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InternalMed_Harrison. Exercise, with a full range of active and passive movements, has been shown to maintain and even improve function for PD patients, and active and passive exercises with full range of motion reduce the risk of arthritis and frozen joints. Some laboratory studies suggest the possibility that exercise might also have neuroprotective effects, but this has not been confirmed in PD. Exercise is generally recommended for all PD patients. It is less clear that physical therapy or specific exercises such as tai chi are required. It is important for patients to maintain social and intellectual activities to the extent possible. Education, assistance with financial planning, social services, and attention to home safety are important elements of the overall care plan. Information is available through numerous PD foundations and on the web, but should be reviewed with physicians to ensure accuracy. The needs of the caregiver should not be neglected. Caring for a person with PD involves a


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InternalMed_Harrison. through numerous PD foundations and on the web, but should be reviewed with physicians to ensure accuracy. The needs of the caregiver should not be neglected. Caring for a person with PD involves a substantial work effort and there is an increased incidence of depression among caregivers. Support groups for patients and caregivers may be useful.


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InternalMed_Harrison. The management of PD should be tailored to the needs of the individual patient, and there is no single treatment approach that is universally accepted and applicable to all individuals. Clearly, if an agent could be demonstrated to have disease-modifying effects, it should be initiated at the time of diagnosis. Indeed, constipation, RBD, and anosmia may represent premotor features of PD and could permit the initiation of a disease-modifying therapy prior to the onset of the classical motor features of the disease. However, no therapy has yet been proved to be disease modifying. For now, physicians must use their judgment in deciding whether or not to introduce rasagiline (see above) or other drugs for their possible disease-modifying effects.


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InternalMed_Harrison. The next important issue to address is when to initiate symptomatic therapy. Several studies now suggest that it may be best to start therapy at the time of diagnosis (or soon after) in order to preserve beneficial compensatory mechanisms and possibly provide functional benefits even in the early stage of the disease. Levodopa remains the most effective symptomatic therapy for PD, and some recommend starting it immediately using low doses (≤400 mg/d), but others prefer to delay levodopa treatment, particularly in younger patients, in order to reduce the risk of inducing motor complications. An alternate approach is to begin with an MAO-B inhibitor and/or a dopamine agonist, and reserve levodopa for later stages when these drugs can no longer provide satisfactory control. In making this decision, the age, degree of disability, and side effect profile of the drug must all be considered. In patients with more severe disability, the elderly, those with cognitive impairment, or those in


InternalMed_Harrison

InternalMed_Harrison. decision, the age, degree of disability, and side effect profile of the drug must all be considered. In patients with more severe disability, the elderly, those with cognitive impairment, or those in whom the diagnosis is uncertain, most physicians would initiate therapy with levodopa. Regardless of initial choice, it is important not to deny patients levodopa when they cannot be adequately controlled with alternative medications.


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InternalMed_Harrison. If motor complications develop, patients can initially be treated by manipulating the frequency and dose of levodopa or by combining lower doses of levodopa with a dopamine agonist, a COMT inhibitor, or an MAO-B inhibitor. Amantadine is the only drug that has been demonstrated to treat dyskinesia without worsening parkinsonism, but benefits may be short-lasting, and there are important side effects related to cognitive function. In advanced cases, it may be necessary to consider a surgical therapy such as DBS if the patient is a suitable candidate, but as described above, these procedures have their own set of complications. Continuous intraintestinal infusion of levodopa/carbidopa intestinal gel (Duodopa) appears to offer similar benefits to DBS, but also requires a surgical intervention with potentially serious complications. Continuous infusion of apomorphine is another treatment option and does not require surgery but is associated with potentially troublesome skin nodules.


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InternalMed_Harrison. with potentially serious complications. Continuous infusion of apomorphine is another treatment option and does not require surgery but is associated with potentially troublesome skin nodules. Comparative studies of these approaches in more advanced patients are awaited. There are ongoing efforts aimed at developing a long-acting oral or transdermal formulation of levodopa that mirrors the pharmacokinetic properties of a levodopa infusion. Such a formulation might provide all of the benefits of levodopa without motor complications and avoid the need for polypharmacy and surgical intervention.


InternalMed_Harrison

InternalMed_Harrison. A decision tree that considers the various treatment options and decision points for the management of PD is provided in Fig. 449-7. Hyperkinetic movement disorders are characterized by involuntary movements unaccompanied by weakness and occurring in isolation or in combination (Table 449-6). The major hyperkinetic movement disorders and the diseases with which they are associated are considered in this section. Tremor consists of alternating contractions of agonist and antagonist muscles in an oscillating, rhythmic manner. It can be most prominent at rest (rest tremor), on assuming a posture (postural tremor), or on actively reaching for a target (kinetic tremor). Tremor is also assessed based on distribution, frequency, and related neurologic dysfunction.


InternalMed_Harrison

InternalMed_Harrison. PD is characterized by a resting tremor, essential tremor (ET) by a postural tremor (trying to sustain a posture), and cerebellar disease by an intention or kinetic tremor (on reaching to touch a target). Normal individuals can have a physiologic tremor that typically manifests as a mild, high-frequency (10–12 Hz), postural or action tremor that is usually of no clinical consequence and often is only appreciated with an accelerometer. An enhanced physiologic tremor (EPT) can be seen in up to 10% of the population, often in association with anxiety, fatigue, a metabolic disturbance (e.g., hyperthyroidism, electrolyte abnormalities), drugs (e.g., valproate, lithium), or toxins (e.g., alcohol). Treatment is initially directed to the control of any underlying disorder and, if necessary, can often be improved with a beta blocker.


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InternalMed_Harrison. Functional disability Parkinson’s disease Surgery/CDS Combination therapy Levodopa/dopamine agonist/COMT Inhibitor/MAO-B Inhibitor Nonpharmacologic intervention Pharmacologic intervention Neuroprotection —? Rasagiline Yes Levodopa No Dopamine agonists


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InternalMed_Harrison. FIGURE 449-7 Treatment options for the management of Parkinson’s disease (PD). Decision points include: (1) Introduction of a neuroprotective therapy: No drug has been established to have or is currently approved for neuroprotection or disease modification, but there are several agents that have this potential based on laboratory and preliminary clinical studies (e.g., rasagiline 1 mg/d, coenzyme Q10 1200 mg/d, the dopamine agonists ropinirole, and pramipexole). (2) When to initiate symptomatic therapy: There is a trend toward initiating therapy at the time of diagnosis or early in the course of the disease because patients may have some disability even at an early stage, and there is the possibility that early treatment may preserve beneficial compensatory mechanisms; however, some experts recommend waiting until there is functional disability before initiating therapy. (3) What therapy to initiate: Many experts favor starting with a monoamine oxidase type B (MAO-B) inhibitor in


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InternalMed_Harrison. recommend waiting until there is functional disability before initiating therapy. (3) What therapy to initiate: Many experts favor starting with a monoamine oxidase type B (MAO-B) inhibitor in mildly affected patients because of the good safety profile of the drug and the potential for a disease-modifying effect; dopamine agonists for younger patients with functionally significant disability to reduce the risk of motor complications; and levodopa for patients with more advanced disease, the elderly, or those with cognitive impairment. Recent studies suggest the early employment of polypharmacy using low doses of multiple drugs to avoid side effects associated with high doses of any one agent. (4) Management of motor complications: Motor complications are typically approached with combination therapy to try and reduce dyskinesia and enhance the “on” time. When medical therapies cannot provide satisfactory control, surgical therapies such as DBS or continuous infusion of


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InternalMed_Harrison. with combination therapy to try and reduce dyskinesia and enhance the “on” time. When medical therapies cannot provide satisfactory control, surgical therapies such as DBS or continuous infusion of levodopa/carbidopa intestinal gel can be considered. (5) Nonpharmacologic approaches: Interventions such as exercise, education, and support should be considered throughout the course of the disease. CDS, continuous dopaminergic stimulation; COMT, catechol-O-methyltransferase. (Adapted from CW Olanow et al: Neurology 72:S1, 2009.)


