Parkinson’s Disease 3B Aug 2023 PDF

MED 7721 CLINICAL NEUROLOGY DISORDERS OF MOVEMENT I: PARKINSON’S DISEASE Reynaldo B. Sta. Mina, Jr., M.D., MMHoA  Learning Objectives Clinical Evaluation of Patients Introduction History Ty...

MED 7721 CLINICAL NEUROLOGY DISORDERS OF MOVEMENT I: PARKINSON’S DISEASE Reynaldo B. Sta. Mina, Jr., M.D., MMHoA  Learning Objectives Clinical Evaluation of Patients Introduction History Types of Abnormal Age at Onset Movements Mode of Onset Tremor Course Postural Tremor Medical History Asterixis Examination Intention (Kinetic) Tremor Investigative Studies Rest Tremor Blood & Urine Tests Chorea Electrophysiologic Tests Hemiballismus Imaging CONTENTS Dystonia & Athetosis Factors Influencing Genetic Studies Psychologic Evaluation Parkinsonism Dystonia Etiology Etiology Myoclonus Pathology Generalized Myoclonus Pathogenesis Focal or Segmental Clinical Findings Myoclonus Differential Diagnosis Propriospinal Myoclonus Treatment Treatment YouTube Video Link Tics Clinical Case Classification Main Reference Bradykinesia & Hypokinesia Related Readings  To learn the different types of abnormal movement To know how to clinically approach a patient presenting with LEARNING abnormal movement OBJECTIVES To understand Parkinson’s disease – its etiology, pathology, pathogenesis, clinical findings, differential diagnosis, and treatment CONTROL OF MOVEMENT Movement is controlled by two motor systems: PYRAMIDAL SYSTEM Pass through the medullary pyramids Corticospinal tract – controls movements of the limbs and trunk Corticobulbar tract – controls movements of the face, head and neck EXTRAPYRAMIDAL SYSTEM Begins in the midbrain and connects with multiple areas and tracts Modulates voluntary movements Does not pass through the medullary pyramids  COMPARISON BETWEEN PYRAMIDAL AND EXTRAPYRAMIDAL SYSTEMS PYRAMIDAL SYSTEM EXTRAPYRAMIDAL SYSTEM NORMAL Function Execution of skillful voluntary Modulation of voluntary movements movements Connections Direct link to spinal cord Multi-neuronal and multi-synaptic ABNORMAL (With Lesion) Muscle tone Spastic Rigid Muscle strength Decreased Normal Contractures Early Late Deep tendon reflexes Hyperreflexia Normal Clonus Present Usually absent Babinski (Plantar response) Present (extensor) Absent (flexor) Involuntary movements Absent Present BASAL NUCLEI (BASAL GANGLIA) A group of subcortical nuclei situated at the base of the forebrain and top of the midbrain. Gray matter within the white matter Interconnected with the cerebral cortex, thalamus and brainstem, as well as several other brain areas. With a variety of functions: Modulation of voluntary movements Procedural or habit learning Eye movements Cognition Emotion COMPONENTS OF BASAL NUCLEI Primarily include: Caudate nucleus Putamen Globus pallidus Subthalamic nucleus Substantia nigra GROUPING OF BASAL NUCLEI STRIATUM Caudate nucleus Putamen LENTIFORM NUCLEUS Globus pallidus Putamen CORPUS STRIATUM Lentiform nucleus Caudate nucleus CLAUSTRUM Lies between the lentiform nucleus and the insular cortex.  The largest component, the striatum (caudate nucleus and putamen), receives input from many brain areas beyond the basal ganglia, but only sends output to other components of the basal ganglia. The globus pallidus receives input from the striatum, and sends inhibitory output to a number of motor-related areas. The substantia nigra is the source of the striatal input dopamine, a neurotransmitter which plays an important role in basal ganglia function. The subthalamic nucleus receives input mainly from the striatum and cerebral cortex and projects to the globus pallidus. BASIC CIRCUITRY OF THE BASAL NUCLEI Three interacting neuronal loops: CORTICOCORTICAL LOOP Passes from the cerebral cortex, through the caudate and putamen, the internal segment of the globus pallidus, and the thalamus, and then back to the cerebral cortex. NIGROSTRIATAL LOOP Connects the substantia nigra with the caudate and putamen. STRIATOPALLIDAL LOOP Projects from the caudate and putamen to the external segment of the globus pallidus, then to the subthalamic nucleus, and finally to the internal segment of the globus pallidus.  EXTRAPYRAMIDAL (STRIATAL) SYSTEM Plays a role in Modulation of somatic motor activity, especially willed (voluntary) movement. Automatic stereotyped postural and reflex motor activity (e.g., normal subjects swing their arms when they walk). STRUCTURE OF THE EXTRAPYRAMIDAL SYSTEM Neocortex Striatum (caudatoputamen or neostriatum) Globus pallidus Subthalamic nucleus Substantia nigra (i.e., pars compacta and pars reticularis) Thalamus (ventral anterior, ventral lateral, and centromedian nuclei)  MOVEMENT (EXTRAPYRAMIDAL) DISORDERS INTRODUCTION Abnormal movements resulting from dysfunction of the basal nuclei, or less commonly, the cerebellum TO Impair the regulation of voluntary motor activity without directly affecting strength, sensation, or cerebellar function. MOVEMENT Include: DISORDERS HYPERKINETIC disorders associated with abnormal, involuntary movements HYPOKINETIC disorders characterized by poverty of movement. TYPES OF ABNORMAL MOVEMENT Categorizing an abnormal movement is generally the first step toward arriving at the neurologic diagnosis. Abnormal movements can be classified as: Hypokinetic: 1. Parkinsonism Hyperkinetic: 1. Tremor 2. Chorea 3. Athetosis or dystonia 4. Ballismus 5. Myoclonus 6. Tics TREMOR Rhythmic oscillatory movement Best characterized by its relationship to voluntary motor activity, that is, according to whether it occurs at rest, during maintenance of a particular posture, or during movement. Enhanced by emotional stress Disappears during sleep RESTING (STATIC) TREMOR Occurs when the limb is at rest ACTION TREMOR POSTURAL TREMOR Present during sustained posture May continue during movement, but movement does not increase its severity. INTENTION (KINETIC) TREMOR Present during movement but not at rest RESTING (STATIC) TREMOR Parkinsonism Has a frequency of 4 to 6 Hz “Pill-rolling” maneuver—rhythmic, opposing circular movements of the thumb and index finger. There may be alternating flexion and extension of the fingers or hand or alternating pronation and supination of the forearm; in the feet, rhythmic alternating flexion and extension are common. Other Causes Less common causes of rest tremor include Wilson disease and poisoning with heavy metals such as mercury. POSTURAL TREMOR Physiologic Tremor 8- to 12-Hz tremor of the outstretched hands Normal finding Enhanced Physiologic Tremor Physiologic tremor enhanced by fear or anxiety. May also be found after excessive physical activity or sleep deprivation. Can complicate treatment with certain drugs (notably lithium, tricyclic antidepressants, sodium valproate, and bronchodilators) Conspicuous in patients with alcoholism or in alcohol or drug withdrawal states, Common in thyrotoxicosis Can also result from poisoning with mercury, lead, arsenic, and carbon