basal ganglia (especially the putamen), or with their connections. Degenerative brain changes are not reported in primary dystonia, but relatively few brains have been studied. One recent study described neuronal inclusions in brainstem structures of patients with DYTl dystonia, and increased copper has been described in the basal ganglia of patients with adult-onset focal dystonia. Functional imaging using fluorodeoxyglucose positron emission tomography (FDG PET) in patients with DYT1 dystonia has shown a pattern of altered metabolism in the supplementary motor cortex, putamen, and cerebellum.
Prevention
No intervention is known to prevent the development of dystonia. Genetic counseling is useful in educating parients about the likelihood of transmitting the condition to successive generations.
Laboratory findings
Similar co most movement disorders, the diagnosis of dystonia is made on clinical grounds rather than on the basis of laboratory testing. Nevertheless, the cause of the dystonia often can be elucidated through further evaluation. Currently, the DYTl variant is the only primary dystonia for which genetic testing is commercially available. DYTl testing is indicated for all patients with onset of dystonia prior to 26 years of age, as well as for parents with later onset who have a relative with early onset dystonia. A positive result obviates the need for further diagnostic testing. Genetic counseling must be available for patients undergoing this test.
If the result of genetic testing is negative or the testing is not indicated, much of the remaining workup is directed toward identifying a secondary cause for the patient's dystonia. Treatable conditions chat should always be considered in the differential diagnosis include dopa-responsive dystonia and Wilson disease Carbidopa-levodopa should be tried in all non-DYT1 patients with early onset of symptoms as well as in late onset patients with features suggesting dopa-responsive dystonia (ie, parkinsonism, diurnal variation). The dose is increased as tolerated over several weeks; although a daily dose of 600 mg of levodopa is sometimes required, failure to respond to a dose of 300 mg/day usually excludes the diagnosis of dopa-responsive dystonia. Wilson disease should be excluded in patients with onset of dystonia prior to age 50. Diagnostic findings in patients with neurologic signs due to Wilson disease include MRI abnormalities involving the putamen, thalamus, and brainstem; reduced level of serum ceruloplasmin; increased 24-hour urinary copper excretion; and Kayser-Fleischer rings in the cornea resulting from deposition of copper in Descemet membrane. These are best seen with slit-lamp examination. Noninvasive
Studies are usually adequate for diagnosing neurologic Wilson disease; however, liver biopsy to assess copper content has high sensitivity and may be useful.
Evaluation of secondary dystonia is dictated by clues provided by the history and examination. Routine blood tests (eg, complete blood count, electrolytes, glucose, calcium, magnesium, coagulation profile, and tests of kidney, liver, and thyroid function) may be supplemented by sedimentation rate, antinuclear antibody screening, and syphilis screening. Specific clinical findings or laboratory abnormalities may dictate further investigations, including electrophysiologic studies, lumbar puncture, biopsy of various tissues, or metabolic studies of blood, urine, or cerebrospinal fluid. HIV resting should be considered in the appropriate setting.
Imaging studies
All patients suspected of having a secondary form of dystonia should undergo MRI (or, if not possible, CT) of the brain. In primary dystonia and in the dystonia-plus syndromes, MRI of the brain is normal. In secondary and hereditary-degenerative dystonias, MRI may show calcification, necrosis, or other abnormalities in the basal ganglia. In some cases, these changes are quite specific; for instance, pancothenate kinase-associated neurodegeneration is often associated with hypointensity in the globus pallidus with medial hyperintensity (the soiled eye-of-the-tiger sign) on T2-weighted imaging. PET scanning may be supportive of primary dystonia but rarely is critical in making the diagnosis.
Differential Diagnosis
Various central and peripheral nervous system disorders, as well as non-neurologic conditions, can be associated with abnormal postures that resemble torsion dystonia (sometimes called pseudodystonia). For example, tonic seizure activity can produce sustained twisting movements. Head tilt can reflect palsy of the cochlear nerve vestibulopathy, pathology in the posterior fossa, or a retropharyngeal soft tissue mass. Stiff-person syndrome causes contraction of axial and proximal limb muscles Nerve and muscle abnormalities include neuromyotonia (Isaac syndrome), the myotonic disorders, inflammatory myopathies, and glycogen storage diseases (eg, Satoyoshi disease). Carpopedal spasms of tetany can be the manifestation of hypocalcemia, hypomagnesemia, or alkalosis. Orthopedic and rheumatologic processes involving bones, ligaments, or joints can result in abnormal postures In Sandifer syndrome, patients (typically young boys) with hiatal hernia develop head tile in association with gastroesophageal reflux.
Complications
Long-standing torsion dystonia can result in fixed contractures or scoliosis. Respiratory compromise resulting 216 / CHAPTER 15 from dystonic laryngospasm is a rare but potentially life threatening complication.
Treatment
Pharmacotherapy
When dystonia occurs secondary to another condition, treatment of the underlying condition may produce improvement in the dystonia. In patients with tardive dystonia or an acute dystonic reaction, dopamine receptor blocking agents should be eliminated or replaced whenever possible. Structural lesions may be amenable to surgical correction. Management of Wilson disease consists of copper chelation therapy (usually with penicillamine as a first-line agent) and oral zinc, which induces copper-binding metallothionein in enterocytes. Some of the inborn errors of metabolism may respond to dietary restriction or supplementation. Patients with dopa-responsive dystonia usually are maintained on low-dose carbidopa-levodopa therapy.
Although currently there is no curative therapy for primary dystonia, several effective options for symptomatic treatment are available; these include oral pharmacologic agents, chemodenervation, and surgery. Of the various oral medications chat have been studied, anticholinergic agents are the most efficacious. Trihexyphenidyl is the best studied and probably the most widely used, although benztropine, diphenhydramine, and ethopropazlne (which is not available in the United Scares) may be useful as well. Use is often limited by peripheral anticholinergic adverse effects, including blurred vision, dry much, urinary retention, sedation, and confusion, and doses should be titrated slowly. Pilocarpine eye drops or oral pyridostigmine, a peripherally acting anticholinesterase, may be effective in counteracting these unwanted side effects. Anticholinergic medications can be used singly or in combination with other drugs, including baclofen, benzodiazepines, and muscle relaxants such as cyclobenzaprine. Dopamine-depleting agents and atypical antipsychotics may be helpful in the treatment of dystonia. Preliminary observations suggest that newer antiepileptic drugs (eg, zonisamide, ropiramace, and levetiracetam) may be useful in suppressing dystonic movements, but further study of (heir role is needed.
Table 2. Oral agents commonly used in the management of dystonia.
Class
Drug
Anticholinergic agent
Trihexyphenidyl
Benztropine
Ethopropazine
Benzodiazepine
Diazepam
Lorazepam
Clonazepam
Dopamine-depleting agent
Tetrabenazine
Reserpine
GABA agonist
Baclofen
Chemodenervation
Denervation of overactive muscles by injection of botulinum toxin is the treatment of choice for focal dystonia. The toxin produces muscle weakness by interfering with proteins in the presynaptic nerve terminal that participate in release of acetylcholine into the neuromuscular junction. This therapy is effective in the treatment of blepharospasm, cervical dystonia, spasmodic dysphonia, writers cramp, and oromandibular dystonia. Side effects can arise from unintended weakness in nearby muscles due to diffusion of toxin. Antibodies to botulinum toxin can develop with repeated injections, resulting in loss of therapeutic effect.