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InternalMed_Harrison. ET is the commonest movement disorder, affecting approximately 5–10 million persons in the United States. It can present in childhood but dramatically increases in prevalence over the age of 70 years. ET is characterized by a high-frequency tremor (6–10 Hz) that predominantly affects the upper extremities. The tremor is most often manifest as a postural or action (kinetic) tremor and, in severe cases, can interfere with functions such as eating and drinking. It is typically bilateral and symmetric but may begin on one side and remain asymmetric. Patients with severe ET can have an intention tremor with overshoot and slowness of movement. Tremor involves the head in ~30% of cases, voice in ~20%, tongue in ~20%, face/jaw in ~10%, and lower limbs in ~10%. The tremor is characteristically improved by alcohol and worsened by stress. Subtle impairment of coordination or tandem walking may be present, and disturbances of hearing, cognition, personality, mood, and olfaction have also been


InternalMed_Harrison

InternalMed_Harrison. improved by alcohol and worsened by stress. Subtle impairment of coordination or tandem walking may be present, and disturbances of hearing, cognition, personality, mood, and olfaction have also been described, but usually the neurologic examination is normal aside from tremor. The major differential is a dystonic tremor (see below) or PD. PD can usually be differentiated from ET based on the presence of bradykinesia, rigidity, micrographia, and other parkinsonian features. However, the examiner should be aware that PD patients may have a postural tremor and ET patients may develop a rest tremor. These typically begin after a latency of a few seconds (emergent tremor). The examiner must take care to differentiate the effect of tremor on measurement of tone in ET from the cogwheel rigidity found in PD.


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InternalMed_Harrison. The etiology and pathophysiology of ET are not known. Approximately 50% of cases have a positive family history with an autosomal dominant pattern of inheritance. Linkage studies have detected loci at chromosomes 3q13 (ETM-1), 2p22-25 (ETM-2), and 6p23 (ETM-3), but no causative genes have been identified to date. GWAS demonstrated an association with the LINGO1 gene, which is involved in oligodendrocyte differentiation and myelination, particularly in patients with young-onset ET. Recently, a nonsense mutation in the fused in sarcoma (FUS) gene was implicated as a cause of ET in a multigenerational family from Canada; this finding is of particular interest because different mutations in FUS are a known cause of familial amyotrophic lateral sclerosis (Chap. 452). It is likely that there are many other undiscovered genes for ET. The cerebellum and inferior olives have been implicated as possible sites of a “tremor pacemaker” based on the presence of cerebellar signs and increased


InternalMed_Harrison

InternalMed_Harrison. are many other undiscovered genes for ET. The cerebellum and inferior olives have been implicated as possible sites of a “tremor pacemaker” based on the presence of cerebellar signs and increased metabolic activity and blood flow in these regions in some patients. Some pathologic studies have described cerebellar pathology with a loss of Purkinje cells and axonal torpedoes, but these findings are controversial and the precise pathologic correlate of ET remains to be defined.


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InternalMed_Harrison. Many cases are mild and require no treatment other than reassurance. Occasionally, tremor can be severe and interfere with eating, writing, and activities of daily living. This is more likely to occur as the patient ages and is often associated with a reduction in tremor frequency. Beta blockers and primidone are the standard drug therapies for ET and help in about 50% of cases. Propranolol (20–120 mg daily, given in 2620 divided doses) is usually effective at relatively low doses, but higher doses may be effective in some patients. The drug is contraindicated in patients with bradycardia or asthma. Hand tremor tends to be most improved, while head tremor is often refractory. Primidone can be helpful but should be started at low doses (12.5 mg) and gradually increased (125–250 mg tid) to avoid sedation. Benefits have also been reported with gabapentin and topiramate. Botulinum toxin injections may be helpful for limb or voice tremor, but treatment can be associated with secondary


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InternalMed_Harrison. to avoid sedation. Benefits have also been reported with gabapentin and topiramate. Botulinum toxin injections may be helpful for limb or voice tremor, but treatment can be associated with secondary muscle weakness. Surgical therapies targeting the VIM nucleus of the thalamus can be very effective for severe and drug-resistant cases.


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InternalMed_Harrison. Dystonia is a disorder characterized by sustained (>100 ms) or repetitive involuntary muscle contractions frequently associated with twisting and abnormal postures. Dystonia can range from minor contractions in an individual muscle group to severe and disabling involvement of multiple muscle groups. The frequency is estimated to be 300,000 cases in the United States but is likely to be much higher because many cases are not recognized. Dystonia is often brought out by voluntary movements (action dystonia) and can extend to involve muscle groups and body regions not required for a given action (overflow). It can be aggravated by stress and fatigue and attenuated by relaxation and sensory tricks such as touching the affected body part (geste antagoniste). Dystonia can be classified according to age of onset (childhood vs adult), distribution (focal, multifocal, segmental, or generalized), or etiology (primary or secondary).


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InternalMed_Harrison. At least 16 gene mutations are associated with dystonia and classified as DYT1–DYT16. Idiopathic torsion dystonia (DYT1) or Oppenheim’s dystonia is predominantly a childhood-onset form of dystonia with an autosomal dominant pattern of inheritance that primarily affects Ashkenazi Jewish families. The majority of patients have an age of onset younger than 26 years (mean 14 years). In young-onset patients, dystonia typically begins in the foot or the arm and in 60–70% progresses to involve other limbs as well as the head and neck. In severe cases, patients can suffer disabling postural deformities that compromise mobility. Severity can vary within family members, with some affected relatives having severe disability and others a mild dystonia that may not even be appreciated. Most childhood-onset cases are linked to a mutation in the DYT1 gene located on chromosome 9q34, resulting in a trinucleotide GAG deletion with loss of one of a pair of glutamic acid residues in the protein torsin


InternalMed_Harrison

InternalMed_Harrison. cases are linked to a mutation in the DYT1 gene located on chromosome 9q34, resulting in a trinucleotide GAG deletion with loss of one of a pair of glutamic acid residues in the protein torsin A. DYT1 mutations are found in 90% of Ashkenazi Jewish patients with DYT1 dystonia and probably relate to a founder effect that occurred about 350 years ago. There is variable penetrance, with only about 30% of gene carriers expressing a clinical phenotype. Why some gene carriers express dystonia and others do not is not known. The function of torsin A is unknown, but it is a member of the AAA+ (ATPase) family that resembles heat-shock proteins and may be related to protein processing and transport. The precise pathology responsible for DYT1 dystonia is not known.