monoxide. No specific treatment Other Causes Benign essential tremor, which may be familial. Wilson disease Cerebellar disorders Dystonic tremor, a postural or intention tremor that occurs in a part of the body already affected by dystonia; Most prominent when an attempt is made to oppose the dystonic posturing. Asterixis “Flapping tremor” May be associated with postural tremor; but is itself more properly considered a form of myoclonus than tremor. Most commonly in patients with metabolic encephalopathy and resolves with clearing of the encephalopathy. To detect asterixis, the patient holds the arms outstretched with fingers and wrists extended. Episodic cessation of muscular activity causes sudden flexion at the wrists followed by a return to extension, so that the hands flap in a regular or, more often, an irregular rhythm. A similar phenomenon may be demonstrable at the ankles. INTENTION (KINETIC) TREMOR Occurs during activity. If the patient is asked to touch his or her nose with a finger, for example, the arm exhibits tremor during movement, often more marked as the target is reached. Sometimes mistaken for limb ataxia, but the latter has no rhythmic oscillatory component. Results from a lesion affecting the superior cerebellar peduncle. Because it is often very coarse, it can lead to severe functional disability. No satisfactory medical treatment exists, but stereotactic surgery of the contralateral ventrolateral nucleus of the thalamus or high-frequency thalamic stimulation through an implanted device is sometimes helpful when patients are severely incapacitated. Along with other signs of cerebellar involvement, a manifestation of toxicity of certain sedative or anticonvulsant drugs (eg, phenytoin) or alcohol Also seen in patients with Wilson disease. CHOREA Rapid irregular muscle jerks that occur involuntarily and unpredictably in different parts of the body. In florid cases, the often forceful involuntary movements of the limbs and head and the accompanying facial grimacing and tongue movements are unmistakable. Voluntary movements may be distorted by superimposed involuntary ones. In mild cases, however, patients may exhibit no more than a persistent restlessness and clumsiness.  Power is full, but there may be difficulty in maintaining muscular contraction such that, for example, handgrip is relaxed intermittently (milkmaid grasp). The gait becomes irregular and unsteady, with the patient suddenly dipping or lurching to one side or the other (dancing gait). Speech often becomes irregular in volume and tempo and may be explosive in character. In some patients, athetotic movements or dystonic posturing may also be prominent. Disappears during sleep. Pathologic basis is unclear, but some cases are associated with cell loss in the caudate nucleus and putamen. Dopaminergic drugs can provoke chorea. When chorea is due to a treatable medical disorder, such as polycythemia vera or thyrotoxicosis, treatment of the primary disorder abolishes it. BALLISMUS/HEMIBALLISMUS Unilateral chorea that is especially violent because the proximal muscles of the limbs are involved. Clinical signs include violent contralateral flinging (ballistic) movements of one or both extremities of the same side. Due most often to vascular disease (stroke) in the contralateral subthalamic nucleus Commonly resolves spontaneously in the weeks after its onset. Sometimes due to other types of structural disease Occasional complication of thalamotomy. Pharmacologic treatment is similar to that for chorea. DYSTONIA & ATHETOSIS ATHETOSIS Abnormal movements that are slow, sinuous, and writhing in character DYSTONIA When the movements are so sustained that they are better regarded as abnormal postures. Excessive or inappropriate contraction of muscles (often agonists and antagonists) leads to sustained abnormal postures of the affected region of the body. May be generalized (involving the trunk and at least two other sites) or restricted in distribution, such as to the neck (torticollis), hand and forearm (writer’s cramp), or mouth (oromandibular dystonia).  With restricted dystonias, two or more contiguous body regions (eg, upper and lower face) may be affected (segmental dystonia), or the disturbance may be limited to localized muscle groups so that only a single body region is involved (focal dystonia). Now classified along a clinical axis that includes age at onset, body distribution, temporal pattern, and associated features such as other movement disorders or neurologic features and along an etiologic axis that includes nervous system pathology and inheritance. May be isolated (ie, occurring without other neurologic symptoms and signs apart from tremor) or secondary, in which case other clinical features are present. FACTORS INFLUENCING DYSTONIA Not present during sleep. Enhanced by emotional stress and by voluntary activity. In some cases, abnormal movements or postures occur only during voluntary activity and sometimes only during specific activities such as writing, speaking, or chewing. ETIOLOGY Perinatal anoxia, birth trauma, and kernicterus from hyperbilirubinemia are the most common causes. In these circumstances, abnormal movements usually develop before 5 years of age. Careful questioning usually discloses a history of abnormal early development and often of seizures. Examination may reveal signs of cognitive dysfunction or a pyramidal deficit in addition to the movement disorder. Dystonic movements and postures are the cardinal features of isolated torsion dystonia. Torsion dystonia may also occur as a manifestation of Wilson disease or Huntington disease or as a sequela of encephalitis. Acute dystonic posturing may result from treatment with dopamine receptor antagonist drugs. Lateralized dystonia may occasionally relate to focal intracranial disease, but the clinical context in which it occurs usually identifies the underlying cause. MYOCLONUS Myoclonic jerks are sudden, rapid, twitch-like muscle contractions. Classified according to their distribution, relationship to precipitating stimuli, site of origin, or etiology. Generalized myoclonus has a widespread distribution Focal or segmental myoclonus is restricted to a particular part of the body. Myoclonus can be spontaneous, or it can be brought on by sensory stimulation, arousal, or the initiation of movement (action myoclonus). Myoclonus may occur as a normal phenomenon (physiologic myoclonus) in healthy persons, as an isolated abnormality (essential myoclonus), or as a manifestation of epilepsy (epileptic myoclonus). It can also occur as a feature of a variety of degenerative, infectious, and metabolic disorders (symptomatic myoclonus) affecting the cerebral cortex, brainstem, or spinal cord. Myoclonus is sometimes manifest not by a sudden twitch-like muscle contraction but by a sudden loss of muscle activity (negative myoclonus). This is best seen as asterixis. Careful clinical