Surgical management
Patients whose dystonia is disabling and refractory to oral medications and chemodenervation may be candidates for surgery of the peripheral or central nervous system. Thalamotomy, pioneered in the 1960s, is the oldest such surgical approach to dystonia. Based on the efficacy of pallidotomy for treating dyskinesias and dystonia in patients with Parkinson disease, and neurophysiological studies that demonstrate an abnormal pattern of neuronal discharging from the globus pallidus in patients with generalized dystonia, current surgical interventions target this region of the basal ganglia. Although either pallidotomy or deep brain stimulation can modulate the pallidal output, brain stimulation has the advantages over ablative surgery of being reversible and having multiple stimulator parameters that can be varied in order to optimize the outcome in a particular patient. Deep brain stimulation is most effective in patients with primary generalized dystonia, but some patients who have cervical dystonia that is unresponsive to other treatments may also benefit. Currently, however, there have been no controlled studies of deep brain stimulation in dystonia, and the duration of its benefit is unknown. Surgical denervation procedures such as ramisectomy and rhizotomy as well as myectomy may be useful in selected patients with cervical dystonia.
References
Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a ctober 2008 [Click to have a look at the home page]
October 29, 2008 — In contrast to its observed positive effects on the cardiovascular system, alcohol does not slow age-related decline in brain volume, a new study has found.
These latest results, from the Framingham Offspring Study, found a negative linear line connecting decreased brain volume with increased alcohol consumption, with that line being more dramatic in women than in men.
However, according to study investigator Carol Ann Paul, from Wellesley College and Boston University School of Public Health, in Massachusetts, it would be premature to warn the public about this impact of alcohol on the brain.
Paul said that at this point she is not ready to speculate on the meaning of the data or make any recommendations regarding changes to alcohol consumption.
For one thing, she said, the brain shrinkage linked to alcohol in the study “is not tremendous,” and more research in the form of prospective longitudinal analyses is needed to verify the results.
The study is published in the October issue of Archives of Neurology.
Alcohol Consumption Categorized
The study included 1839 healthy offspring of the original subjects of the Framingham Heart Study, a longitudinal study launched in 1948. The offspring were asked between 1991 and 2001 to participate in this current analysis. At the time, the offspring sample ranged in age from 33 to 88 years.
Subjects reported on their weekly alcohol consumption (beer, white and red wine, and liquor). Consumption was divided into five categories: abstainers, former drinkers, low (1 to 7 drinks, the majority), moderate (8 to 14 drinks), and high (more than 14 drinks).
Researchers used multivariate linear regression models to evaluate the association between these levels of alcohol consumption and brain volume as measured using magnetic resonance imaging (MRI), adjusting for age, sex, education, and other factors.
For former drinkers, researchers did not collect information on how long they had been “dry” or why or how they had stopped drinking.
Previous research has shown that moderate alcohol consumption — perhaps a glass of wine a day — may protect against cardiovascular disease. Moderate alcohol consumption is also associated with improved cognitive function, a lower risk for Alzheimer’s disease, and less severe white-matter lesions.
It is also known that brain volume declines naturally at about 0.19% per year, or almost 2% per decade, while white-matter lesions increase with age.
Hoped to See Trend Similar to Heart
The goal going into this current study was to determine whether alcohol has the same protective effect on brain volume as it has on the heart, said Paul. “I was hoping to see some sort of reduction in [brain volume] decline with a small amount of alcohol, the same trend seen with the heart.
“The brain is heavily perfused with blood from the cardiovascular system, so the hypothesis was that those same blood vessels must be getting the same advantage of drinking alcohol every day; it dilates the blood vessels and sort of flushes things out,” said Paul.
She found the opposite, however; the more a group of subjects drank, the larger their decline in brain volume. “There was a significant negative linear trend between the alcohol-consumption groups and brain volume,” said Paul.
Between every group, there was a decline in brain volume of, on average, 0.25%, which translates into at least a 1-year additional decline in brain volume than would be expected with normal aging.
Paul interprets this to mean that alcohol’s positive effect on blood vessels does not translate into the same effect elsewhere in the brain. “It seems that the cells of the brain are differently affected than the blood vessels of the brain.”
The researchers did not find an association between alcohol and white-matter lesions. Past research has noted larger white-matter lesions and lower brain volume associated with the progression of dementia and cognitive decline as well as higher cardiovascular risk.
Decline More Pronounced In Women
Although there were more men than women in the moderate drinking category and twice as many in the heavy drinking group, the decline in brain volume was more pronounced among women in every alcohol-consumption category.
“Women have higher relative brain volume than men, but alcohol has more of an effect on them,” said Paul. “In other words, the trend is in the same direction but their [negative decreasing] line is slightly steeper.”
Paul pointed out that women are generally smaller than men, have less blood to dilute the alcohol they drink, and are more vulnerable to its effects.
The study was based on self-reports of alcohol consumption, and since people tend to underreport their use of alcohol, the association between alcohol and brain volume may actually be even greater than that uncovered by the study.
In addition, the participants were predominantly of European descent with a relatively high level of education, so the authors caution that the results may not be generalized to other racial and economic groups.
The next step is to compare the same alcohol-consumption patterns of this sample with cognition, said Paul.
October 29, 2008 — Gait is the attitude of a person in the upright position. Abnormal types include the following:
Hemiparetic gait
In hemiparesis, the facial paresis may not be obvious. In mild cases, subtle features of facial paralysis (eg, flattening of the nasolabial fold on one side compared to the other, mild asymmetry of the palpebral fissures or of the face as the patient smiles) may be sought. The shoulder is adducted; the elbow is flexed; the forearm is pronated, and the wrist and fingers are flexed. In the lower extremities, the only indication of paresis may be that the ball of the patient’s shoe may be worn more on the affected side.
In severe cases, the hand may be clenched; the knee is held in extension and the ankle is plantar flexed, making the paralyzed leg functionally longer than the other. The patient therefore has to circumduct the affected leg to ambulate.
In hemiplegic patients in whom all the paralysis is on the same side of the body, the lesion is of the contralateral upper motor neuron. In most cases, the lesion lies in the cortical, subcortical, or capsular region (thus above the brain stem). In the so-called alternating or crossed hemiplegias, the cranial nerve paralysis is on one side and the body paralysis is on the opposite side. The cranial nerve paralysis in such cases is of the lower motor neuron type, and the location of the affected cranial nerve helps determine the level of the lesion.
Video 1. Hemiparetic gait
Ataxic gait
In ataxia, the patient spreads the legs apart to provide a wider base of support to compensate for an imbalance while standing or walking. In more severe cases, patients stagger as they walk. The heel-to-toe or tandem walking maneuvers and standing on one leg uncover subtle forms of ataxia.
Ataxia results from lesions of the cerebellum and may be isolated or may be associated with other cerebellar findings (see Cerebellar signs). When the lesion is unilateral, the patient may veer to the side of the lesion; in bilateral cerebellar involvement, the patient may fall to either side.
Video 2. Ataxic gait
Shuffling gait
The individual takes very short steps to the point of not moving forward, practically staying in the same position. In other words, the patient appears to shuffle his legs rather than put them forward. In some patients, the steps (albeit short) and pace may vary with a tendency for the patient to accelerate (festinating gait) as he or she walks. Both types are seen in Parkinson disease and may be associated with other extrapyramidal signs.
Video 3. Shuffling gait
Steppage gait
In steppage (high-stepping, slapping), the individual takes high steps as if climbing a flight of stairs while walking on a level surface. This peculiar gait pattern results from the patient trying to avoid injury to the feet by stepping high. However, as the patient puts the feet down one by one, they slap the ground, hence the description of a foot-slapping gait. This is one condition that can be diagnosed even before the patient enters the room because the sound is so characteristic.