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InternalMed_Harrison. Dopa-responsive dystonia (DRD) or the Segawa variant (DYT5) is a dominantly inherited form of childhood-onset dystonia caused by a mutation in the gene that encodes GTP cyclohydrolase-I, the rate-limiting enzyme for the synthesis of tetrahydrobiopterin. This mutation leads to a defect in the biochemical synthesis of tyrosine hydroxylase, the rate-limiting enzyme in the formation of dopamine. DRD typically presents in early childhood (1–12 years) and is characterized by foot dystonia that interferes with walking. Patients often experience diurnal fluctuations, with worsening of gait as the day progresses and improvement with sleep. DRD is typified by an excellent and sustained response to small doses of levodopa. Some patients may present with parkinsonian features, but can be differentiated from juvenile PD by normal striatal dopamine imaging and the absence of levodopainduced dyskinesias. DRD may occasionally be confused with cerebral palsy because patients appear to have spasticity,


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InternalMed_Harrison. from juvenile PD by normal striatal dopamine imaging and the absence of levodopainduced dyskinesias. DRD may occasionally be confused with cerebral palsy because patients appear to have spasticity, increased reflexes, and Babinski responses (which likely reflect a dystonic contraction rather than an upper motor neuron lesion). Any patient suspected of having a childhood-onset dystonia should receive a trial of levodopa to exclude this treatable condition.


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InternalMed_Harrison. Mutations in the THAP1 gene (DYT6) on chromosome 8p21q22 have been identified in Amish families and are the cause of as many as 25% of cases of non-DYT1 young-onset primary torsion dystonia. These patients are more likely to have dystonia beginning in the brachial and cervical muscles, which later can become generalized and associated with speech impairment. Myoclonic dystonia (DYT11) results from a mutation in the epsilon-sarcoglycan gene on chromosome 7q21. It typically manifests as a combination of dystonia and myoclonic jerks, frequently accompanied by psychiatric disturbances.


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InternalMed_Harrison. These are the most common forms of dystonia. They typically present in the fourth to sixth decades and affect women more than men. The major types are as follows: (1) blepharospasm—dystonic contractions of the eyelids with increased blinking that can interfere with reading, watching television, and driving. This can sometimes be so severe as to cause functional blindness. (2) Oromandibular dystonia (OMD)—contractions of muscles of the lower face, lips, tongue, and jaw (opening or closing). Meige’s syndrome is a combination of OMD and blepharospasm that predominantly affects women older than age 60 years. (3) Spasmodic dysphonia—dystonic contractions of the vocal cords during phonation, causing impaired speech. Most cases affect the adductor muscles and cause speech to have a choking or strained quality. Less commonly, the abductors are affected, leading to speech with a breathy or whispering quality. (4) Cervical dystonia—dystonic contractions of neck muscles causing the head to


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InternalMed_Harrison. or strained quality. Less commonly, the abductors are affected, leading to speech with a breathy or whispering quality. (4) Cervical dystonia—dystonic contractions of neck muscles causing the head to deviate to one side (torticollis), in a forward direction (anterocollis), or in a backward direction (retrocollis). Muscle contractions can be painful and associated with a secondary cervical radiculopathy. (5) Limb dystonias—these can be present in either arms or legs and are often brought out by task-specific activities such as handwriting (writer’s cramp), playing a musical instrument (musician’s cramp), or putting (the yips). Focal dystonias can extend to involve other body regions (about 30% of cases) and are frequently misdiagnosed as psychiatric or orthopedic in origin. Their cause is not known, but genetic factors, autoimmunity, and trauma have been suggested. Focal dystonias are often associated with a high-frequency tremor that resembles ET. Dystonic tremor can usually be


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InternalMed_Harrison. is not known, but genetic factors, autoimmunity, and trauma have been suggested. Focal dystonias are often associated with a high-frequency tremor that resembles ET. Dystonic tremor can usually be distinguished from ET because it tends to occur in conjunction with the dystonic contraction and disappears when the dystonia is relieved.


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InternalMed_Harrison. These develop as a consequence of drugs or other neurologic disorders. Drug-induced dystonia is most commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients and may be acute or chronic (see below). Secondary dystonia can also be observed following discrete lesions in the striatum and occasionally in the pallidum, thalamus, cortex, and brainstem due to infarction, anoxia, metabolic disorders, trauma, tumor, infection, or toxins such as manganese or carbon monoxide. In these cases, dystonia often assumes a segmental distribution, but it can be generalized when lesions are bilateral or widespread. More rarely, dystonia can develop following peripheral nerve injury and be associated with features of complex regional pain syndrome (Chap. 454). A psychogenic origin is responsible for some cases of dystonia presenting with fixed, immobile dystonic postures (see below).


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InternalMed_Harrison. Dystonia may occur as a part of another neurodegenerative conditions such as Huntington’s disease, PD, Wilson’s disease, corticobasilar ganglionic degeneration, PSP, the Lubag form of dystonia-parkinsonism (DYT3), and mitochondrial encephalopathies. In contrast to the primary dystonias, dystonia is usually not the dominant neurologic feature in these conditions.


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InternalMed_Harrison. The pathophysiologic basis of dystonia is not completely known. The phenomenon is characterized by co-contracting synchronous bursts of agonist and antagonist muscle groups with recruitment of muscle groups that are not required for a given movement (overflow). Dystonia is characterized by derangement of the basic physiological principle of action-selection, leading to abnormal recruitment of inappropriate muscles for a given action with inadequate inhibition of this undesired motor activity. Physiologically, loss of inhibition is observed at multiple levels of the motor system (e.g., cortex, brainstem, spinal cord) accompanied by increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of at least some types of dystonia because there are alterations in blood flow and metabolism in these structures. Further, lesions of the GPi can induce dystonia, and surgical ablation or DBS of the globus pallidus can ameliorate dystonia.


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InternalMed_Harrison. there are alterations in blood flow and metabolism in these structures. Further, lesions of the GPi can induce dystonia, and surgical ablation or DBS of the globus pallidus can ameliorate dystonia. The dopamine system has also been implicated, because dopaminergic therapies can both induce and treat some forms of dystonia. Interestingly, no specific pathology has been consistently identified in primary dystonia.


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InternalMed_Harrison. Treatment of dystonia is for the most part symptomatic except in rare cases where correction of a primary underlying condition is possible. Wilson’s disease should be ruled out in young patients with dystonia. Levodopa should be tried in all cases of childhood-onset dystonia to rule out DRD. High-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of side effects related to cognitive impairment with hallucinations. Oral baclofen (20–120 mg) may also be helpful, but benefits, if present, are usually modest, and side effects of sedation, weakness, and memory loss can be problematic. Intrathecal infusion of baclofen is more likely to be useful, particularly for leg and trunk dystonia, but benefits are frequently not sustained, and complications can be serious and include infection, seizures, and coma. Tetrabenazine (the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 mg/d) is


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InternalMed_Harrison. not sustained, and complications can be serious and include infection, seizures, and coma. Tetrabenazine (the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 mg/d) is another consideration, but use may be limited by sedation and the development of parkinsonism. Neuroleptics can improve as well as induce dystonia, but they are typically not recommended because of their potential to induce parkinsonism and other movement disorders, including tardive dystonia. Clonazepam and diazepam are rarely effective.