evaluation—noting the age of onset, character and distribution of myoclonus, precipitating stimuli and relieving factors, family history, and presence of any associated symptoms and signs—may suggest the cause and limit unnecessary investigations. GENERALIZED MYOCLONUS Physiologic myoclonus includes the myoclonus that occurs upon falling asleep or awakening (nocturnal myoclonus) as well as hiccup. Essential myoclonus is a benign condition that occurs in the absence of other neurologic abnormalities and is sometimes inherited. Epileptic myoclonus may be impossible to differentiate clinically from nonepileptic forms. They may be distinguished electrophysiologically, however, by the duration of the electromyographic burst associated with the jerking, by demonstrating an electroencephalographic (EEG) correlate related temporally to the jerks, or by determining whether muscles involved in the same jerk are activated synchronously. FOCAL OR SEGMENTAL MYOCLONUS Can arise from lesions affecting the cerebral cortex, brainstem, spinal cord, or peripheral nerve. Can result from many of the same disturbances that produce symptomatic generalized myoclonus. Metabolic disorders such as hyperosmolar nonketotic hyperglycemia can cause epilepsia partialis continua, in which a repetitive focal epileptic discharge occurs from the contralateral sensorimotor cortex and leads to segmental myoclonus. Brainstem involvement of the dentatorubroolivary pathway by stroke, multiple sclerosis, tumors, or other disorders can produce palatal myoclonus, which may be associated with an audible click or synchronous movements of ocular, facial, or other bulbar muscles. Rhythmic vertical oscillation of the soft palate occurs that is best regarded as a tremor. Irritative lesion of a peripheral or cranial nerve may lead to myoclonus, as exemplified by hemifacial spasm. Segmental myoclonus is usually unaffected by external stimuli and persists during sleep. PROPRIOSPINAL MYOCLONUS Arises in the spinal cord and then spreads up and down the cord, leading to a brief bodily contraction. Electromyographic surface recordings may be necessary to show the spread of muscle activity in an orderly sequence and may help to localize the site of origin of the myoclonus. Idiopathic or secondary to diverse pathology that in some cases is revealed by imaging. May also have a psychogenic basis. TREATMENT Can be difficult to treat Cortical myoclonus in particular sometimes responds to anticonvulsant drugs such as valproic acid 250 to 500 mg orally three times daily or levetiracetam titrated up to 500 to 1,500 mg orally twice daily. It may also respond to piracetam. Benzodiazepines such as clonazepam 0.5 mg orally three times daily, gradually increased to as much as 12 mg/d, may help all types of myoclonus. A combination of medications is often necessary. Postanoxic action myoclonus is remarkably responsive to 5-hydroxytryptophan, the precursor of the neurotransmitter 5-hydroxytryptamine (serotonin). The 5- hydroxytryptophan is increased gradually to a maximum of 1 to 1.5 mg/d orally and may be combined with carbidopa (maximum, 400 mg/d orally) to inhibit metabolism in peripheral tissues. Localized myoclonus, regardless of origin, may respond to botulinum toxin injections. A variety of other medications have been used to treat different types of myoclonus, including carbamazepine, primidone, topiramate, zonisamide, diazepam, and—for essential myoclonus—anticholinergic agents, with anecdotal reports of benefit. TICS Sudden, recurrent, quick, coordinated abnormal movements that can usually be imitated without difficulty. Occurs repeatedly Can be suppressed voluntarily for short periods, although doing so may cause anxiety. Worsen with stress, diminish during voluntary activity or mental concentration Disappear during sleep. CLASSIFICATION Tics can be classified into four groups depending on whether they are simple or multiple and transient or chronic as follows: TRANSIENT SIMPLE TICS are common in children, usually terminate spontaneously within 1 year (often within a few weeks), and generally require no treatment. CHRONIC SIMPLE TICS can develop at any age but often begin in childhood, and treatment is unnecessary in most cases. The benign nature of the disorder must be explained to the patient. PERSISTENT SIMPLE OR MULTIPLE TICS of childhood or adolescence generally begin before 15 years of age. There may be single or multiple motor tics, and often vocal tics, but complete remission occurs by the end of adolescence. GILLES DE LA TOURETTE SYNDROME or simply TOURETTE SYNDROME is a common neurodevelopmental disorder that begins in childhood or adolescence, characterized by multiple movement (motor) tics and at least one vocal (phonic) tic. It was named after the French physician who described its clinical features. Common MOTOR TICS are blinking, coughing, throat clearing, sniffing, facial movements, and stereotyped movements of the extremities. These are typically preceded by an unwanted urge or sensation in the affected muscles, and characteristically change in location, strength, and frequency. Go unnoticed by casual observers. May occur with levodopa or amphetamine use and after chronic neuroleptic use (tardive tic), after head trauma or viral encephalitis, and in autistic children. They can occur in association with degenerative disorders of the basal ganglia, such as Huntington disease, and are well described in neuroacanthocytosis, when they may have a self-mutilating character. BRADYKINESIA & HYPOKINESIA Bradykinesia (slowed movement) and hypokinesia or akinesia (poverty or lack of movement) are major features of parkinsonism and may be quite disabling. Manifestations include a fixity of facial expression (the so-called masked facies, with reduced blinking, widened palpebral fissures, and an apparently impassive appearance) and a paucity of spontaneous movement of the limbs (eg, a reduced arm swing on walking). Some patients have “freezing,” that is, a temporary inability to move. Such symptoms are difficult for patients to describe and are often attributed erroneously to weakness. These phenomena are tested clinically by, for example, asking the patient to make repetitive alternating movements of each extremity in turn. This can involve tapping of the index or third finger on the pad of the thumb, pronation and supination of the raised arm (as if screwing a light bulb into the ceiling), opening and closing of the fist, stomping with the foot on the ground, and tapping the foot on the floor while the heel is maintained on the ground. A progressive reduction in amplitude or speed of the movements, irregularity in rhythm, or arrests in movement indicate abnormality. Activity should be continued until at least 15 repetitions have occurred, and sometimes for longer. Abnormalities must be distinguished from the slowness of movement without fatiguing and decrement that may occur in patients with pyramidal or cerebellar dysfunction (often with an irregular rhythm in the latter context). The inexpressive face of depressed patients may simulate the masked facies of parkinsonism and should be distinguished by the lack of other extrapyramidal findings and the abnormal affect.  