Steppage gait is seen in chronic peripheral neuropathies and can be the result of the functional elongation of the legs due to bilateral drop foot.
Video 4. Steppage gait
Spastic or scissor gait
In this condition, the legs are held in adduction at the hip and the thighs rub against each other as the patient walks; spasm of the inner thigh muscles also occurs. If the spasm is severe, with each advancing step the knees tend to slide over each other like the blades of a pair of scissors. This is typically seen in cerebral diplegia, a form of cerebral palsy.
Video 5. Spastic or scissor gait
References
Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008 [Click to have a look at the home page]
October 29, 2008 — Results of a randomized trial suggest that treatment with tissue plasminogen activator (tPA) given 3 to 4.5 hours after symptom onset can still provide “modest but significant” improvement in clinical outcomes after an acute ischemic stroke vs placebo.
The trial, the third European Cooperative Acute Stroke Study (ECASS 3), showed that although symptomatic intracerebral hemorrhage was higher in treated patients, the rate was not higher than reported previously in patients treated within the currently approved 3-hour window and was not associated with increased mortality rates.
However, the ECASS investigators, with lead author Werner Hacke, MD, from the University of Heidelberg in Heidelberg, Germany, caution that treatment as early as possible after symptom onset is still the goal.
“Having more time does not mean we should be allowed to take more time,” the authors emphasize.
The results appear in the September 25 issue of the New England Journal of Medicine and will be presented at the World Stroke Congress in Vienna on September 25, 2008. The study was supported by Boehringer Ingelheim.
Thinking Outside the Window
Intravenous tPA is the only approved treatment of acute ischemic stroke, but the approval is limited to use within 3 hours of symptom onset. Its efficacy and safety, when given beyond that period, are not established, although there has been some indication from a pooled analysis of the randomized trials that there may be benefit beyond 3 hours up to 4.5 hours, the authors note.
Another study indicating some evidence of benefit beyond 3 hours was published in the September 15 Online First issue of The Lancet. Results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry, an observational audit of patients treated with intravenous tPA for acute ischemic stroke showed no significant difference in outcomes between patients treated between 3 and 4.5 hours after symptom onset and those treated before the recommended threshold of 3 hours.
“Today, only a minority of stroke patients can be treated, mainly because of the restriction of the time window, and an increase of that window by 50% would make it possible to treat more patients,” first author Nils Wahlgren, MD, at Karolinska University Hospital in Stockholm, Sweden, said in an interview. However, a change in practice would await evidence of benefit from a randomized trial.
ECASS 3 was a randomized trial comparing tPA treatment vs placebo in 821 patients with stroke who presented 3 to 4.5 hours after symptom onset. After those with evidence of brain hemorrhage or major infarction on computed tomography scan were excluded, patients were randomly assigned to receive treatment with intravenous tPA in the approved regimen of 0.9 mg/kg body weight (n = 418) or to placebo (n = 403).
In this trial, the median time for the administration of tPA was 3 hours and 59 minutes. Approximately 10% of patients were treated between 3 and 3.5 hours, 50% between 3.5 and 4 hours, and 40% between 4.0 and 4.5 hours.
The primary endpoint was disability at 90 days, dichotomized as a favorable outcome (modified Rankin scale, 0 or 1) or unfavorable outcome (modified Rankin scale, 2 – 6).
The authors report that significantly more patients treated with tPA had a favorable outcome by this measure vs those who received placebo.
Table 1. ECASS 3 Primary Endpoint: Favorable Outcome at 90 Days by Treatment Group*
A secondary endpoint, a global analysis combining 4 neurologic and disability scores also showed an improvement with treatment vs placebo (odds ratio 1.28; 95% confidence interval, 1.00 – 1.65;, P < .05).
In safety, the incidence of intracerebral hemorrhage was significantly higher with tPA vs placebo and for symptomatic intracerebral hemorrhage, the authors note, although this difference did not translate into an increase in mortality.
Table 2. ECASS 3: Intracerebral Hemorrhage and Mortality by Treatment Group*
The authors point out that in ECASS 3, they modified the ECASS definition of symptomatic intracerebral hemorrhage by specifying that the hemorrhage had to have been identified as the predominant cause of the neurologic deterioration. With that definition, the rate was higher with treatment vs placebo but was still low overall.
When the investigators used the definitions used in other trials, they add, “the rate of symptomatic intracerebral hemorrhage in our trial was no higher than that reported in previous randomized trial or in SITS-MOST [Safe Implementation of Treatments in Stroke–Monitoring Study], despite the extended time window in our study.”
There was no significant difference in the rate of other adverse events, they note.
A Long, Difficult Path
In an editorial accompanying the article, Patrick Lyden, MD, from the University of California, San Diego, points out that the results of ECASS 3, like the National Institute for Neurological Disorders and Stroke trial that established the efficacy of tPA in stroke treatment, was robust across multiple endpoints, and showed efficacy for treatment despite an increased rate of hemorrhage. Based on this, he writes, “one cannot help wondering why thrombolytic therapy has travelled such a long, difficult path to wider clinical use.”
The inclusion and exclusion criteria for ECASS 3 were broad, and in general, patients who present with an acute stroke will qualify for treatment, he writes. When collected properly, the evidence consistently shows that one-third of patients with stroke come to an emergency department within the appropriate time window and satisfy the criteria for thrombolytic therapy, Dr. Lyden writes.
“The frequently quoted statistic that only 4% of all patients with stroke receive rt-PA [recombinant tissue plasminogen activator] must be viewed as an important indictment of our health care system and of the field of neurology in particular,” he asserts. “The patients are coming in but we are not.”
Policies and procedures should be instituted to ensure that patients are promptly identified and treated, quality outcome data must be used to select and designate treatment centers of excellence for patients with acute stroke, and patients should be diverted to these centers, Dr. Lyden concludes. “The public expects no less, and given the past decade of distortion of the NINDS [National Institute for Neurological Disorders and Stroke] study findings and delay in implementing thrombolytic therapy for acute stroke, we have not a minute to lose.”
ECASS 3 was supported by Boehringer Ingelheim. Dr. Hacke has received consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim, and grant support from Lundbeck. A complete list of disclosures is available in the original article.
Clinical Context
Intravenous thrombolytic therapy, initiated within 3 hours of acute symptoms, is the only medical therapy available for acute ischemic stroke. Use of alteplase at 0.9 mg/kg within 3 hours of symptoms has been associated with a 30% greater likelihood of minimal or no disability at 3 months vs placebo.
This is a randomized, placebo-controlled, phase 3 trial conducted at 130 sites in 19 European countries to examine if alteplase can be extended beyond the window of 3 hours in the treatment of acute ischemic stroke and to examine adverse effects.
Study Highlights
Included were 821 patients aged 18 to 80 years who had received a clinical diagnosis of acute ischemic stroke confirmed by computed tomography scan or magnetic resonance imaging and were able to receive intravenous treatment within 3 to 4.5 hours.
The treatment window was extended to 4.5 hours because of data suggesting benefits beyond 4 hours and slow recruitment.
Excluded were those with severe stroke symptoms, intracranial hemorrhage, or major ischemic infarction.
An interactive voice-randomization system was used, and 418 patients were assigned to receive intravenous alteplase 0.9 mg/kg (maximum, 90 mg) and 403 assigned to placebo.
10% of alteplase was given as an intravenous push and the remaining as an infusion during 1 hour.