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InternalMed_Harrison. Botulinum toxin has become the preferred treatment for patients with focal dystonia, particularly where involvement is limited to small muscle groups such as in blepharospasm, torticollis, and spasmodic dysphonia. Botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction, leading to reduced dystonic muscle contractions, but excessive weakness may ensue and can be troublesome particularly if it involves neck and swallowing muscles. Two serotypes of botulinum toxin are available (A and B). Both are effective, and it is not clear that there are advantages of one over the other. No systemic side effects are encountered with the doses typically used, but benefits are transient, and repeat injections are required at 2to 5-month intervals. Some patients fail to respond after having experienced an initial benefit. This has been attributed to antibody formation, but improper muscle selection, injection technique, and inadequate dose should be excluded.


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InternalMed_Harrison. Surgical therapy is an alternative for patients with severe dystonia who are not responsive to other treatments. Peripheral procedures such as rhizotomy and myotomy were used in the past to treat cervical dystonia, but are now rarely used. DBS of the pallidum can provide dramatic benefits for patients with primary DYT1 dystonia. This represents a major therapeutic advance because previously there was no consistently effective therapy, especially for these patients who had severe disability. Benefits tend to be obtained with a lower frequency of stimulation and often occur after a relatively long latency (weeks) in comparison to PD. Better results are typically obtained in younger patients with shorter disease duration. Recent studies suggest that DBS may also be valuable for patients with focal and secondary dystonias, although results are less consistent. Supportive treatments such as physical therapy and education are important and should be a part of the treatment regimen.


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InternalMed_Harrison. Physicians should be aware of dystonic storm, a rare but poten-2621 tially fatal condition that can occur in response to a stress situation such as surgery in patients with preexisting dystonia. It consists of the acute onset of generalized and persistent dystonic contractions that can involve the vocal cords or laryngeal muscles, leading to airway obstruction. Patients may experience rhabdomyolysis with renal failure and should be managed in an intensive care unit with airway protection if required. Treatment can be instituted with one or a combination of anticholinergics, diphenhydramine, baclofen, benzodiazepines, and dopaminergic agents. Spasms may be difficult to control, and anesthesia with muscle paralysis may be required. Most, if not all, cases of dystonic storm are due to a secondary cause.


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InternalMed_Harrison. HD is a progressive, fatal, highly penetrant autosomal dominant disorder characterized by motor, behavioral, oculomotor, and cognitive dysfunction. The disease is named for George Huntington, a family physician who described cases on Long Island, New York, in the nineteenth century. Onset is typically between the ages of 25 and 45 years (range, 3–70 years) with a prevalence of 2–8 cases per 100,000 and an average age at death of 60 years. It is prevalent in Europe, North and South America, and Australia but is rare in African blacks and Asians. HD is characterized by rapid, nonpatterned, semipurposeful, involuntary choreiform movements, and for this reason was formerly referred to as Huntington’s chorea. In the early stages, the chorea tends to be focal or segmental, but progresses over time to involve multiple body regions. Dysarthria, gait disturbance, oculomotor abnormalities, behavioral disturbance, and cognitive impairment with dementia are also common features. With advancing


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InternalMed_Harrison. time to involve multiple body regions. Dysarthria, gait disturbance, oculomotor abnormalities, behavioral disturbance, and cognitive impairment with dementia are also common features. With advancing disease, there tends to be a reduction in chorea and the emergence of dystonia, rigidity, bradykinesia, and myoclonus. Functional decline is often predicted by progressive weight loss despite adequate calorie intake. In younger patients (~10% of cases), HD can present as an akinetic-rigid or parkinsonian syndrome (Westphal variant). HD patients eventually develop behavioral and cognitive disturbances, and the majority progress to dementia. Depression with suicidal tendencies, aggressive behavior, and psychosis can be prominent features. HD patients may also develop non-insulin-dependent diabetes mellitus and neuroendocrine abnormalities (e.g., hypothalamic dysfunction). A clinical diagnosis of HD can be strongly suspected in cases of chorea with a positive family history, but genetic


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InternalMed_Harrison. mellitus and neuroendocrine abnormalities (e.g., hypothalamic dysfunction). A clinical diagnosis of HD can be strongly suspected in cases of chorea with a positive family history, but genetic testing provides the ultimate confirmation of the diagnosis. The disease predominantly affects the striatum. Progressive atrophy of the heads of the caudate nuclei, which form the lateral margins of the lateral ventricles, can be visualized by MRI (Fig. 449-8), but the putamen can be equally or even more severely affected. More diffuse cortical atrophy is seen in the middle and late stages of the disease. Supportive studies include reduced metabolic activity in the caudate nucleus and putamen. Genetic testing can be used to confirm the diagnosis and to detect at-risk individuals in the family, but must be performed with caution and in conjunction with trained counselors, because positive results can worsen depression and generate suicidal reactions. The neuropathology of HD consists of prominent


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InternalMed_Harrison. be performed with caution and in conjunction with trained counselors, because positive results can worsen depression and generate suicidal reactions. The neuropathology of HD consists of prominent neuronal loss and gliosis in the caudate nucleus and putamen; similar changes are also widespread in the cerebral cortex. Intraneuronal inclusions containing aggregates of ubiquitin and the mutant protein huntingtin are found in the nuclei of affected neurons.


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InternalMed_Harrison. In anticipation of developing neuroprotective therapies, there has been an intensive effort to define the premanifest stage of HD. Subtle motor impairment, cognitive alterations, and imaging changes can be detected in at-risk individuals who later go on to develop the manifest form of the disease. Defining the rate of progression of these features is paramount for future studies of putative disease-modifying therapies. HD is caused by an increase in the number of polyglutamine (CAG) repeats (>40) in the coding sequence of the huntingtin gene located on FIGURE 449-8 Huntington’s disease. A. Coronal fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging shows enlargement of the lateral ventricles reflecting typical atrophy (arrows). B. Axial FLAIR image demonstrates abnormal high signal in the caudate and putamen (arrows).


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InternalMed_Harrison. the short arm of chromosome 4. The larger the number of repeats, the earlier the disease is manifest. Intermediate forms of the disease with 36–39 repeats are described in some patients, typically with less severe clinical involvement. Acceleration of the process tends to occur, particularly in males, with subsequent generations having larger numbers of repeats and earlier age of disease onset, a phenomenon referred to as anticipation. The gene encodes the highly conserved cytoplasmic protein huntingtin, which is widely distributed in neurons throughout the central nervous system (CNS) but whose function is not known. Models of HD with striatal pathology can be induced by excitotoxic agents such as kainic acid and 3-nitropoprionic acid, which promote calcium entry into the cell and cytotoxicity. Mitochondrial dysfunction has been demonstrated in the striatum and skeletal muscle of symptomatic and presymptomatic individuals. Fragments of the mutant huntingtin protein can be toxic,


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InternalMed_Harrison. Mitochondrial dysfunction has been demonstrated in the striatum and skeletal muscle of symptomatic and presymptomatic individuals. Fragments of the mutant huntingtin protein can be toxic, possibly by translocating into the nucleus and interfering with transcriptional regulation of proteins. Neuronal inclusions found in affected regions in HD may represent a protective mechanism aimed at segregating and facilitating the clearance of these toxic proteins.