HISTORY AGE AT ONSET Onset in infancy or early childhood suggests birth trauma, kernicterus, cerebral anoxia, or an inherited disorder Abnormal facial movements developing in childhood are more likely to represent tics than other involuntary movements Tremor presenting in early adult life is more likely to be of the benign essential variety than due to Parkinson disease CLINICAL Age at onset can also influence the prognosis. In isolated torsion dystonia, for example, progression to severe disability is much more common when symptoms develop in childhood rather than later life. EVALUATION Tardive dyskinesia is more likely to be permanent and irreversible when it develops in the elderly than during adolescence. OF PATIENTS MODE OF ONSET Abrupt onset of dystonic posturing in a child or young adult suggests a drug- induced reaction More gradual onset in an adolescent suggests a chronic disorder such as isolated torsion dystonia or Wilson disease Abrupt onset of severe chorea or ballismus suggests a vascular cause Abrupt onset of severe parkinsonism suggests a neurotoxic cause More gradual, insidious onset suggests a degenerative process. COURSE Sydenham chorea usually resolves within about 6 months after onset. MEDICAL HISTORY Drug History An accurate account of all drugs taken by the patient over the years is important, because many movement disorders are iatrogenic. Neuroleptic drugs may lead to abnormal movements developing either while patients are taking them or after their use has been discontinued, and the dyskinesia may be irreversible. Reversible dyskinesia may develop in patients taking certain other drugs, including oral contraceptives, levodopa, and phenytoin. Several drugs, especially lithium, tricyclic antidepressants, valproic acid, and bronchodilators, can cause tremor. Serotonin reuptake inhibitors have been associated with a number of movement disorders including parkinsonism, akathisia, chorea, dystonia, and bruxism. General Medical History Chorea may be symptomatic of rheumatic fever, thyroid disease, systemic lupus erythematosus, polycythemia, hypoparathyroidism, or cirrhosis of the liver. Movement disorders, including tremor, chorea, hemiballismus, dystonia, and myoclonus, may occur in patients with acquired immunodeficiency syndrome (AIDS). Opportunistic infections such as cerebral toxoplasmosis or cryptococcosis are often responsible, and infection with human immunodeficiency virus type 1 (HIV-1) may also have a direct pathogenic role. A history of birth trauma or perinatal distress may suggest the cause of a movement disorder that develops during childhood. Encephalitis lethargica, epidemic in the 1920s, was often followed by a wide variety of movement disorders, including parkinsonism. Various other viral encephalitides (Japanese encephalitis, West Nile, St Louis, herpes simplex, dengue, mumps, measles) may be accompanied or followed by movement disorders. Family History Some movement disorders have an inherited basis and a complete family history must be obtained, supplemented if possible by personal scrutiny of close relatives. Any possibility of consanguinity should be noted. EXAMINATION Clinical examination indicates the nature of the abnormal movements, the extent of neurologic involvement, and the presence of coexisting disease; these in turn may suggest the diagnosis. Psychiatric illness or cognitive impairment raises the possibility that the movement disorder is related to that or its treatment with psychoactive medication—or that the patient has a disorder with both abnormal movements and behavioral disturbances, such as Huntington disease or Wilson disease. Focal motor or sensory deficits and papilledema raise the possibility of a structural space-occupying lesion Kayser–Fleischer rings suggest Wilson disease. Signs of vascular, hepatic, or metabolic disease may suggest other causes for a movement disorder, such as acquired hepatocerebral degeneration or vasculitis. INVESTIGATIVE STUDIES BLOOD & URINE TESTS SERUM AND URINE COPPER; SERUM CERULOPLASMIN Wilson disease COMPLETE BLOOD COUNT AND ERYTHROCYTE SEDIMENTATION RATE Polycythemia, vasculitis, or systemic lupus erythematosus Wet film of the blood may reveal circulating acanthocytes. BLOOD CHEMISTRIES Hepatic dysfunction related to Wilson disease or acquired hepatocerebral degeneration Hyperthyroidism Hypocalcemia Metabolic disorders associated with myoclonus. SEROLOGIC TESTS Systemic lupus erythematosus or lupus anticoagulant syndrome Neurosyphilis HIV-1 infection ELECTROPHYSIOLOGIC TESTS EEG May help in evaluating myoclonus and in distinguishing paroxysmal dyskinesias from seizures; otherwise, it is of limited usefulness. ELECTROMYOGRAPHY AND SOMATOSENSORY EVOKED POTENTIALS May help to determine the level of neural involvement in myoclonus. IMAGING Intracranial calcification may be found by skull X-rays or computed tomography (CT) scans; the significance of this finding, however, is not always clear. CT scans or magnetic resonance imaging (MRI) may also reveal a tumor or other lesion associated with focal dyskinesia or dystonia or with symptomatic myoclonus, caudate atrophy due to Huntington disease, or basal ganglia abnormalities associated with Wilson disease. Positron emission tomography (PET) using 18F-dopa can monitor the loss of nigrostriatal projections in Parkinson disease and may be helpful diagnostically in patients with incomplete parkinsonian syndromes; but is not widely available. Dopamine transporter imaging (DaT scan) using single-photon emission computed tomography (SPECT) can also be used for this purpose. GENETIC STUDIES Recombinant DNA technology has been used to generate probes for genes that determine certain inheritable movement disorders, such as Huntington disease and Wilson disease. Their use may be limited, however, by the genetic heterogeneity of some diseases, imprecise gene localization by certain probes, ethical concerns about adverse psychologic reactions to the presymptomatic diagnosis of fatal disorders, and the potential for misuse of such information by prospective employers, insurance companies, and government agencies. PSYCHOLOGIC EVALUATION Cognitive and affective disturbances can be documented and characterized by neuropsychologic evaluation. This may be helpful in diagnosing certain disorders such as Huntington disease or diffuse Lewy body dementia. Some movement disorders, such as Gilles de la Tourette syndrome, are associated with behavioral abnormalities such as attention deficit disorder and obsessive-compulsive disorder. The findings also may be important in guiding decisions regarding invasive interventions such as deep brain stimulation, which is contraindicated in patients with atypical parkinsonian syndromes or in classic Parkinson disease when significant dementia or major depression is also present.  