Case Files Neurology - part 2 pptx

APPROACH TO DYSTONIA Definitions Dystonia—Sustained muscle contractions cause twisting and repetitive movements or abnormal postures. Myoclonus—Sudden, involuntary jerking of a muscle or group of muscles. Opisthotonos—Great rigid spasm of the body with the back fully arched and the heels and head bent back. Clinical Approach Dystonia is classified according to etiology, as idiopathic or symptomatic. Primary dystonia is defined as a condition with no etiology that can be iden- tified, and dystonia is the sole or major symptom. Primary dystonias are further subdivided by criteria such as age of onset, distribution of affected body parts, presence of diurnal variation of symptoms, responsiveness to drugs, and genetic markers. Secondary dystonia refers to dystonia in the context of a neurologic disease in which dystonia is only one of several symptoms or in which dysto- nia is the result of an environmental insult. There are at least 15 genetic causes of dystonia. Generalized dystonia tends to have its onset in childhood. A three–- base-pair guanine–adenine–guanine (GAG) deletion in exon 5 of DYT1 (TOR1A) is the most frequent cause of early onset, generalized dystonia starting in a limb and is known as DYT-1 dystonia. However, there is a large phenotypic variability even within families with an identical mutation. Primary generalized torsion dystonia is a progressive, disabling disorder that usually begins in child- hood and is linked to several genetic loci. Many cases are inherited as autosomal CLINICAL CASES 33 Table 3–1 DIFFERENTIAL DIAGNOSIS OF DYSTONIA Secondary dystonias Drug-induced tardive dystonias Antipsychotic drugs: dopamine receptor–blocking older typical and newer atypical drugs Anxiolytic drug: buspirone Antidepressant agents: selective serotonin-reuptake inhibitors Dopaminergic drugs: levodopa and dopamine agonists Antiemetic drugs: metoclopramide Antiseizure drugs: phenytoin, carbamazepine, gabapentin Cerebral palsy Wilson disease Mitochondrial encephalopathies Neuroacanthocytosis Pantothenate kinase–associated neurodegeneration (Hallervorden–Spatz disease) Fahr disease dominant traits caused by a deletion in the torsin A gene (DYT1 locus), result- ing in the deletion of glutamate in torsin A, a brain protein of unknown func- tion with highest concentrations in the substantia nigra. Penetrance is 30–40%, and clinical expression varies from generalized dysto- nia to occasional adult-onset focal dystonias. It begins as a focal action dystonia before the middle of the third decade of life with most cases beginning in child- hood. Because of its rarity and unfamiliar features, it is sometimes misdiagnosed a psychogenic disorder. Approximately 65% of cases progress to a generalized or multifocal distribution, 10% become segmental, and 25% remain focal. Childhood-onset cases commonly evolve to generalized dystonia, which pro- duces severe disability owing to serious gait and posture abnormalities (Fig. 3–1). This can result in a life-threatening condition called status dystonicus. The diagnosis of DYT-1 can be made by commercially available testing. Most primary dystonias have normal routine neuroimaging studies. [18F]- fluorodeoxyglucose and positron emission tomography (PET) has been used with a novel regional network analytical approach to identify a reproducible pattern of abnormal regional glucose metabolism in primary torsion dystonia. This pattern is not specific for the DYT1 genotype, can be present in other pri- mary dystonia genotypes, and is not routinely available. 