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InternalMed_Harrison. Although the gene for HD was identified more than two decades ago, there is still no disease-modifying therapy for this disorder. Current treatment involves a multidisciplinary approach, with medical, neuropsychiatric, social, and genetic counseling for patients and their families. Dopamine-blocking agents may control the choreatic movements. Tetrabenazine (a presynaptic dopamine depleting agent) has been approved for the treatment of chorea in the United States, but can cause secondary parkinsonism. Neuroleptics are generally not recommended because of their potential to induce other more troubling movement disorders and because HD chorea tends to be self-limited and is usually not disabling. Depression and anxiety can be greater problems, and patients should be treated with appropriate antidepressant and antianxiety drugs and monitored for mania and suicidal ideations. Psychosis can be treated with atypical anti-psychotics such as clozapine (50–600 mg/d), quetiapine (50–600 mg/d),


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InternalMed_Harrison. antidepressant and antianxiety drugs and monitored for mania and suicidal ideations. Psychosis can be treated with atypical anti-psychotics such as clozapine (50–600 mg/d), quetiapine (50–600 mg/d), and risperidone (2–8 mg/d). There is no adequate treatment for the cognitive or motor decline. A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in HD. Drugs that enhance mitochondrial function and increase the clearance of defective mitochondria are being tested as possible disease-modifying therapies. Antiglutamate agents, dopamine stabilizers, caspase inhibitors, neurotrophic factors, and transplantation of fetal striatal cells are areas of active research, but none has as yet been demonstrated to have a beneficial effect in HD. The potential to use transcriptional blockade of the mutant huntingtin gene with small interfering RNAs (siRNAs) is an exciting area currently being explored.


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InternalMed_Harrison. A group of rare inherited conditions that can mimic HD, designated HD-like (HDL) disorders, have also been identified. HDL-1, -2, and -4 are autosomal dominant conditions that typically present in adulthood. HDL-1 is due to expansion of an octapeptide repeat in PRNP, the gene encoding the prion protein (Chap. 453e). Thus HDL-1 is properly considered a prion disease. Patients exhibit onset of personality change in the third or fourth decade, followed by chorea, rigidity, myoclonus, ataxia, and epilepsy. HDL-2 manifests in the third or fourth decade with a variety of movement disorders, including chorea, dystonia, or parkinsonism and dementia. Most patients are of African descent. Acanthocytosis can sometimes be seen in these patients, and this condition must be distinguished from neuroacanthocytosis. HDL-2 is caused by an abnormally expanded CTG/ CAG trinucleotide repeat expansion in the junctophilin-3 (JPH3) gene. The pathology of HDL-2 consists of intranuclear inclusions


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InternalMed_Harrison. neuroacanthocytosis. HDL-2 is caused by an abnormally expanded CTG/ CAG trinucleotide repeat expansion in the junctophilin-3 (JPH3) gene. The pathology of HDL-2 consists of intranuclear inclusions immunoreactive for ubiquitin and expanded polyglutamine repeats. HDL-4, the most common condition in this group, is caused by expansion of trinucleotide repeats in TBP, the gene that encodes the TATA box binding protein involved in regulating transcription; this condition is identical to spinocerebellar ataxia (SCA) 17 (Chap. 451e), and most patients present primarily with ataxia rather than chorea. Mutations of the C9Orf gene associated with amyotrophic lateral sclerosis have also been reported in some individuals with an HDL phenotype.


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InternalMed_Harrison. Chorea can be seen in a number of additional disorders. Sydenham’s chorea (originally called St. Vitus’s dance) is more common in females and is typically seen in childhood (5–15 years). It often develops in association with prior exposure to group A streptococcal infection and is thought to be autoimmune in nature. It is characterized by the acute onset of choreiform movements and behavioral disturbances. With the reduction in the incidence of rheumatic fever, the incidence of Sydenham’s chorea has fallen, but it can still be seen in developing countries. The chorea generally responds to dopamine-blocking agents, valproic acid, and carbamazepine, but is self-limited, and treatment is generally restricted to those with severe chorea. Chorea may recur in later life, particularly in association with pregnancy (chorea gravidarum) or treatment with sex hormones. Several reports have documented cases of chorea associated with NMDA receptor antibody–positive encephalitis following herpes


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InternalMed_Harrison. with pregnancy (chorea gravidarum) or treatment with sex hormones. Several reports have documented cases of chorea associated with NMDA receptor antibody–positive encephalitis following herpes simplex virus encephalitis.


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InternalMed_Harrison. Chorea-acanthocytosis (neuroacanthocytosis) is a progressive and typically fatal autosomal recessive disorder that is characterized by chorea coupled with red cell abnormalities on peripheral blood smear (acanthocytes). The chorea can be severe and associated with self-mutilating behavior, dystonia, tics, seizures, and a polyneuropathy. Mutations in the VPS13A gene encoding chorein have been described. A phenotypically similar X-linked form of the disorder has been described in older individuals who have reactivity with Kell blood group antigens (McLeod syndrome). A benign hereditary chorea of childhood (BHC1) due to mutations in the gene for thyroid transcription factor 1 and a late-onset benign senile chorea (BHC2) have also been described. It is important to ensure that patients with these types of choreas do not have HD.


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InternalMed_Harrison. Chorea may also occur in association with vascular diseases, hypoand hyperglycemia, and a variety of infections and degenerative disorders. Systemic lupus erythematosus is the most common systemic disorder that causes chorea, which can last for days to years. Chorea can also be seen with hyperthyroidism, autoimmune disorders including Sjögren’s syndrome, infectious disorders including HIV disease, metabolic alterations, and polycythemia rubra vera; following open-heart surgery in the pediatric population; and in association with many medications (especially anticonvulsants, cocaine, CNS stimulants, estrogens, and lithium). Chorea is commonly seen in association with chronic levodopa treatment (discussed in the section on PD above). Chorea can also be seen in paraneoplastic syndromes associated with anti-CRMP-5 or anti-Hu antibodies (Chap. 122).


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InternalMed_Harrison. Hemiballismus is a violent form of chorea comprised of wild, flinging, large-amplitude movements on one side of the body. Proximal limb muscles tend to be predominantly affected. These movements may affect just one limb (monoballism) or, more exceptionally, both upper or lower limbs (paraballism). The movements may be so severe as to cause exhaustion, dehydration, local injury, and, in extreme cases, death. Fortunately, dopamine-blocking drugs can be very helpful, and importantly, hemiballismus is usually self-limiting and tends to resolve spontaneously after weeks or months. The most common cause is a partial lesion (infarct or hemorrhage) in the STN, but cases can also be seen with lesions in the putamen, thalamus, and parietal cortex. In extreme cases, pallidotomy can be very effective. Interestingly, surgically induced lesions and DBS of the STN in PD patients are usually not associated with hemiballismus.