PARKINSONISM No ethnic predilection No sex or gender predilection Common in older age group PARKINSONISM ETIOLOGY Idiopathic AND Most common variety PARKINSON’S No obvious cause Also called Parkinson’s disease or paralysis agitans DISEASE Preclinical phase extending back for several years before the onset of motor symptoms: hyposmia, constipation, anxiety, depression, and rapid eye-movement (REM) sleep behavior disorder Encephalitis In the first half of the 20th century, parkinsonism often developed in patients with a history of von Economo encephalitis lethargica, but such cases of postencephalitic parkinsonism are becoming rare, although parkinsonism still occasionally follows other encephalitic illnesses. Drug- or Toxin-Induced Parkinsonism Therapeutic drugs—Many drugs, such as phenothiazines, butyrophenones, metoclopramide, reserpine, and tetrabenazine, can cause a reversible parkinsonian syndrome. This is usually reversible by withdrawing the offending medication, although symptoms and signs may take many months to resolve. Toxic substances—Environmental toxins such as manganese dust or carbon disulfide can lead to parkinsonism; manganese used in the home manufacture of methcathinone appears to have been responsible for parkinsonism in intravenous users of this illegal stimulant. The disorder may also appear as a sequela of severe carbon monoxide poisoning and rarely after exposure to pesticides or fumes during welding. MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)—A drug-induced form of parkinsonism occurred in individuals who synthesized and self-administered a meperidine analogue, MPTP. This compound is metabolized to a toxin that selectively destroys dopaminergic neurons in the substantia nigra and adrenergic neurons in the locus ceruleus and induces a severe form of parkinsonism in humans and nonhuman primates. The ability of this drug to reproduce neurochemical, pathologic, and clinical features of Parkinson disease suggests that an environmental toxin could be responsible for the idiopathic disorder. MPTP-induced parkinsonism has been used as a model to assist in the development of new drugs for treatment of this disease. Vascular Parkinsonism Multiple subcortical white-matter infarcts may lead to symptoms and signs suggestive of parkinsonism, usually accompanied by brisk tendon reflexes and extensor plantar responses. Tremor is often relatively inconspicuous and, in some patients, abnormalities of gait are especially evident (“lower-body parkinsonism”). The MRI findings help to suggest or support the diagnosis, and management is focused on preventing stroke. The response to antiparkinsonian medication is usually disappointing. Post-traumatic Parkinsonism Boxers and those in certain other contact sports, such as football, may develop a syndrome of dementia (dementia pugilistica), behavioral and psychiatric disturbances, parkinsonism, and pyramidal and cerebellar deficits from recurrent head trauma leading to a chronic traumatic encephalopathy. There is no satisfactory treatment. Familial & Genetic Parkinsonism Rarely, parkinsonism occurs on a familial basis. Approximately 3% of cases arise from a single genetic cause, and it is often not possible to distinguish these from the idiopathic disorder. Early onset and a familial incidence favor a genetic cause. Susceptibility loci are being identified. Autosomal dominant parkinsonism may result from mutations of one of several genes, including α- synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), vacuolar protein sorting-associated protein 35 (VPS35), and, possibly, ubiquitin carboxyl-terminal esterase L1 (UCHL1) and DNA J heat shock protein family (Hsp40) member C13 (DNAJC13). Mutations in PARKIN, DJ1, and PINK1 cause early onset, autosomal recessive, and sporadic juvenile onset parkinsonism. Several other genes or chromosomal regions have been implicated in familial forms of the disease or as susceptibility factors, including the gene for beta glucosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease. Parkinsonism Associated With Other Neurologic Diseases Parkinsonism may occur in association with symptoms and signs of other neurologic disorders. PATHOLOGY Idiopathic parkinsonism (Parkinson disease) is a proteinopathy Misfolding and aggregation of α-synuclein Also referred to as a synucleinopathy. Loss of pigmentation and cells in the substantia nigra and other brainstem centers, cell loss in the globus pallidus and putamen, and filamentous eosinophilic intraneural inclusion granules (Lewy bodies) containing α-synuclein in the basal ganglia, brainstem, spinal cord, and sympathetic ganglia. Widespread distribution of Lewy bodies, with early involvement of the lower brainstem (eg, dorsal motor nucleus of the vagus [X] nerve), olfactory bulb, and enteric nervous system, and subsequent spread to the locus ceruleus, substantia nigra, transentorhinal cortex, hippocampus, and neocortex. Lewy bodies are not seen in postencephalitic parkinsonism; instead, there may be nonspecific neurofibrillary degeneration in a number of diencephalic structures, as well as changes in the substantia nigra. Microscopic sections of the substantia nigra at high magnification power showing reduction in the number of normal melanin-containing, pigmented, dopaminergic neurons and the presence of eosinophilic, intracellular, cytoplasmic inclusions (Lewy bodies) in the neurons (arrow). PATHOGENESIS Triggered by protein misfolding and aggregation. In Parkinson’s disease, the protein involved is α-synuclein. Abnormal protein may subsequently spread from cell to cell and thereby propagate the disease to contiguous parts of the nervous system. Has been linked to the microbiome, ie, the bacterial content of the gut Abnormalities of mitochondrial function Other possible factors include the inappropriate production of reactive oxygen species and the occurrence of an inflammatory response in the absence of infection.  