Treatment with intravenous heparin, oral anticoagulants, or volume expanders was prohibited, but subcutaneous heparin or low-molecular-weight heparin was permitted for prophylaxis against deep vein thrombosis.
Patients were examined by a blinded examiner at 1, 2, and 24 hours after presentation and on days 7, 30, and 90; clinical condition was closely monitored in the first 24 hours.
Initial examinations included magnetic resonance imaging and computed tomography scans, physical examination, and assessment of neurologic deficit with the National Institute for Neurological Disorders and Stroke Scale, a 15-item scale with scores from 0 to 42.
The modified Rankin scale was used on days 30 and 90 and ranged from 0 for no symptoms at all to 6 for death.
Primary outcome was disability at day 90, defined as a favorable outcome if the modified Rankin score was 0 or 1 and unfavorable if it was 2 to 6.
Secondary outcome was a composite of neurologic assessments with a global measure representing the National Institute for Neurological Disorders and Stroke Scale, Modified Rankin score, the Barthel Index, and the Glasgow Outcome Scale.
Safety endpoints included intracranial hemorrhage, symptomatic intracranial hemorrhage, brain edema, and death.
375 patients received alteplase and 355 received placebo.
Mean age was 65 years, 57% to 63% were men, mean weight was 78 kg, 15% had diabetes, two thirds had hypertension, and 12% to 14% had atrial flutter or fibrillation.
10% of patients were treated between 3 and 3.5 hours, 46.8% between 3.5 and 4 hours, and 39.2% between 4 and 4.5 hours.
Mean time to treatment was 3 hours and 59 minutes.
The alteplase group was more likely to have a favorable outcome at 90 days by modified Rankin score (52.4% vs 45.2% for placebo; odds ratio, 1.34; relative risk, 1.16; P = .04) representing an absolute improvement of 7.2 percentage points.
For the global endpoint, the alteplase group also did better vs the placebo group, with an odds ratio of 1.28 (P < .05).
The mortality rate was 7.7% in the alteplase group and 8.4% in the placebo group (not significantly different).
Intracranial hemorrhage was more likely to occur in the alteplase group (27.0% vs 17.6%; P = .001).
The odds ratio for symptomatic intracranial hemorrhage for alteplase was 9.85 vs placebo (P = .008).
All symptomatic intracranial hemorrhages occurred within the first 22 to 36 hours after initiation of treatment.
The rate of symptomatic brain edema did not differ significantly (6.9% vs 7.2%), and other serious adverse effects were similar in incidence.
The authors concluded that use of alteplase was beneficial even when treatment was extended to 4.5 hours but recommended that treatment should be given as soon as possible after presentation of ischemic stroke.
Pearls for Practice
Use of alteplase for acute ischemic stroke within 4.5 hours of presentation is associated with improved clinical outcomes at 90 days vs placebo.
Use of alteplase for patients with acute ischemic stroke is associated with a higher risk for intracranial hemorrhage within 22 to 36 hours of treatment.
October 29, 2008 — New data from 1 center’s series of patients with asymptomatic carotid stenosis (ACS) have shown that institution of intensive medical therapy in 2003 was associated with reduced plaque progression, fewer microemboli, and events to levels below the threshold of risk associated with carotid stenting or surgery.
Researchers at Robarts Research Institute, in London, Ontario, while studying the higher stroke risk associated with microemboli on Doppler ultrasound from carotid plaque, found that microemboli and cardiovascular events declined significantly with more intensive risk-factor management in patients with ACS.
“What this means is that for patients with asymptomatic carotid stenosis, the treatment of choice is intensive medical therapy, not stenting or endarterectomy,” lead author J. David Spence, MD, told attendees here. “Less than 5% of asymptomatic patients can possibly benefit from stenting or endarterectomy with risks of 4% or 5%.” Those who can benefit can be identified by the presence of microemboli, he said.
In the United States, between half and two-thirds of stenting and endarterectomy procedures are for asymptomatic vs symptomatic patients, he said. “What we’re showing is it’s unwarranted in 95% of them.”
Treatment of asymptomatic stenosis is based largely on results published in 1995 of the Asymptomatic Carotid Atherosclerosis Study (ACAS), which showed that endarterectomy reduced the aggregate risk of surgery and ipsilateral stroke from about 11.0% to 5.1% in these patients, he said (Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421-1428).
“But in those days, people weren’t using high-dose statins routinely in patients with asymptomatic stenosis,” Dr. Spence said. “So we shouldn’t be using data that old to justify doing procedures now.”
Dr. Spence presented their findings here at the 6th World Stroke Congress.
Treating Arteries
The work he is presenting here has “2 beginnings,” Dr. Spence said. In the first, he and colleagues began studying carotid total plaque area in 1990, largely for research purposes, and found that those patients in the top quartile for carotid plaque area had a 3.4-times higher risk for stroke or death after adjustment for a wide variety of risk factors. In addition, 50% of these patients had progression of plaque, and those patients were at higher risk for events.
“What this meant was that we were failing in half our patients, just treating according to traditional treatment of risk factors, so we changed the paradigm in our clinic from treating risk factors to treating arteries,” he said. That is, regardless of the risk factors, they intensify therapy in the setting of high plaque burden, with the goal of plaque regression. This change occurred in 2003.
They were also studying microemboli on transcranial Doppler (TCD) in patients with asymptomatic carotid stenosis and in 2005 reported that TCD “perfectly defined the patients at risk,” he said. The 90% of patients who had no microemboli had a 1% risk for stroke with tight confidence limits (1.01 – 1.36), and the 10% with microemboli had a 15.6% risk for stroke. “This meant the patients without microemboli cannot benefit from revascularization, because their risk is lower than the risk of surgery or stents,” Dr. Spence noted.
He and colleagues obtained grant funding to study the biology associated with plaque with and without microemboli, but 2 years into the study had to report to their funders, the Heart & Stroke Foundation of Ontario, that the microemboli were disappearing. They hypothesized that the decline might be related to the institution of more intensive medical therapy, and in the current study examined secular trends in microemboli and cardiovascular events in their population.
The Decline of Microemboli — and Events
Of 468 patients with asymptomatic carotid stenosis followed at their institution, 199 were studied prior to the shift in practice in 2003, and 169 after. All had baseline microembolus detection by international consensus criteria. The last patients entered were studied for at least a year, Dr. Spence noted, and the database was closed July 1, 2008.
“What we found was that microemboli were present before 2003 in 12.6% of patients, but since 2003, it’s only 3.7%, so microemboli had been declining,” he said. The annual rate of plaque progression was significant before 2003 and very low after 2003 and the institution of intensive medical therapy.
They also studied 4328 patients from their prevention clinics who had had plaque measurements between 1997 and 2007 to establish the rate of plaque progression. They report that plaque rises steeply with age, particularly after menopause. With an aging population and more patients referred because of stroke and less because of hypertension, he said, “you would expect the rate of plaque progression would be going up and then remain high.”
They found the rate did rise, until 2003, when it stopped progressing and they began to see regression on average. The proportion of patients showing regression almost doubled, from 25% to 50%, after the move to intensive therapy. The decline was mirrored by a decline in cholesterol, triglycerides, and low-density lipoprotein and an increase in high-density lipoprotein over the same period, suggesting the changes were due to the intensive medical therapy, he said.
The larger population showed a similar trend in microemboli, showing a 14% risk for stroke in the first year when microemboli were present, and 1.2% without. “Almost all the events occur in the first year of follow-up,” he said.