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InternalMed_Harrison. A tic is a brief, rapid, recurrent, and seemingly purposeless stereotyped motor contraction. Motor tics can be simple, with movement only affecting an individual muscle group (e.g., blinking, twitching of the nose, jerking of the neck), or complex, with coordinated involvement of multiple muscle groups (e.g., jumping, sniffing, head banging, and echopraxia [mimicking movements]). Phonic (or vocal) tics can also be simple (e.g., grunting) or complex (e.g., echolalia [repeating other people’s words], palilalia [repeating one’s own words], and coprolalia [expression of obscene words]). Patients may also experience sensory tics, composed of unpleasant focal sensations in the face, head, or neck. These can be mild and of little clinical consequence or severe and disabling to the patient.


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InternalMed_Harrison. TS is a neurobehavioral disorder named after the French neurologist Georges Gilles de la Tourette. It predominantly affects males, and the prevalence is estimated to be 0.03–1.6%, but it is likely that many mild cases do not come to medical attention. TS is characterized by multiple motor tics often accompanied by vocalizations (phonic tics). Patients characteristically can voluntarily suppress tics for short periods of time, but then experience an irresistible urge to express them. Tics vary in intensity and may be absent for days or weeks only to recur, occasionally in a different pattern. Tics tend to present between ages 2 and 15 years (mean 7 years) and often lessen or even disappear in adulthood. Associated behavioral disturbances include anxiety, depression, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. Patients may experience personality disorders, self-destructive behaviors, difficulties in school, and impaired interpersonal relationships. Tics


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InternalMed_Harrison. disorder, and obsessive-compulsive disorder. Patients may experience personality disorders, self-destructive behaviors, difficulties in school, and impaired interpersonal relationships. Tics may present in adulthood and can also be seen in association with a variety of other disorders, including PD, HD, trauma, dystonia, drugs (e.g., levodopa, neuroleptics), and toxins.


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InternalMed_Harrison. Etiology and Pathophysiology TS is thought to be a genetic disorder, but no specific gene mutation has been identified. Current evidence supports a complex inheritance pattern, with one or more major genes, multiple loci, low penetrance, and environmental influences. The risk of a family with one affected child having a second is about 25%. The pathophysiology of TS is not known, but alterations in dopamine neurotransmission, opioids, and second-messenger systems have been 2623 proposed. Some cases of TS may be the consequence of an autoimmune response to β-hemolytic streptococcal infection (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection [PANDAS]); however, this entity remains controversial.


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InternalMed_Harrison. Patients with mild disease often only require education and counseling (for themselves and family members). Drug treatment is indicated when the tics are disabling and interfere with quality of life. Therapy is individualized, and there is no singular treatment regimen that has been properly evaluated in double-blind trials. Some physicians use the α-agonist clonidine, starting at low doses and gradually increasing the dose and frequency until satisfactory control is achieved. Guanfacine (0.5–2 mg/d) is an α-agonist that is preferred by some because it only requires once-a-day dosing. Other physicians prefer to use neuroleptics. Atypical neuroleptics are usually used initially (risperidone, olanzapine, ziprasidone) because they are thought to be associated with a reduced risk of tar-dive dyskinesia. If they are not effective, low doses of classical neuroleptics such as haloperidol, fluphenazine, pimozide, or tiapride can be tried because the risk of tardive dyskinesia in young people


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InternalMed_Harrison. dyskinesia. If they are not effective, low doses of classical neuroleptics such as haloperidol, fluphenazine, pimozide, or tiapride can be tried because the risk of tardive dyskinesia in young people is relatively low. Botulinum toxin injections can be effective in controlling focal tics that involve small muscle groups. Behavioral features, and particularly anxiety and compulsions, can be a disabling feature of TS and should be treated. The potential value of DBS targeting the anterior portion of the internal capsule, the GPi, or the thalamus is currently being explored.


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InternalMed_Harrison. Myoclonus is a brief, rapid (<100 ms), shock-like, jerky movement consisting of single or repetitive muscle discharges. Myoclonic jerks can be focal, multifocal, segmental, or generalized and can occur spontaneously, in association with voluntary movement (action myoclonus) or in response to an external stimulus (reflex or startle myoclonus). Negative myoclonus consists of a brief loss of muscle activity (e.g., asterixis in hepatic failure). Myoclonic jerks can be severe and interfere with normal movement or benign and of no clinical consequence as is commonly observed in normal people when waking up or falling asleep (hypnogogic jerks).


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InternalMed_Harrison. Myoclonic jerks differ from tics in that they are not typically repetitive, can interfere with normal voluntary movement, and are not suppressible. They can arise in association with abnormal neuronal discharges in cortical, subcortical, brainstem, or spinal cord regions and can be associated with lesions in each of these regions, particularly in association with hypoxemia (especially following cardiac arrest), encephalopathy, and neurodegeneration. Reversible myoclonus can be seen with metabolic disturbances (renal failure, electrolyte imbalance, hypocalcemia), toxins, and many medications. Essential myoclonus is a relatively benign familial condition characterized by multifocal, very brief, lightning-like movements that are frequently alcohol sensitive. A mutation in the epsilon-sarcoglycan gene has been associated with a variety of myoclonus seen in association with dystonia (myoclonic dystonia).


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InternalMed_Harrison. Treatment primarily consists of managing the underlying condition or removing an offending agent. Pharmacologic therapy involves one or a combination of GABAergic agents such as valproic acid (800–3000 mg/d), piracetam (8–20 g/d), clonazepam (2–15 mg/d), levetiracetam (1000–3000 mg/d), or primidone (500–1000 mg/d) and may be associated with striking clinical improvement in chronic cases (e.g., postanoxic myoclonus, progressive myoclonic epilepsy). The serotonin precursor 5-hydroxitriptophan (plus carbidopa) may be useful in some cases of postanoxic myoclonus.


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InternalMed_Harrison. This important group of movement disorders is primarily associated with drugs that block dopamine receptors (neuroleptics) or central dopaminergic transmission. These drugs are widely used in psychiatry, but it is important to appreciate that drugs used in the treatment of nausea or vomiting (e.g., prochlorperazine [Compazine]) or gastroesophageal disorders (e.g., metoclopramide) are neuroleptic agents. Hyperkinetic movement disorders secondary to neuroleptic drugs can be divided into those that present acutely, subacutely, or after prolonged exposure (tardive syndromes). Dopamine-blocking drugs can also be associated with a reversible parkinsonian syndrome for which anticholinergics are often concomitantly prescribed, but there is concern that this may increase the risk of developing a tardive syndrome.


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InternalMed_Harrison. Dystonia is the most common acute hyperkinetic drug reaction. It is typically generalized in children and focal in adults (e.g., blepharospasm, torticollis, or oromandibular dystonia). The reaction can develop within minutes of exposure and can be successfully treated in most cases with parenteral administration of anticholinergics (benztropine or diphenhydramine), benzodiazepines (lorazepam, clonazepam, or diazepam), or dopamine agonists. The abrupt onset of severe spasms may occasionally be confused with a seizure; however, there is no loss of consciousness, automatisms, or postictal features typical of epilepsy. The acute onset of chorea, stereotypic behavior, and tics may also be seen, particularly following exposure to CNS stimulants such as methylphenidate, cocaine, or amphetamines.