Motor manifestations of Parkinson disease result from altered patterns of inhibition and excitation within the basal ganglia and its connections via direct and indirect pathways. Dopamine and acetylcholine act as neurotransmitters. In idiopathic parkinsonism, the normal balance between these two antagonistic neurotransmitters is disturbed because of dopamine depletion in the dopaminergic nigrostriatal system. Other neurotransmitters, such as norepinephrine, are also depleted in the brains of patients with parkinsonism CLINICAL FINDINGS MOTOR SYMPTOMS Tremor 4- to 6-Hz Most conspicuous at rest Increases at times of emotional stress and often improves during voluntary activity. Begins with rhythmic, opposing circular movements of the thumb and index finger (“pill-rolling”); as rhythmic flexion–extension of the fingers, hand, or foot; or as rhythmic pronation–supination of the forearm. Involves the lower jaw and chin as well. Not uncommon for the tremor to be confined to one limb, or both limbs on one side, for months or years before it becomes more generalized. In some patients, tremor never becomes prominent. Rigidity Increased tone (ie, increased resistance to passive movement) Disturbance in tone is responsible for the flexed posture Resistance is uniform throughout the range of movement at a particular joint and affects agonist and antagonist muscles alike—in contrast to spasticity, where it is often greatest at the beginning of the passive movement (clasp-knife phenomenon) and more marked in some muscles than others. Rigidity in parkinsonism is described as cogwheel rigidity because of ratchet-like interruptions of passive movement that may be due, in part, to the presence of tremor. Hypokinesia, Bradykinesia or Akinesia Most disabling feature of parkinsonism Slowness of voluntary movement and a reduction in automatic movement, such as swinging the arms while walking. Face is relatively immobile (hypomimia or mask-like facies), with widened palpebral fissures, infrequent blinking, a certain fixity of facial expression, and a smile that develops and fades slowly. Voice is soft (hypophonia) and poorly modulated. Fine or rapidly alternating movements are impaired Power is not diminished if time is allowed for it to develop. Handwriting is small (micrographia), tremulous, and hard to read. Abnormal Gait & Posture Difficult to get up from bed or an easy chair and adopts a flexed posture on standing. Difficult to start walking, so the patient may lean farther and farther forward while walking in place before being able to advance. Gait itself characterized by small, shuffling steps and absence of the arm swing that normally accompanies locomotion Unsteadiness on turning Difficulty in stopping. Retained arm swing, wide-based gait, or marked imbalance at an early stage suggests a non-parkinsonian disorder. In advanced cases, the patient tends to walk with increasing speed to prevent a fall (festinating gait) because of the altered center of gravity that results from the abnormal posture. Other Motor Abnormalities Mild blepharoclonus (fluttering of the closed eyelids) Blepharospasm (involuntary closure of the eyelids). Drooling because of impairment of swallowing. No alteration in the tendon reflexes (although a mild hyperreflexia may occur on the affected side in asymmetric parkinsonism) Plantar responses are flexor. Repetitive tapping (approximately twice per second) over the bridge of the nose produces a sustained blink response (Myerson sign); the response is not sustained in normal subjects. Rigidity Blepharospasm Masked facies Micrographia Cogwheel rigidity  NON-MOTOR MANIFESTATIONS Anosmia is an early symptom (but may arise from many other causes, and is therefore not a specific indicator of Parkinson disease). Cognitive decline, executive dysfunction, and personality changes are common, as are depression and anxiety. Apathy may be conspicuous. A sense of fatigue may be prominent, and some patients complain of pain or sensory disturbances. Dysautonomic symptoms include urinary urgency and urge incontinence, and constipation; postural hypotension relates most commonly to dopaminergic therapy or inactivity but may also reflect baroreflex failure or denervation of cardiac muscle. Pathologic involvement of the medulla may relate to these dysautonomic changes. Seborrheic dermatitis Sleep disorders, including REM behavior disorder, are common, and there may be excessive daytime somnolence. Frequent awakenings occur during nocturnal sleep; difficulty in turning over in bed, nocturia, involuntary movements (especially tremor or dystonia), and pain can make it difficult to settle down again. Seborrheic dermatitis may occur due to dysregulation of the autonomic nervous system. MANAGEMENT PRINCIPLES OF TREATMENT Early parkinsonism requires no drug treatment. Discuss with the patient the nature of the disorder and the availability of medical treatment if symptoms become more severe, and to encourage activity. Treatment of the motor symptoms, when indicated, is directed toward restoring the dopaminergic–cholinergic balance in the striatum by blocking the effect of acetylcholine with anticholinergic drugs or by enhancing dopaminergic transmission.  DOPAMINERGIC AGENTS (LEVODOPA) Converted in the body to dopamine Ameliorates all the major clinical features of parkinsonism Particularly helpful against hypokinesia/bradykinesia. Carbidopa is a drug that reduces the extracerebral metabolism of levodopa to dopamine by inhibiting dopa decarboxylase, but it does not cross the blood–brain barrier. When levodopa is given with carbidopa, the breakdown of levodopa is limited PHARMACOLOGIC outside the brain. TREATMENT Carbidopa is generally combined with levodopa in a fixed proportion (1:10 or 1:4) as carbidopa/levodopa.  Fluctuations commonly occur after it has been used for several years and may be particularly disabling. These may relate to the disease itself or to the duration of levodopa treatment. Many physicians therefore defer the introduction of levodopa for as long as possible or use dopamine agonists in conjunction with it to keep the levodopa dose low. Treatment is started with a small dose, such as carbidopa/levodopa 10/100 mg or 25/100 mg orally three times daily, and the dose is gradually increased, depending on the response. Many patients ultimately require carbidopa/levodopa 25/250 (mg) three or four times daily. Carbidopa should total at least 75 mg/d. The medication is best taken about 30 to 45 minutes before meals or 2 hours after meals to maximize absorption and uptake into the brain. A tablet of carbidopa/levodopa (25/100, 10/100, 25/250) that disintegrates in the mouth and is then swallowed with the saliva is also available and is best taken about 1 hour before meals.  The most common side effects of levodopa are nausea, vomiting, hypotension, abnormal movements (dyskinesias), restlessness, and confusion. Cardiac arrhythmias and sleep disturbances occur occasionally. The incidence of nausea, vomiting, hypotension, and cardiac irregularities is reduced when levodopa is taken with carbidopa. The late dyskinesias and behavioral side effects of levodopa occur as dose- related phenomena, but reduction in dose may diminish any therapeutic benefit. Treatment with olanzapine, quetiapine, or risperidone may relieve confusion and psychotic mental disturbances without blocking the effects of levodopa or exacerbating parkinsonism. Pimavanserin is a novel atypical antipsychotic agent specifically approved for the treatment of the psychosis of Parkinson disease. Clozapine, a dibenzodiazepine derivative that does not block the therapeutic effects of dopaminergic medication, may also relieve confusion and psychotic mental disturbances and, in some instances, the dyskinesias, but requires regular monitoring of the leukocyte count.  