Prior to 2003, the 1-year risk of stroke in patients with asymptomatic stenosis was 4%, he noted, which has declined to 0.8% in the latter period, again with almost no risk seen in year 2. Similarly, myocardial infarction (MI) declined from 6.5% before intensive therapy was introduced to 0% afterward.
Table 1. Decline in Events Associated with Asymptomatic Carotid Stenosis With and Without Intensive Medical Therapy
Event
No Microemboli (%)
Microemboli (%)
P
Before 2003 (%)
After 2003 (%)
P
Stroke in year 1
1.2
14.3
< .0001
4
0.8
.02
MI in year 1
2.4
8.6
.07
6.5
0
.0001
Death in year 1
2.9
12.1
.027
5.1
2
.12
Dr. Spence noted that in his view, intima-media thickness (IMT), used as an end point now in some trials, cannot provide the basis for this kind of monitoring.
“IMT change annually is around 0.015 mm, and the resolution of carotid ultrasound is 0.3 mm, so the rate of change in an individual cannot be measured from year to year,” he said. “On the other hand, the average rate of change of plaque area is 11 mm2 per year, which can readily be measured with a resolution of 0.3 mm.
“So our mantra is trying to treat arteries without measuring plaque is like trying to treat hypertension without measuring blood pressure,” he concluded.
The SPACE 2 trial, just getting under way in Europe, will provide some insight into this issue, as it is comparing carotid endarterectomy with carotid stenting in patients with asymptomatic carotid stenosis, but unlike other trials comparing these modalities in asymptomatic patients, it includes an intensive-medical-therapy group.
References
6th World Stroke Congress, Vienna, Austria: Abstract FC01-02. Presented September 25, 2008.
October 29, 2008 — Long-term combination therapy with memantine and cholinesterase inhibitors significantly slows the rate of cognitive and functional decline in patients with Alzheimer’s disease (AD), new research suggests.
In the first long-term real-world study of Alzheimer’s drugs, investigators at Massachusetts General Hospital, Boston, found that extended combination therapy slowed disease progression and helped patients maintain their ability to perform activities of daily living.
“Based on these results, we believe combination therapy should be strongly considered for first-line treatment in patients with Alzheimer’s disease, as it appears this regimen helps individuals maintain their cognitive and functional abilities for a longer period of time,” said principal investigator Alireza Atri, MD, PhD.
The study is published in the July/September issue of Alzheimer Disease and Associated Disorders.
Real-World, All-Comers Study
According to Dr. Atri, to date, the majority of AD drug studies have been randomized, placebo-controlled trials of limited duration — usually 6 months — conducted in highly selected cohorts.
The findings of such studies, said Dr. Atri, give the impression that AD medications only work in a limited number of patients and only for a short period.
“There’s almost a myth that has developed that [AD] drugs only work for some people and that if you respond early, you don’t respond later. But the fact is this assertion is not backed up by any data,” he said.
He added that long-term effectiveness data for monotherapy or combination therapy in a real-world setting that includes a heterogeneous all-comers population is lacking.
To gather such data, researchers conducted a prospective study of patients treated at the Massachusetts General Hospital’s Memory Disorders Unit from 1990 to 2005 who were subsequently enrolled in the Massachusetts Alzheimer’s Disease Research Center Patient Registry Database.
All study participants had a clinical diagnosis of probable AD; had at least 3 examinations in the memory disorders unit, with completed assessments of their cognitive and functional capacities; and were categorized according to the type of treatment they received.
Maintenance of Functional Status
Individuals were evaluated using the Information-Memory-Concentration subscale of the Blessed Dementia scale (BDS) and the Weintraub Activities of Daily Living (ADL) scale.
Of 382 subjects, 144 received no AD treatment with either cholinesterase inhibitor or memantine. A total of 122 were treated with cholinesterase inhibitors alone, and 116 received both a cholinesterase inhibitor and memantine.
Subjects in the no-therapy group were enrolled between 1990 and 1995, when cholinesterase inhibitors and memantine were not routinely used. Those receiving cholinesterase inhibitor and combination therapy were enrolled after 1997, when widespread use of cholinesterase inhibitors began in the United States.
All subjects received standard care and treatment for AD during the study. The practice was to prescribe cholinesterase inhibitors at initial diagnosis of AD. Memantine was added on an individual basis.
As a whole, the entire group declined. However, the researchers found significant differences in the rate of symptom progression among the 3 study groups. With a mean follow up of 2.5 years, the lowest rate of decline was seen in patients receiving combination therapy, particularly with respect to maintenance of functional status.
Furthermore, using a statistical model to predict probability outcomes out to 4 years, the investigators predicted that the longer patients received combination therapy, the smaller the rate of decline would become.
Disease-Modifying Effect?
“My gut feeling is these are mostly symptomatic drugs, but there was an indication that the combination therapy may actually be disease modifying. However, we need more research before we can draw any firm conclusions with respect to this,” Dr. Atri said.
According to Dr. Atri, the study’s main take-home point is that taking AD medication for a longer period slows decline and symptom progression. Giving medication for 6 months, he said, is not an accurate measure of effectiveness because the effects are quite small even for patients who do respond in this short period.
“It appears we need to give these drugs over a much longer period of time in order for them to demonstrate their full effect. So in some ways this study debunks the theory that if you don’t respond early, you’re never going to respond,” said Dr. Atri.
In light of the sheer numbers of patients that are likely to develop AD during the next 20 years, the findings have important global health implications. It is estimated there are currently 5 million individuals in the United States alone with AD. In the absence of preventive therapies, within the next 30 to 40 years the number of cases is expected to triple to 15 million.
“We didn’t measure this in our study, but it would make sense that by delaying the decline in patients’ cognitive and functional status, even a small difference would translate into major benefits for patients, their families, and healthcare systems not only in the United States but globally,” he said.
The study was supported by the National Institutes on Aging. The authors have disclosed no relevant financial relationships.
Clinical Context
AD will affect more than 6 million Americans by 2050, and treatment currently consists of cholinesterase inhibitors and memantine, which have modest symptomatic but not curative effects. However, long-term, real-time effectiveness data on combination therapy with both cholinesterase inhibitors and memantine (combination therapy) and cholinesterase inhibitors alone on cognition and functional ability are limited.
This is an observational longitudinal study conducted since 1990 to examine and compare the effects of the combination cholinesterase inhibitors and memantine with placebo and cholinesterase inhibitor therapy alone during 30 months of follow-up.
Study Highlights
Included were 382 patients attending a memory disorders clinic with a known diagnosis of AD who had completed at least 3 examinations showing functional and cognitive impairment.
Patients were assigned to the cholinesterase inhibitor group if they received any cholinesterase inhibitors for any duration but did not receive memantine (n = 122).
Patients were assigned to the cholinesterase inhibitors with memantine group (combination therapy) if they were treated with cholinesterase inhibitors and memantine for any duration (n = 116).
Cholinesterase inhibitors used were donezepil, glantamine, and rivastigmine-tacrine.
The control group consisted of patients who received neither treatment.
Because memantine was always added to cholinesterase inhibitor therapy, there was no group for memantine alone.
All subjects underwent a comprehensive clinical dementia evaluation.
Instruments used included the Information-Memory-Concentration subscale of the BDS and the Weintraub ADL.
The ADL was a 31-question questionnaire completed by a family member or caretaker.
Assessments were performed every 6 months.
The start date of medication was the day of the prescription.
Subjects in the combination therapy group were younger and had lower BDS scores than the other groups.
The cumulative duration of medication treatment for those in the cholinesterase inhibitor and combination therapy groups was at least 6 months.