34 CASE FILES: NEUROLOGY Figure 3–1. Incapacitating postural deformity in a young man with dystonia. (With permission from Ropper AH, Brown RH. Adams and Victor’s principles of neurology, 8th ed. New York: McGraw-Hill; 2005: Fig. 4–5c.) In any given case, the first consideration is whether this represents a sec- ondary dystonia, particularly one which is amenable to effective treatment, including discontinuation of offending agents. Some clues that dystonia is sec- ondary include: • History of trauma or exposure to drugs, infections, cerebral anoxia • Dystonia at rest, rather than with action, at its onset • Atypical site for age of onset—for example, leg onset in an adult, cranial onset in a child • Early onset of speech abnormality • Hemidystonia • Presence of abnormalities other than dystonia on neurologic examination or general medical examination • Nonphysiologic findings suggesting a psychogenic basis • Abnormal brain imaging • Abnormal laboratory tests Table 3–2 summarizes common etiologies of secondary dystonia. The current functional model of basal ganglia suggests that dystonia results from abnormally low or generally abnormal pattern of activity of basal ganglia output structures: the internal segment of globus pallidus (GPi) and substantia nigra pars reticulata. CLINICAL CASES 35 Table 3–2 CAUSES OF SECONDARY DYSTONIA Hereditary disorders associated with Neurodegeneration (Huntington disease, juvenile Parkinson disease (parkin), Wilson disease, lysosomal storage disorders, Rett syndrome) Dystonia-plus syndromes (dopa-responsive dystonia, myoclonus-dystonia, rapid- onset dystonia-parkinsonism) Acquired/exogenous causes (Medication: dopamine receptor-blocking agents, Antiepileptic agents, levodopa, dopamine agonists, calcium-channel blockers; Toxins: manganese, carbon monoxide, carbon disulphide, methanol, wasp sting; Perinatal cerebral injuries: cerebral palsy, kernicterus; Vascular lesions: stroke, arteriovenous malformation, antiphospholipid syndrome ; Infection: encephalitis, subacute sclerosing panencephalitis, HIV/AIDS, abscess; Brain tumors; paraneo- plastic syndromes; demyelination: multiple sclerosis, pontine myelinolysis; Trauma: head trauma, cervical cord injury; Structural: atlanto-axial subluxation, Klippel-Feil syndrome, Arnold-Chiari malformation) Parkinson disease and other parkinsonian disorders (progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy) Other movement disorders (tic disorders, familial paroxysmal kinesigenic dyski- nesias, familial paroxysmal non-kinesigenic dyskinesias, episodic ataxia syndromes) This low activity consequently disinhibits the motor thalamus and cortex, giv- ing rise to abnormal movements. In addition, drugs that inhibit the action of dopamine (through type 2 dopamine [D2] receptors) can cause acute or chronic dystonia. This seems to be mediated by disinhibition of cholinergic neurons. Symptomatic treatment of dystonia in the past has employed primarily phar- macologic agents. These include systemic agents such as levodopa, blockers of central muscarinic cholinergic receptors, benzodiazepines, and baclofen. Anatomically targeted administration of agents is also feasible including botu- linum toxin and intrathecal administration of baclofen. There is mounting evi- dence that the most effective treatment for generalized dystonia is high-frequency stimulation of the GPi, through the surgical placement of a deep brain stimulator. Comprehension Questions [3.1] The drug most likely to help dystonic symptoms in a patient with DYT-1 dystonia is: A. Haloperidol B. Trihexyphenidyl (Artane) C. Phenytoin D. Chlorpromazine [3.2] A 12-year-old boy has the acute onset of sustained contractions of the left leg and right arm as well as loss of sensation above the neck. The severity of the symptoms is highly variable. The most likely diagnosis is: A. DYT-1 dystonia B. Acute dystonia from a medication C. Bilateral ischemic infarction of the globus pallidi D. Psychogenic disorder E. A right spinal cord hemisection syndrome [3.3] A 32-year-old woman is seen in the emergency department. She has no medical problems nor allergies to medications. She receives a medica- tion intravenously and has an acute dystonic reaction with muscle spasm of the neck. Which of the following drugs is most likely respon- sible for this reaction? A. Haloperidol B. Trihexyphenidyl (Artane) C. Phenytoin D. Levodopa 36 CASE FILES: NEUROLOGY CLINICAL CASES 37 Answers [3.1] B. Trihexyphenidyl (Artane) is an antimuscarinics anticholinergic. [3.2] D. This is likely psychogenic because there is a physiologically incon- gruent examination. [3.3] A. Haloperidol is a potent blocker of dopamine D2 receptors and is a common agent responsible for dystonic reactions in otherwise healthy individuals. CLINICAL PEARLS ❖ DYT-1 dystonia is an autosomal dominant disease, which can be confirmed with genetic testing. ❖ DYT-1 and other primary dystonias usually have the abnormal movements in association with action early in the course of the disease. ❖ In mild cases of DYT-1 and other primary generalized dystonias, systemic drugs, such as anticholinergics, benzodiazepines, and baclofen may control symptoms, in severe cases, deep brain stim- ulation of the globus pallidi may be required. REFERENCES Albanese A. The clinical expression of primary dystonia. J Neurol 2003;250:1145–1151. Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force. Eur J Neurol 2006;13(5):433–444. Geyer HL, Bressman SB. The diagnosis of dystonia. Lancet Neurol 2006;5:780–790. Krauss JK, Yianni J, Loher TJ, et al. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004;21(1):18–30. Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and its management. Brain 1998;121:243–252. Tarsy D, Simon DK. Dystonia. N Engl J Med 2006;355:818–829. This page intentionally left blank ❖ CASE 4 The patient is a 55-year-old man in good health until about 6 months ago. At that time he noticed development of a tremor. He has no other complaints. On examination, there is a tremor in the right arm at rest and while he walks, he has a sustained tremor in both arms, and to some degree during finger-nose- finger maneuver (fairly fine and without an obvious rhythm). He has a poker face and a slow, deliberate gait. Tone is increased in the right arm and leg. The physical examination is otherwise unremarkable. He and his wife deny his use of alcohol or any other medications. ◆ What is the most likely diagnosis? ◆ What is the next diagnostic step? ◆ What is the next step in therapy? ANSWERS TO CASE 4: Parkinson Disease Summary: This is a middle-aged man with asymmetric onset of tremor. In addition he has mild poverty of movement (otherwise known as akinesia of the face and body), tremor at rest, as well as increased tone. ◆ Most likely diagnosis: Parkinson disease. ◆ Next diagnostic step: Do an MRI of the brain to evaluate other disorders in the differential diagnosis. ◆ Next step in therapy: If the current symptoms are causing the patient disability, initiate therapy with either dopamine agonist or monoamine oxidase type B (MAO-B) inhibitor. Analysis Objectives 1. Understand the differential diagnosis of parkinsonism. 2. Know the clinical characteristics of Parkinson disease. 3. Describe the usefulness of different imaging modalities for evaluating spinal cord injury and the importance of patient age. 4. Be aware of the different treatment options for Parkinson disease and their role and liabilities. Considerations The patient described in the case above has tremor at rest, rigidity, and hypoki- nesia, which are the three cardinal features of Parkinson disease–and consti- tute the syndrome of parkinsonism. The fourth of the cardinal features is postural instability, which in idiopathic Parkinson disease typically has onset several years later. The most common cause of parkinsonism is idiopathic Parkinson disease. A careful search for secondary causes of parkinsonism should be undertaken such as a history of medication use (antipsychotic agents), metabolic or structural diseases of the brain (hydrocephalus), and infectious etiologies. MRI of the brain is typically performed. Levodopa is a standard agent used to treat the symptoms of Parkinson disease; unfortunately, no agent has been shown to slow the progress of the disease. APPROACH TO SUSPECTED PARKINSON DISEASE Definitions Substantia nigra—(Latin for “black substance”) or locus niger is a heteroge- neous portion of the midbrain, and a major element of the basal ganglia sys- tem. It consists of the pars compacta, pars reticulata, and the pars lateralis. 