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InternalMed_Harrison. Akathisia is the commonest reaction in this category. It consists of motor restlessness with a need to move that is alleviated by movement. Therapy consists of removing the offending agent. When this is not possible, symptoms may be ameliorated with benzodiazepines, anticholinergics, beta blockers, or dopamine agonists.


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InternalMed_Harrison. These disorders develop months to years after initiation of neuroleptic treatment. Tardive dyskinesia (TD) is most common and typically presents with choreiform movements involving the mouth, lips, and tongue. In severe cases, the trunk, limbs, and respiratory muscles may also be affected. In approximately one-third of patients, TD remits within 3 months of stopping the drug, and most patients gradually improve over the course of several years. Abnormal movements may also develop or worsen after stopping the offending agent. The movements are often mild and more upsetting to the family than to the patient, but they can be severe and disabling, particularly in the context of an underlying psychiatric disorder. Atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are thought to be associated with a lower risk of TD in comparison to traditional antipsychotics, although this remains to be established in controlled studies. Younger


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InternalMed_Harrison. ziprasidone, and aripiprazole) are thought to be associated with a lower risk of TD in comparison to traditional antipsychotics, although this remains to be established in controlled studies. Younger patients have a lower risk of developing neuroleptic-induced TD, whereas the elderly, females, and those with underlying organic cerebral dysfunction have been reported to be at greater risk. Chronic use is associated with increased risk, and specifically, the U.S. Food and Drug Administration has warned that use of metoclopramide for more than 12 weeks increases the risk of TD. Because TD can be permanent and resistant to treatment, antipsychotics should be used judiciously, atypical neuroleptics should be the preferred agent when possible, and the need for continued use should be regularly monitored.


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InternalMed_Harrison. Treatment primarily consists of stopping the offending agent. If the patient is receiving a traditional antipsychotic and withdrawal is not possible, replacement with an atypical antipsychotic should be tried. Abrupt cessation of a neuroleptic should be avoided because acute withdrawal can induce worsening. TD can persist after withdrawal of antipsychotics and can be difficult to treat. Benefits may occasionally be achieved with valproic acid, anticholinergics, or botulinum toxin injections. In refractory cases, catecholamine depleters such as tetrabenazine may be helpful, but this drug can be associated with dose-dependent sedation and orthostatic hypotension and may induce parkinsonism as a side effect. Other approaches include baclofen (40–80 mg/d), clonazepam (1–8 mg/d), or valproic acid (750–3000 mg/d). In some cases, the abnormal movement is refractory to therapy.


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InternalMed_Harrison. Chronic neuroleptic exposure can also be associated with tardive dystonia, with preferential involvement of axial muscles and characteristic rocking movements of the trunk and pelvis. Tardive dystonia can be more troublesome than tardive dyskinesia and frequently persists despite stopping medication. Valproic acid, anticholinergics, and botulinum toxin may occasionally be beneficial, but patients are frequently refractory to medical therapy. Tardive akathisia, tardive Tourette’s, and tardive tremor syndromes are rare but may also occur after chronic neuroleptic exposure.


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InternalMed_Harrison. Neuroleptic medications can also be associated with a neuroleptic malignant syndrome (NMS). NMS is characterized by the acute or subacute onset of muscle rigidity, elevated temperature, altered mental status, hyperthermia, tachycardia, labile blood pressure, renal failure, and markedly elevated creatine kinase levels. Symptoms typically evolve within days or weeks after initiating the drug. NMS can also be precipitated by the abrupt withdrawal of dopaminergic medications in PD patients. Treatment involves immediate cessation of the offending antipsychotic drug and the introduction of a dopaminergic agent (e.g., a dopamine agonist or levodopa), dantrolene, or a benzodiazepine. Treatment may need to be undertaken in an intensive care setting and include supportive measures such as control of body temperature (antipyretics and cooling blankets), hydration, electrolyte replacement, and control of renal function and blood pressure.


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InternalMed_Harrison. Drugs that have serotonin-like activity (tryptophan, MDMA or “ecstasy,” meperidine) or that block serotonin reuptake can induce a rare, but potentially fatal, serotonin syndrome that is characterized by confusion, hyperthermia, tachycardia, and coma as well as rigidity, ataxia, and tremor. Myoclonus is often a prominent feature, in contrast to NMS, which it resembles. Patients can be managed with propranolol, diazepam, diphenhydramine, chlorpromazine, or cyproheptadine as well as supportive measures.


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InternalMed_Harrison. A variety of drugs can also be associated with parkinsonism (see above) and hyperkinetic movement disorders. Some examples include phenytoin (chorea, dystonia, tremor, myoclonus), carbamazepine (tics and dystonia), tricyclic antidepressants (dyskinesias, tremor, myoclonus), fluoxetine (myoclonus, chorea, dystonia), oral contraceptives (dyskinesia), β-adrenergics (tremor), buspirone (akathisia, dyskinesias, myoclonus), and digoxin, cimetidine, diazoxide, lithium, methadone, and fentanyl (dyskinesias).


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InternalMed_Harrison. Paroxysmal dyskinesias are a group of rare disorders characterized by episodic, brief involuntary movements that can manifest as various types of hyperkinetic movements, including chorea, dystonia, tremor, and myoclonus. There are two main categories: (1) paroxysmal kinesigenic dyskinesia, where the involuntary movements are triggered by sudden movement, and (2) paroxysmal nonkinesigenic dyskinesias, where the attacks are not induced by movement. There are rare cases of exercise-induced dyskinesia, where attacks are induced by prolonged exercise.


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InternalMed_Harrison. Paroxysmal kinesigenic dyskinesia (PKD) is characterized by brief, self-limited attacks induced by movement onset such as running but also occasionally by unexpected sound or photic stimulation. Attacks may affect one side of the body, last seconds to minutes at a time, and recur several times a day. They usually manifest as dystonic posturing of a limb but may also become generalized. PKD is most commonly familial with an autosomal dominant pattern of inheritance but may also occur secondary to various brain disorders such as multiple sclerosis or hyperglycemia. PKD is more frequent in males (4:1), and the onset is typically in the first or second decade of life. About 70% report sensory symptoms such as tingling or numbness of the affected limb preceding the attack by a few milliseconds. The evolution is relatively benign, and there is a trend toward resolution of the attacks over time. The cause is not known, but a mutation in the prolinerich transmembrane protein 2 (PRRT2) gene


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InternalMed_Harrison. The evolution is relatively benign, and there is a trend toward resolution of the attacks over time. The cause is not known, but a mutation in the prolinerich transmembrane protein 2 (PRRT2) gene that may be involved in neurotransmitter release has now been identified. Treatment with low-dose anticonvulsant therapy such as carbamazepine or phenytoin is advised when the attacks are frequent and interfere with daily life activities and is effective in about 80% of patients. Some clinical features of PKD (abrupt and short-lasting attacks preceded by an “aura”) and its favorable response to anticonvulsant drugs have led to speculation that it is epileptic in origin, but this has not been established.