The median duration of medication use was 1.9 years for the cholinesterase inhibitors and 1.55 years for the combination therapy group.
Mean cumulative duration of treatment time was 22.5 months.
90% of patients in the cholinesterase inhibitors and combination therapy groups had a cumulative duration of treatment of 1 or more years.
The dropout rate (those who did not have follow-up data) was 18% for the control, 34% for the cholinesterase inhibitors, and 25% for the combination therapy groups, respectively.
The combination therapy group was superior to both the cholinesterase inhibitor and control groups in decreasing the rate of progression of cognitive impairment.
The annualized rates of deterioration of BDS and ADL scores was significantly lower in the combination therapy group compared with the other 2 groups.
The cholinesterase inhibitor group was superior to the control group for cognitive function with slower rate of decline.
The combination therapy group had a lower rate of decline of ADL than the control and cholinesterase inhibitor groups, which did not differ significantly from one another.
The authors concluded that the effect of combination therapy was superior to cholinesterase inhibitor monotherapy or no therapy and that the effects persisted for years.
Pearls for Practice
Use of combination cholinesterase inhibitor and memantine therapy for patients with AD over time is associated with a greater reduced rate of decline of cognitive and ADL function than cholinesterase inhibitor therapy alone.
Use of combination cholinesterase inhibitor and memantine therapy for patients with AD over time is associated with a greater reduced rate of decline of cognitive and ADL function than no therapy.
October 28, 2008 — Tremor is a symptom of many disorders, including Parkinson’s disease, essential tremor, orthostatic tremor, cerebellar disease, peripheral neuropathy and alcohol withdrawal. Tremors may be classified as postural, rest or action tremors. Symptomatic treatment is tailored to the tremor type. Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor. Essential tremor may be amenable to propranolol or primidone. Propranolol may be useful in treating alcohol withdrawal tremor, and isoniazid may control the cerebellar tremor associated with multiple sclerosis. Clonazepam may relieve orthostatic tremor. Other agents are also available for the treatment of tremor. When medical therapy fails to control the tremor, surgical options such as thalamotomy, pallidotomy and thalamic stimulation should be considered in severe cases. Thalamic stimulation, the most recent of these surgical approaches, offers the advantage over ablative procedures of alleviating tremor without the creation of a permanent lesion.
Tremor is the involuntary, rhythmic oscillation of reciprocally innervated, antagonistic muscle groups, causing movement of a body part about a fixed plane in space.1,2 Effective treatment of tremor requires distinguishing this type of movement disorder from other movement disorders.
Rhythmicity distinguishes tremor from disorders in which tremor may be a component, such as choreoathetosis and dystonia, and its biphasic nature distinguishes tremor from clonus.1 The frequency and amplitude of a tremor vary to the degree that the tremor may be hardly noticeable or severely disabling. Frequency can be divided into three categories of oscillations per second: slow (3 to 5 Hz), intermediate (5 to 8 Hz) or rapid (9 to 12 Hz).3 Amplitude may be classified as fine, medium or coarse, depending on the displacement produced by the tremor about the fixed plane.3 A coarse tremor has a large displacement, whereas a fine tremor is barely noticeable. Tremor may be unifocal, multifocal or generalized, and may affect the head, face, jaw, voice, tongue, trunk or extremities.
Table1. Classification of Tremors, and Their Characteristics and Treatment
Type of tremo
Frequency
Occurrence
Etiology
Treatment*
Postural tremor
5 to 9 Hz
When limb is positioned against gravity
Physiologic tremor, essential tremor, alcohol or drug withdrawal, metabolic disturbances, drug-induced tremor, psychogenic tremor
*–Drugs and other treatments are generally listed in the order in which they should be tried. An adequate trial of each medication must be tried before the agent is judged to be ineffective. Many of these drugs are not specifically labeled for the treatment of tremor or have not undergone extensive studies to support their use in the treatment of tremor.
†–Action tremor includes intention tremor (exacerbation toward the end of goal-directed movement), kinetic tremor (during any type of movement) and task-specific tremor (only during performance of highly skilled activities, such as writing or playing a musical instument).
Classification: Postural, Rest and Action Tremors
Tremor is primarily classified on the basis of when it occurs, either with a certain posture, at rest or during action (Table 1). A resting tremor occurs when the patient is attempting to maintain the position of a body part at rest (e.g., when the patient’s hands exhibit a tremor as they are resting in the patient’s lap). Postural tremor is observed when the patient tries to maintain a posture against gravity, such as holding the arms out in front of the body. An action tremor (kinetic or intention tremor) occurs during movement of the affected body part from one point to another. A task-specific tremor occurs only when the patient begins to perform a highly skilled activity, such as writing or speaking.2
Tremor may be either physiologic or pathologic. Physiologic tremor is a normal variant, occurring at a frequency of 8 to 12 Hz in the hands yet as slow as 6.5 Hz in other body parts during maintenance of a posture.2,4 It can be increased by emotions such as anxiety, stress or fear, by exercise and fatigue, hypoglycemia, hypothermia, hyperthyroidism and alcohol withdrawal. When such an increase occurs, physiologic tremor is then called enhanced or exaggerated physiologic tremor.1,4 Certain drugs can also exacerbate physiologic tremor5 (Table 2). Pathologic tremor is either idiopathic or occurs secondary to some disorders (Table 3). Essential tremor and parkinsonian tremor are two common types of pathologic tremor.
Identification of the type of tremor depends on keen observation. The location of the tremor or the patient’s position when it occurs should be identified first, and special attention must be paid to other signs of illness. Careful observation will reveal if the tremor occurs at rest, during posture maintenance or during movement. The patient should be asked what produces or modulates the amplitude and frequency of the tremor.2,3 A correct diagnosis is essential for proper treatment of the disorder, because different types of tremor require different treatments.
Table 2 Commonly Used Agents That Exacerbate Physiologic Tremor
Caffeine
Fluoxetine (Prozac)
Haloperidol (Haldol)
Lithium
Methylphenidate (Ritalin)
Metoclopramide (Reglan)
Phenylpropanolamine
Pseudoephedrine
Theophylline
Valproic acid
Table 3.Selected Secondary Causes of Tremor
Alcohol or drug withdrawal
Brain abscess
Brain tumor
Multiple sclerosis
Peripheral neuropathy
Pheochromocytoma
Psychogenic disorders
Thyrotoxicosis
Tremor Types Based on Etiology
Parkinsonian Tremor
The tremor in Parkinson’s disease occurs at rest and is characterized by a frequency of 4 to 6 Hz and a medium amplitude. It is classically referred to as a “pill rolling” tremor of the hands but can also affect the head, trunk, jaw and lips.2,3 Although rare, a rest tremor may also be found in patients with other neurodegenerative diseases, such as multiple-systems atrophy and progressive supranuclear palsy. The tremor associated with these disorders is usually symmetric and not as prominent as the tremor that accompanies Parkinson’s disease.
A physiologic tremor occurs in the hands at a frequency of 8 to 12 Hz during maintenance of a posture.