Another late complication of levodopa therapy or consequence of advancing disease is response fluctuation such as the wearing-off effect, in which deterioration occurs shortly before the next dose is to be taken, or the on–off phenomenon, in which abrupt but transient fluctuations in the severity of parkinsonism occur at frequent intervals during the day, apparently without any relationship to the last dose of levodopa. Such fluctuations may be disabling and may relate to discontinuous (pulsatile) levels of cerebral dopamine. They can be controlled only partly by varying the dosing intervals restricting dietary protein intake; use of a controlled-release preparation of carbidopa/levodopa or of a novel extended-release formulation of carbidopa/levodopa; addition of entacapone, selective monoamine oxidase type B inhibitors, or dopamine agonists to the medication regimen; administration of carbidopa/levodopa via portable intraduodenal pump. They often respond well to deep brain stimulation. Levodopa therapy (either alone or in conjunction with carbidopa) is contraindicated in patients with narrow- angle glaucoma or psychotic illness and should be avoided in patients receiving monoamine oxidase type A (MAO-A) inhibitors. Should also be used with care in patients with active peptic ulcers or suspected malignant melanomas. ANTICHOLINERGIC DRUGS Muscarinic anticholinergic drugs are more helpful in alleviating tremor and rigidity than in ameliorating hypokinesia; but are generally less effective than dopaminergic drugs. A number of preparations are available, and individual patients tend to favor different drugs. Among the most commonly prescribed drugs are trihexyphenidyl and benztropine. Treatment is started with a small dose of one of the anticholinergics; the dosage is then gradually increased until benefit occurs or side effects limit further increments. If treatment is not helpful, the drug is withdrawn and another anticholinergic preparation is tried. Best avoided in the elderly because of their side effects, which include dry mouth, constipation, urinary retention, defective pupillary accommodation, and confusion. ANTIGLUTAMINERGIC (AMANTADINE) Can be given for mild parkinsonism either alone or in combination with an anticholinergic agent. Blockade of NMDA-preferring glutamate and muscarinic cholinergic receptors and stimulation of dopamine release. Improves all the motor features of parkinsonism, its side effects (restlessness, confusion, skin rashes, edema, disturbances of cardiac rhythm) are relatively uncommon, its effects are exerted rapidly, and it is given in a standard dose of 100 mg orally twice daily. Many patients fail to respond to this drug, or its benefit is short-lived. May also be useful in reducing the sense of extreme fatigue experienced by some patients and for iatrogenic dyskinesias in patients with advanced disease (100 mg two or three times daily). DOPAMINE AGONISTS The older agonists are ergot derivatives such as bromocriptine, which stimulates dopamine D2 receptors. Bromocriptine is less effective than levodopa in relieving the symptoms of parkinsonism but is also less likely to cause dyskinesias. Now used infrequently, as more effective dopamine agonists are available. The newer dopamine agonists are not ergot derivatives. They seem to be as effective as the older agonists but are without their potential ergot-related adverse effects and may be used in early or advanced Parkinson disease. Pramipexole is started at 0.125 mg three times daily; the daily dose is doubled after 1 week and again after another week; it is then increased by 0.75 mg each week according to response and tolerance. A common maintenance dose is between 0.5 and 1.5 mg three times daily. Ropinirole is started at 0.25 mg three times daily, and the total daily dose increased at weekly intervals by 0.75 mg until the fourth week and by 1.5 mg thereafter. Most patients need between 2 and 8 mg three times daily for benefit. Rotigotine is given as a transdermal patch applied to a clean and healthy area of skin and replaced every 24 hours; skin reactions may occur at the application site.  Adverse effects of these medications include fatigue, somnolence, nausea, peripheral edema, dyskinesias, confusion, hallucinations, and orthostatic hypotension. An irresistible urge to sleep at inappropriate times sometimes occurs and may lead to injury. Disturbances of impulse control may lead to such behaviors as compulsive gambling or abnormal sexual activity. Extended-release preparations of both pramipexole and ropinirole are available. Apomorphine hydrochloride, a nonselective dopamine receptor agonist administered by subcutaneous injection, may help rescue patients with advanced parkinsonism and severe “off ” episodes of akinesia despite optimized oral therapy. Side effects include severe nausea and vomiting, somnolence, hallucinations, chest pain, and hyperhidrosis; dyskinesias may be enhanced. CATECHOL-O-METHYLTRANSFERASE INHIBITORS Catechol-O-methyltransferase (COMT) is one of two principal enzymes involved in the metabolic breakdown of dopamine; the other is monoamine oxidase. COMT inhibitors may be used to reduce the dose requirements of and any response fluctuations to levodopa. Their use improves levodopa transport into the blood and across the blood–brain barrier and thus leads to more sustained plasma levels of levodopa. Side effects include diarrhea, confusion, dyskinesias, and abnormalities of liver function tests. Two of these inhibitors are in widespread use. Tolcapone is taken in a daily dose of 100 or 200 mg three times daily. Acute hepatic necrosis has occurred in rare instances in patients receiving this medication; accordingly, entacapone (200 mg) taken with carbidopa/levodopa up to five times daily is generally preferred. A commercial preparation combines levodopa with both carbidopa and entacapone. It provides the convenience of simplifying the drug regime and requiring the consumption of fewer tablets. More sustained plasma levels of levodopa may lead to more continuous delivery of levodopa to the brain, with a theoretical reduction in the risk of response fluctuations and dyskinetic complications. However, initiating levodopa therapy with Stalevo rather than carbidopa/levodopa fails to delay the time of onset or reduce the frequency of dyskinesia; indeed, dyskinesias may occur sooner and with increased frequency. MONOAMINE OXIDASE INHIBITORS SELEGILINE Irreversible monoamine oxidase type B (MAO-B) inhibitor Inhibits the metabolic breakdown of dopamine. Enhances the antiparkinsonian effect of levodopa and may reduce mild on– off fluctuations in responsiveness May also delay the progression of Parkinson disease When used for neuroprotection, selegiline is best kept for