40 CASE FILES: NEUROLOGY Lewy body—an eosinophilic, round inclusion found in the cell cytoplasm of substantia nigra, the nucleus basalis of Meynert, locus ceruleus, dor- sal raphe, and the dorsal motor nucleus of cranial nerve X. They contain alpha-synuclein, a presynaptic protein, the function of which is unknown. Neurofilament proteins and ubiquitin are other important con- stituents of Lewy bodies. Clinical Approach Parkinson disease is a disorder that gets its name from the Essay on the Shaking Palsy by James Parkinson. Features of Parkinson disease can be expressed in other ways including: difficulty arising from a chair, difficulty turning in bed, micrographia, masked face, stooped, shuffling gait with decreased arm swing; and sialorrhea. Although Parkinson disease is thought of as a motor disorder, sensory systems are also affected. Loss of sense of smell is almost universal. Pain is very common. Other system involvement can result in autonomic disturbance, depression, a variety of speech disturbances includ- ing dysarthria, palilalia, and stuttering. In Parkinson’s monograph, he specifi- cally stated “the senses and intellect are preserved.” Research has shown that isolated cognitive deficits are extremely common in Parkinson disease, espe- cially executive dysfunction. In addition approximately 50% of patients develop dementia. The most obvious pathologic feature of Parkinson disease is loss of pig- ment in the substantia nigra caused by loss of neurons in this region. The remaining neurons may show an intra-cytoplasmic eosinophilic inclusion called a Lewy body (Fig. 4–1). These neurons project rostrally in the brain to innervate the striatum as well as the cerebral cortex. Parkinson disease is asso- ciated with marked striatal dopamine (DA) depletion and is considered by many to be a striatal dopamine deficiency syndrome. At death, DA loss is greater than 90%, and approximately 70% DA loss results in symptom expres- sion. Severity of DA loss best correlates with bradykinesia in Parkinson disease—the correlation with tremor is very poor. In recent years, we have seen a much more comprehensive picture of the pathologic destruction by Parkinson disease, which helps us to understand the wide variety of signs and symptoms besides bradykinesia. Other morphologic and chemical deficits have also been demonstrated in the brains of patients with Parkinson disease in the cholinergic pedunculopontine nucleus, noradrenergic locus coeruleus, serotonergic raphe nuclei, and glutamatergic centromedian/parafascicularis complex of the thalamus. Still, there are many signs and symptoms that are atypical for Parkinson disease and should raise our level of vigilance that another disorder is present. These include: • Early onset of, or rapidly progressing, dementia • Rapidly progressive course CLINICAL CASES 41 • Supranuclear gaze palsy • Upper motor neuron signs • Cerebellar signs—dysmetria, ataxia • Urinary incontinence • Early symptomatic postural hypotension • Early falls The majority of cases of Parkinson disease are unknown. Familial Parkinson disease, while rare, does occur, and is most commonly associated with a muta- tion of the parkin gene, which is inherited in an autosomal recessive pattern. This mutation is the most common cause of early onset Parkinson disease, without Lewy bodies. Routine neuroimaging is usually normal in Parkinson disease. Functional imaging designed to visualize the dopamine innervation of the striatum, especially in combination with other imaging techniques may provide a way to positively identify the disease, however these techniques are still under investigation and are not available under routine clinical circum- stances. Imaging is useful, however, to identify some of the other entities in the differential diagnosis. The differential diagnosis of parkinsonism includes the following categories: 42 CASE FILES: NEUROLOGY Figure 4–1. Lewy body on microscopy. (With permission from Ropper AH, Brown RH. Adams and Victor’s principles of neurology, 8th ed. New York: McGraw-Hill; 2005: Fig. 39–5.) [...]... saccades SCA-8 2 5 13q21 CTG (3’UTR) (100 25 0) Ataxia, dysarthria, mild sensory neuropathy Nystagmus, saccadic pursuit Source: C Mariotti, R Fancellu, S Di Donato An overview of the patient with ataxia J Neurol 20 05 ;25 2:511–518  52 CASE FILES: NEUROLOGY Other types of repeat expansions that cause SCA have been discovered For example, SCA-10 involves an ATTCT repeat expansion of the SCA10 gene, and SCA-8 involves... tardive dyskinesia  62 CASE FILES: NEUROLOGY REFERENCES Chou KL, Friedman JH Tardive syndromes in the elderly Clin Geriatr Med 20 06 Nov ;22 (4):915–933 Fernandez HH, Friedman JH Classification and treatment of tardive syndromes Neurologist 20 03 Jan;9(1):16 27 Kenney C, Jankovic J Tetrabenazine in the treatment of hyperkinetic movement disorders Expert Rev Neurother 20 06 Jan;6(1):7–17 Soares-Weiser K, Rathbone... 