Parkinson’s disease results from a slow degeneration of a small area in the midbrain, called the substantia nigra. Specifically, excitatory and inhibitory dopaminergic neurons degenerate in the substantia nigra pars compacta. These neurons project to the striatum and then to the globus pallidus. From there, multiple connections in the basal ganglia project to one another, to the thalamus and, finally, to the cortex, which makes up the extrapyramidal system. This system regulates the initiation and control of movement, and dysfunction of any of these connections can lead to various types of movement disorders.6 As a consequence of neuronal degeneration in the substantia nigra pars compacta, the ventral intermediate nucleus of the thalamus becomes overactive, possibly producing the tremor of Parkinson’s disease. The neurons in the ventral intermediate nucleus of the thalamus fire at a rate that matches the tremor.7
Video 1. Parkinsonian tremors
Essential Tremor
Essential tremor is the most common movement disorder.2,3,8 This postural tremor may have its onset anywhere between the second and sixth decades of life and its prevalence increases with age.8 It is slowly progressive over a period of years.3
The specific pathophysiology of essential tremor remains unknown. Essential tremor occurs sporadically or can be inherited. While the exact genetic defect has not been identified, familial transmission seems to be autosomal dominant with variable penetrance.4
The frequency of essential tremor is 4 to 11 Hz, depending on which body segment is affected. Proximal segments are affected at lower frequencies, and distal segments are affected at higher frequencies.3 Although typically a postural tremor, essential tremor may occur at rest in severe and very advanced cases.2 It most commonly affects the hands but can also affect the head, voice, tongue and legs.2,3,9 In some patients essential tremor is alleviated by small amounts of alcohol, an effect not found in Parkinson’s disease.
Video 2. Essential Tremor
Propranolol (Inderal) and primidone (Mysoline) are both effective in the treatment of essential tremor.
Cerebellar Tremor
The most common type of cerebellar tremor is kinetic, or goal directed. Cerebellar tremors are due to lesions of the lateral cerebellar nuclei or superior cerebellar peduncle, or its connections. Classically, a lesion within a cerebellar hemisphere or nuclei leads to an action tremor on the ipsilateral side of the body. Midline cerebellar disease may cause tremor of both arms, the head and the trunk.2 Lesions in the location of the red nucleus produce a wing-beating type of tremor (called rubral tremor), which is also present to a lesser degree with rest and posture.
Video 3. Rubral tremors (coarse resting tremor that increases with movement)
During examination, a cerebellar tremor increases in severity as the extremity approaches its target. Other signs of cerebellar pathology, such as abnormalities of gait, speech and ocular movements, and the ability to perform rapidly alternating movements, may be present and may help to confirm the diagnosis of cerebellar tremor.3
Another type of tremor may also be associated with damage to the cerebellum. Termed “cerebellar postural tremor,” it is prominent with both action and posture.4 In its most severe form, cerebellar postural tremor has a frequency of 2.5 to 4 Hz and may wax and wane in amplitude, increasing progressively with prolonged posture. It persists and worsens with goal-directed movement.4 The milder form of the tremor has a more rapid frequency, approaching 10 Hz, and appears more distally, making it harder to identify than the severe type.4
Multiple sclerosis is the most common cause of the cerebellar postural tremor.4 Other causes of this tremor include tumors and strokes, as well as neural degeneration in the cerebellum.
Video 4. Cerebellar Tremor
Alcohol Withdrawal Tremor
Alcohol withdrawal tremor is similar to essential tremor on examination but with subtle differences. Alcohol withdrawal tremor has a frequency between 6 and 10.5 Hz. In one study,10 74 percent of the patients with alcohol withdrawal tremors had tremors at a frequency above 8 Hz. In this same series, tremors in all of the patients who had essential tremor were at a frequency below 8 Hz. Thus, the tremor of alcohol withdrawal tends to be more rapid than essential tremor.
A family history of tremor was found in only 1 percent of the patients with alcohol withdrawal tremor, as compared with almost one half of the patients with essential tremor.10 In addition, severity and degree of functional disability were less with alcohol withdrawal tremor.
Only the hands are affected in patients with alcohol withdrawal tremor, but multiple sites of involvement are possible in patients with essential tremor. Overactivity of the sympathetic nervous system is thought to be responsible for alcohol withdrawal tremor, and prolonged alcohol abuse can result in a chronic tremor disorder.10
Psychogenic Tremor
Psychogenic tremor is a complex tremor that can occur at rest, during postural movement and during kinetic movement. The etiology and pathophysiology of psychogenic tremor are likely to differ from patient to patient, and the main focus of treatment should be psychotherapy, not medication.
Clinical features of psychogenic tremor include an abrupt onset, a static course, spontaneous remission and unclassifiable tremors.11 Unresponsiveness to antitremor drugs, an increase in frequency and amplitude with attention and a decrease in frequency and amplitude with distraction, responsiveness to placebo, absence of other neurologic signs and remission with psychotherapy are also signs of psychogenic tremor.11 Clinical inconsistencies, such as being able to write words yet not being able to draw a spiral, and changing characteristics, such as direction and affected body part, are also representative of psychogenic tremor.11
Other Tremors
Other types of tremor occur much less commonly than the previously described tremors. Orthostatic tremor is defined as a postural tremor of the legs, occurring at a frequency of 13 to 18 Hz, initiated on standing and alleviated by walking or sitting.12 It is more readily noticeable during palpation than by sight and is not influenced by peripheral feedback.13 Unsteadiness, feelings of imbalance or weakness, and trembling and shaking in the lower limbs are associated features of orthostatic tremor.14 The etiology of orthostatic tremor is unknown, but it is currently regarded as an entity separate from essential tremor.12-14
Tremor associated with peripheral neuropathy is clinically similar to essential tremor. Its etiology is diverse. Not only can it be idiopathic, it can also be caused by demyelination from immunoglobulin M paraproteinemic neuropathies.2 Tremor in association with peripheral neuropathy can also result from Charcot-Marie-Tooth disease, diabetes mellitus, uremia and porphyria.2
Management of tremors
Medical treatment of tremors
There is no established treatment for cerebellar tremor.2 In patients with multiple sclerosis, severe cerebellar tremor may be improved with isoniazid, in a dosage of 600 to 1,200 mg per day, given together with pyridoxine.4
Propranolol in a dosage of 160 mg per day is very effective in reducing the tremor associated with alcohol withdrawal.10
Treatment of orthostatic tremor should first be attempted with clonazepam (Klonopin). In one small study,14 eight of nine patients responded to clonazepam in dosages ranging from 0.5 to 2.0 mg per day. The patient who did not respond to clonazepam responded to chlordiazepoxide (Librium), in a dosage of 30 mg twice a day. In another study,12 10 of 18 patients had sustained improvement with clonazepam, and valproic acid was effective in the remaining eight patients. However, propranolol in daily dosages of up to 320 mg had no effect on controlling orthostatic tremor.
Tremor due to peripheral neuropathy may be ameliorated with propranolol, primidone, benzodiazepines or baclofen (Lioresal), but the underlying cause of the neuropathy itself should be treated as well.2
Other medications have been shown to be helpful in the management of tremor but should probably only be tried in consultation with a neurologist, when the previously mentioned drugs have failed to control the tremor.
Drug Treatment of of specific Tremor
Parkinsonian Tremor
Treatment of Parkinson’s disease includes both medical and surgical intervention. Dopamine replacement therapy by means of levodopa clearly revolutionized the treatment of Parkinson’s disease. Levodopa is almost exclusively given in combination with the peripheral decarboxylase inhibitor carbidopa (Sinemet). Carbidopa blocks the peripheral metabolism of levodopa to dopamine, decreasing the peripheral adverse effects of levodopa, such as nausea and vomiting, while increasing levodopa’s availability in the brain.15,16 In addition to modulating the tremor associated with Parkinson’s disease, levodopa improves bradykinesia, rigidity and other commonly associated symptoms. Carbidopalevodopa is available in formulations of 10/100 mg, 25/100 mg and 25/250 mg. It is advantageous to begin treatment of mild disease with the 25/100-mg dosage, one tablet three times a day, and then increase the dosage as symptoms become less manageable.