patients with mild disease. Dose is 5 mg orally twice daily, usually given early in the day to avoid insomnia. RASAGILINE More potent and selective, and well-tolerated Irreversible MAO-B inhibitor that is taken in a dose of 0.5 or 1 mg once daily. Effective in the initial treatment of early parkinsonism and in addition as adjunctive therapy in patients with more advanced disease and response fluctuations to levodopa. May also slow disease progression  SAFINAMIDE Monoamine oxidase B inhibitor Reduces response fluctuations to levodopa, diminishing off-periods in patients with wearing-off effect or on-off phenomenon. Not effective as monotherapy for Parkinson disease. Started at 50 mg orally once daily, increased after 2 weeks to 100 mg once daily. Patients treated with monoamine oxidase B inhibitors should not take meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, St. John’s wort, the antitussive dextromethorphan, or other monoamine oxidase inhibitors. Theoretical risk of precipitating acute toxic interactions of the serotonin syndrome type in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors. Adverse effects of levodopa, especially dyskinesias, mental changes, nausea, and sleep disorders, may be increased.  ABLATIVE SURGERY Surgical treatment (thalamotomy or pallidotomy) often undertaken when patients became unresponsive to pharmacologic measures or developed intolerable adverse reactions to antiparkinsonian medication. The rate of significant complications was less than 5% after unilateral pallidotomy or thalamotomy, but approximately 20% or more after bilateral procedures. Ablative surgery has now largely been replaced by high-frequency SURGICAL stimulation of target structures, with a significant reduction in morbidity. TREATMENT DEEP BRAIN STIMULATION High-frequency stimulation of the globus pallidus internus or subthalamic nucleus Reduces the time spent in the off-state in patients with response fluctuations. Gait disturbances and akinesia may be helped by stimulation of the pedunculopontine nucleus. Has the advantage of being reversible, of having a much lower morbidity than ablative surgical procedures (especially when bilateral procedures are contemplated), and of causing minimal damage to the brain. It is thus preferred over ablative procedures. Candidates should: have classic Parkinson disease (rather than atypical parkinsonism) be cognitively intact and cooperative have previously responded well to pharmacologic treatment have developed response fluctuations with a significant amount of off-time have realistic expectations of the procedure.  CELLULAR THERAPIES Autologous or fetal adrenal medullary tissue or fetal substantia nigra has been transplanted to the putamen or caudate nucleus in the belief that the transplanted tissue would continue to synthesize and release dopamine. In two controlled trials involving intracerebral transplantation of human embryonic mesencephalic tissue containing dopaminergic neurons, dyskinetic complications occurred and were sometimes incapacitating. Lewy body pathology sometimes spreads to the transplanted tissue. OTHER FORMS Research is currently focused on potential cellular therapies involving neural stem cells, but much work needs to be done before clinical trials can commence in OF TREATMENT Parkinson disease. PROTECTIVE THERAPY Slows the progression of Parkinson disease by influencing the mechanisms involved in cell death. Treatment with monoamine oxidase inhibitors such as selegiline or rasagiline (which also have antiapoptotic properties) Candidate therapies include those that enhance mitochondrial function or cell energetics, limit glutamate toxicity, inhibit inflammatory responses, or have antiapoptotic effects. Isradipine, a calcium channel antagonist, has neuroprotective properties in animal models of Parkinson disease GENERAL MEASURES, PHYSICAL THERAPY & AIDS FOR DAILY LIVING COGNITIVE SYMPTOMS Rivastigmine (3-12 mg daily), donepezil (5-10 mg daily), or memantine (5-10 mg daily); PSYCHIATRIC SYMPTOMS (HALLUCINATIONS) Adjustment of dopaminergic regimen or addition of atypical antipsychotics (eg, quetiapine); SLEEP PROBLEMS Excessive daytime sleepiness treated with modafinil (100-400 mg daily) REM sleep behavior disorder treated with clonazepam (0.5-2 mg at night) HYPERACTIVE BLADDER Oxybutynin (5-15 mg daily) or tolterodine (2-4 mg daily). CONSTIPATION May respond to stool softeners or osmotic laxatives FATIGUE May respond to amantadine or modafinil PHYSICAL AND SPEECH THERAPY Physical therapy and speech therapy (Lee Silverman technique) are beneficial to many patients, QUALITY OF LIFE/SIMPLE AIDS TO DAILY LIVING May include extra rails or banisters placed strategically about the home for additional support, table cutlery with large handles, nonslip rubber table mats, devices to amplify the voice, and chairs that gently eject the occupant at the push of a button. YouTube Parkinson’s Disease: Etiology, Pathology, Clinical Features, Diagnosis, and Treatment VIDEO LINK https://www.youtube.com/watch?v=ARdGaE1sbBM  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. He and his wife deny his use of alcohol or any other medications. CLINICAL 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-to-nose maneuver (fairly fine and without an obvious rhythm). He has a poker face and a CASE slow, deliberate gait. Tone is increased in the right arm and leg. The physical examination is otherwise unremarkable. QUESTIONS 1. What is the most likely diagnosis? What are the other possibilities? 2. How will you work up this patient? 3. How will you manage him? MAIN Clinical Neurology, 10ed, Roger P. Simon et al, Chapter 11, pp 311- REFERENCE 328 The contents of this slide presentation are largely lifted from the above reference book, with some minor alterations in wordings, sentence construction and sequence of sentences or paragraphs to suit the needs of the students of AMA School of Medicine. Materials in the presentation that are not found in the above reference are taken from the references listed under Related Readings or from various internet sources. RELATED Hankey’s Clinical Neurology, 2ed, Philip B. Gorelick et al, Chapter 14, pp 577-596 READINGS Current Diagnosis & Treatment Neurology, 3ed, John C.M. Brust, Chapter 15, pp 199-207 DISCLAIMER The contents of the presentation including texts, pictures, diagrams, etc are largely lifted from different internet sources and accessible books and e-books listed under Main Reference and Related Readings, all under public domain, with some minor alterations in wordings, sentence construction and sequence of sentences or paragraphs to suit the needs of the students of AMA School of Medicine. Credit must be appropriated to rightful owners. We do not claim ownership to them. Use of this organized and prepared presentation in other locations or for other purposes especially without proper permission is strictly prohibited.