6–10, 12, and 17) Table 5–1 SELECT LIST OF AUTOSOMAL DOMINANT SPINOCEREBELLAR ATAXIAS DISEASE INCIDENCE (%) LOCUS PROTEIN MUTATION CLINICAL FEATURES OCULOMOTOR ABNORMALITIES SCA-1 6 6p23 Ataxin-1 CAG repeats (38–83) Ataxia, dysarthria, pyramidal signs, peripheral neuropathy, hyperreflexia, cognitive impairment Nystagmus, hypermetric saccades, slow saccades, ophthalmoparesis SCA -2 14 12q24 Ataxin -2 CAG... syndromes: approaches to diagnosis and treatment Semin Neurol 20 03 Jun ;23 (2) :21 5 22 4 Duen AM, Goold R, Giunti P Molecular pathogenesis of spinocerebellar ataxias Brain 20 06; 129 :1357–1370 Hadjivassiliou M, Grunewald R, Sharrack B, et al Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics Brain 20 03; 126 :685–691 Harding AE Hereditary spastic paraplegias Seminar... SCA-3 21 14q 32 Ataxin-3 CAG repeats (61–84) Ataxia, dysarthria, spasticity, parkinsonism, amyotrophy Lid retraction, nystagmus, saccade dysmetria, ophthalmoparesis, square-wave jerks SCA-6 15 19p13 CACNA1A CAG repeats (20 –33) Ataxia, dysarthria, sometimes episodic ataxia, very slow progression, lack of family history Nystagmus (60% downbeating), saccadic pursuit SCA-7 5 3p14 Ataxin-7 CAG repeats (3 7-. .. Syst Rev 20 06 Jan 25 ;(1):CD000459 Tarsy D, Baldessarini RJ Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 20 06 May ;21 (5):589–598 ❖ CASE 7 A 13-year-old right-handed male is brought to the emergency room (ER) following a moderate speed motor vehicle accident (MVA) The patient was an unrestrained front-seat passenger but was not ejected during the head-on collision... prospectus (affected), father, 1 /2 brothers, 0 /2 sister, paternal grandfather and uncle C Male prospectus, neither parent, 1 /2 brothers, 1 /2 sister, paternal great-grandfather [poor penetrance] D Male prospectus, neither parent, 0 /2 brothers, 0 /2 sister, paternal grandfather and uncle [poor penetrance] Answers [5.1] A–the parkinsonism of SCA is often responsive to levodopa [5 .2] B is characteristic of neoplastic... review): report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 20 06;66:983–995 Tolosa E, Wenning G, Poewe W The diagnosis of Parkinson’s disease Lancet Neurol 20 06;5:75–86 ❖ CASE 5 This 57-year-old man of Portuguese descent noticed that he had difficulty marching in line as a soldier From age 20 until the age of 40 he had a slow progression of symptoms Since then he... repeated Finally, SCA-4 involves a mutation in a gene that does not involve a trinucleotide repeat expansion The average age of onset for all of these types is from 20 to 30 years of age except for SCA-6, which usually occurs between the ages of 40 and 50 People with SCA-8 usually develop symptoms in their late 30s SCA -2 patients usually develop dementia and slow eye movements SCA-8 patients, who have... most likely diagnosis? ◆ What is the next diagnostic step? ◆ What is the next step in therapy? 64 CASE FILES: NEUROLOGY ANSWERS TO CASE 7: Spinal Cord Injury, Traumatic Summary: This 13-year-old presents to the ER significantly obtunded with flaccid quadriparesis and agonal respirations following a head-on MVA in which he was an unrestrained passenger He is now intubated, and his cervical spine is immobilized . impairment SCA -2 14 12q24 Ataxin -2 CAG repeats Ataxia, dysarthria, Slow saccades, (35–64) peripheral neuropathy, ophthalmoplegia hyporeflexia, dementia, myoclonus SCA-3 21 14q 32 CAG repeats Ataxia,. Clin Neurophysiol 20 04 ;21 (1):18–30. Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and its management. Brain 1998; 121 :24 3 25 2. Tarsy D, Simon DK. Dystonia. N Engl J Med 20 06;355:818– 829 . This. American Academy of Neurology. Neurology 20 06;66:983–995. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 20 06;5:75–86. ❖ CASE 5 This 57-year-old man of Portuguese