When tremor is the predominant presenting symptom of Parkinson’s disease or when tremor persists despite adequate control of other parkinsonian symptoms with low dosages of levodopa, an anticholinergic agent such as trihexyphenidyl (Artane) or benztropine (Cogentin) may be the treatment of choice. In most patients, however, anticholinergics do not significantly improve bradykinesia and rigidity. Trihexyphenidyl dosages necessary to improve tremor are between 4 and 10 mg per day (maximum: 32 mg), and useful benztropine dosages range from 1 to 4 mg per day. The side effects of these agents are their limiting factor, particularly in the elderly. Side effects include memory impairment, hallucinations, dry mouth, urinary difficulties and blurred vision.15
Other antiparkinsonian drugs–for example, amantadine (Symmetrel), tolcapone (Tasmar) and dopamine agonists such as pergolide (Permax), bromocriptine (Parlodel), ropinirole (Requip) and pramipexole (Mirapex)–are most helpful in patients whose tremor responds poorly to levodopa alone.
Essential Tremor
As with other tremors, effective treatment of essential tremor is not found in a single, universal agent. Some therapies may be satisfactory in some patients and ineffective in others. The most widely used drugs for essential tremor are the beta-adrenergic blocker propranolol (Inderal) and the anticonvulsant primidone (Mysoline). The typical dosage range for propranolol is 80 to 320 mg per day and for primidone, 25 to 750 mg per day.3 Other beta-adrenergic receptor antagonists used in the treatment of essential tremor include metoprolol (Lopressor) and nadolol (Corgard).2 Alcohol is also effective in relieving essential tremor, but abuse may be an adverse consequence.3
In our experience, propranolol and primidone are equally effective in the treatment of essential tremor. Patients who do not respond to one medication after a few weeks of therapy should be tried on the other one. Primidone may be preferred, because of the exercise intolerance associated with high-dose beta blockade. Patients who have a very-low-amplitude rapid tremor are generally more responsive to these agents than those who have a slower tremor with greater amplitude. Patients who have tremor of the head and voice may also be more resistant to treatment than patients with essential tremor of the hands.
Surgical Treatment of Tremor
Thalamotomy
Surgical therapy for tremor should only be considered if drug therapy fails to produce adequate relief. Stereotactic thalamotomy is the surgical procedure most often used to quell essential tremor. Before the introduction of levodopa, thalamotomy was an often-selected option in the treatment of Parkinson’s disease. Because the benefits of levodopa wane after four to seven years of therapy, this procedure remains an option in some patients with severe parkinsonian tremor refractory to drug therapy. However, problems associated with bilateral thalamotomy, such as dysphagia and dysarthria, limit its use. Thalamotomy is usually only considered in patients with severe, drug-resistant essential tremor and in a very small subset of patients with Parkinson’s disease who have severe, disabling, predominantly unilateral tremor.
In one study of the use of stereotactic thalamotomy in the treatment of tremor,17 86 percent of the 42 patients with parkinsonian tremor and 83 percent of the six patients with essential tremor had cessation of tremor or moderate to marked improvement in tremor after the procedure. Follow-up in some patients was as long as 13 years (mean follow-up: 53.4 months). The investigators used three criteria for patient selection: (1) predominantly unilateral, severe and incapacitating tremor, (2) a poor response to or intolerance of optimal medical therapy and (3) no potentially serious risk factors for surgery. Postoperative complications included weakness, dysarthria and confusion, but these problems subsided with time.
Catastrophic complications in the perioperative period include bleeding in the thalamus or the subdural or epidural area, which can lead to death, paralysis, aphasia or significant cognifive deficits.
Pallidotomy
Producing lesions in the globus pallidus by means of pallidotomy is an alternative to thalamotomy in the treatment of parkinsonian tremor. Pallidotomy also improves other symptoms of Parkinson’s disease, such as bradykinesia and levodopa-induced dyskinesias.18 As with thalamotomy, pallidotomy should only be considered in cases of severe tremor unresponsive to medical treatment.
In a series of 259 patients who underwent pallidotomy for parkinsonian tremor,18 complete relief of all symptoms on the side contralateral to the procedure occurred in 212 patients (81.9 percent). Of the remaining 47 patients, 36 experienced substantial improvement and 11 had only minor or no improvement. In many of the patients, pallidotomy also produced a significant reduction in bradykinesia, rigidity and levodopa-induced dyskinesias. The side effects associated with the procedure were similar to those of thalamotomy and included visual field defects, such as lower central visual field scotomas, and hemiparesis. Cognitive deficits, dysarthria and foot apraxia occurred in less than 1 percent.
If the pallidal lesion is large enough and placed at the posteroventral margin of the lateral pallidum, it abolishes the tremor as often as thalamotomy. However, because of theoretic concerns that bilateral pallidotomy may cause cognitive deficits, this approach must be explored before it is comonly used in the treatment of tremo
Thalamic Stimulation
During physiologic localization in preparation for thalamotomy, the observation that high-frequency stimulation of the ventral intermediate nucleus of the thalamus abolished tremor led to investigation of thalamic stimulation as a treatment for tremor. The first study of this technique as a long-term therapy for tremor was reported in 1993.19
Thalamic stimulation by means of an implanted electrode may effectively control tremor in patients with essential tremor or Parkinson’s disease.
Thalamic stimulation involves implanting an electrode in the thalamic area found to be responsible for the tremor. After the wire of the electrode leaves the skull, it is tunneled under the scalp and down the neck to a purse generator located in the subclavicular pouch. The implanted stimulating device is much like a modified pacemaker, and its electrical impulses can suppress tremor indefinitely. The stimulator can be reprogrammed by using a small portable computer that communicates with the device by radio frequency. Moreover, the patient can turn the device on and off with a magnet. Patients usually turn the device on in the morning, leave it on during waking hours and turn it off at bedtime, since most tremors cease during sleep.
In the first study of this technique,19 as many as 88 percent of the patients with Parkinson’s disease had either good or excellent relief of tremor. The operative risk of implanting the device is proving to be similar to that of thalamotomy; death, paralysis, aphasia and significant cognitive deficits are possible complications.
Tremor recurrence after placement of the electrode can be controlled by adjusting the stimulation parameter rather than by reoperation.20 The U.S. Food and Drug Administration has approved thalamic stimulation as an accepted therapy for unilateral suppression of uncontrolled essential tremor or parkinsonian tremor in an upper extremity. As with the other surgical techniques, thalamic stimulation is an option that should be chosen only after medical therapy has failed.
Promising Surgical Approaches
At the forefront of new surgical therapies for tremor are pallidal stimulation and subthalamic nucleus stimulation.21-23 With new advances in deep brain stimulation, procedures can be performed bilaterally to relieve tremor in patients with bilateral involvement. Either a combination of thalamotomy and stimulation or bilateral stimulation without ablation is now a possibility.23 Targets in the brain that are too dangerous to approach for producing a lesion by means of thalamotomy may be treated with stimulation instead, and electrical stimulation can be modified to alleviate tremor as it progresses.22 Thus, deep brain stimulation has become a promising option for abolishing tremors that cannot be controlled by medical therapy.
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Benabid AL, Pollak P, Seigneuret E, Hoffman D, Gay E, Perret J. Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor and extra-pyramidal dyskinesias. Acta Neurochir Suppl 1993;58:39-44.
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