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InternalMed_Harrison. Paroxysmal nonkinesigenic dyskinesia (PNKD) involves attacks of generalized dyskinesias precipitated by alcohol, caffeine, stress, or fatigue. In comparison to PKD, the episodes have a relatively longer duration (minutes to hours) and are less frequent (one to three per day). PNKD is inherited as autosomal dominant with incomplete penetrance pattern in some 80% of cases. A missense mutation in the myofibrillogenesis regulator (MR-1) gene has been identified in several families. Recognition of the condition and elimination of the underlying precipitating factors, where possible, are the first priority. Tetrabenazine, neuroleptics, dopamine-blocking agents, propranolol, clonazepam, and baclofen may be helpful. Treatment may not be required if the condition is mild and self-limited. Most patients with PNKD do not benefit from anticonvulsant drugs, but some may respond to clonazepam or other benzodiazepines.


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InternalMed_Harrison. Restless legs syndrome (RLS) is a neurologic disorder that affects approximately 10% of the adult population (it is rare in Asians) and can cause significant morbidity in some. It was first described in the seventeenth century by an English physician (Thomas Willis), but has only recently been recognized as being a bona fide movement disorder. The four core symptoms required for diagnosis are as follows: an urge to move the legs, usually caused or accompanied by an unpleasant sensation in the legs; symptoms that begin or worsen with rest; partial or complete relief by movement; and worsening during the evening or night.


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InternalMed_Harrison. Symptoms most commonly begin in the legs, but can spread to or even begin in the upper limbs. The unpleasant sensation is often described as a creepy-crawly feeling, paresthesia, or burning. In about 80% of patients, RLS is associated with periodic leg movements (PLMs) during sleep and occasionally while awake. These involuntary movements are usually brief, lasting no more than a few seconds, and recur every 5–90 s. The restlessness and PLMs are a major cause of sleep disturbance in patients, leading to poor-quality sleep and daytime sleepiness.


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InternalMed_Harrison. RLS is a heterogeneous condition. Primary RLS is genetic, and several loci have been found with an autosomal dominant pattern of inheritance, although penetrance may be variable. The mean age of onset in genetic forms is 27 years, although pediatric cases are recognized. The severity of symptoms is variable. Secondary RLS may be associated with pregnancy or a range of underlying disorders, including anemia, ferritin deficiency, renal failure, and peripheral neuropathy. The pathogenesis probably involves disordered dopamine function, which may be peripheral or central, in association with an abnormality of iron metabolism. Diagnosis is made on clinical grounds but can be supported by polysomnography and the demonstration of PLMs. The neurologic examination is normal. Secondary RLS should be excluded, and ferritin levels, glucose, and renal function should be measured.


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InternalMed_Harrison. Most RLS sufferers have mild symptoms that do not require specific treatment. General measures to improve sleep hygiene and quality should be attempted first. If symptoms remain intrusive, low doses of dopamine agonists, e.g., pramipexole (0.25–0.5 mg) or ropinirole (1–2 mg), are given 1–2 h before bedtime. Levodopa can be effective but is frequently associated with augmentation (spread and worsening of restlessness and its appearance earlier in the day) or rebound (reappearance sometimes with worsening of symptoms at a time compatible with the drug’s short half-life). Other drugs that can be effective include anticonvulsants, analgesics, and opiates. Management of secondary RLS should be directed to correcting the underlying disorder; for example, iron replacement for anemia. Iron infusion may also be helpful for severe primary RLS but requires expert supervision.


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InternalMed_Harrison. Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper metabolism that may manifest with neurologic, psychiatric, and liver disorders, alone or in combination. It is caused by mutations in the gene encoding a P-type ATPase. The disease was first comprehensively described by the English neurologist Kinnier Wilson at the beginning of the twentieth century, although at around the same time the German physicians Kayser and Fleischer separately noted the characteristic association of corneal pigmentation with hepatic and neurologic features. WD has a worldwide prevalence of approximately 1 in 30,000, with a gene carrier frequency of 1 in 90. About half of WD patients (especially younger patients) manifest with liver abnormalities. The remainder present with neurologic disease (with or without underlying liver abnormalities), and a small proportion have hematologic or psychiatric problems at disease onset.


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InternalMed_Harrison. Neurologic onset usually manifests in the second decade with tremor and rigidity. The tremor is usually in the upper limbs, bilateral, and asymmetric. Tremor can be on intention or occasionally resting and, in advanced disease, can take on a wing-beating characteristic. Other features include parkinsonism with bradykinesia, dystonia (particularly facial grimacing), dysarthria, and dysphagia. More than half of those with neurologic features have a history of psychiatric disturbances, including depression, mood swings, and overt psychosis. Kayser-Fleischer (KF) rings are seen in 80% of those with hepatic presentations and virtually all with neurologic features. KF rings represent the deposition of copper in Descemet’s membrane around the cornea. They consist of a characteristic grayish rim or circle at the limbus of the cornea and are best detected by slit-lamp examination. Neuropathologic examination is characterized by neurodegeneration and astrogliosis in the basal ganglia,


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InternalMed_Harrison. rim or circle at the limbus of the cornea and are best detected by slit-lamp examination. Neuropathologic examination is characterized by neurodegeneration and astrogliosis in the basal ganglia, particularly in the striatum.


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InternalMed_Harrison. WD should always be considered in the differential diagnosis of a movement disorder in the first decades of life. Low levels of blood copper and ceruloplasmin and high levels of urinary copper may be present, but normal levels do not exclude the diagnosis. A computed tomography (CT) scan usually reveals generalized brain atrophy in established cases, and ~50% have signal hypointensity in the caudate head, putamen, globus pallidum, substantia nigra, and red nucleus on T2-weighted MRI. However, correlation of imaging changes with clinical features is not good. It is very rare for WD patients with neurologic features not to have KF rings, and therefore when the diagnosis is considered, examination by slit-lamp is essential. Liver biopsy with demonstration of high copper levels remains the gold standard for the diagnosis.


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InternalMed_Harrison. In the absence of treatment, the course is progressive and leads to severe neurologic dysfunction and early death. Treatment is directed at reducing tissue copper levels and maintenance therapy to prevent reaccumulation. There is no clear consensus on treatment, and all patients should be managed in a unit with expertise in WD. Penicillamine is frequently used to increase copper excretion, but it may lead to a worsening of symptoms in the initial stages of therapy. Side effects are common and can to some degree be attenuated by coadministration of pyridoxine. Tetrathiomolybdate blocks the absorption of copper and can be used instead of penicillamine. Trientine and zinc are useful drugs for maintenance therapy. Effective treatment can reverse the neurologic features in most patients, particularly when started early. Some patients stabilize, and a few may still progress, especially those with hepatocerebral disease. KF rings tend to decrease after 3–6 months and disappear by 2 years.


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InternalMed_Harrison. when started early. Some patients stabilize, and a few may still progress, especially those with hepatocerebral disease. KF rings tend to decrease after 3–6 months and disappear by 2 years. Adherence to maintenance therapy is a major challenge in long-term care.


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InternalMed_Harrison. Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited disorders characterized by iron accumulation in the basal ganglia. Clinically, they can manifest as a progressive neurologic disorder manifesting a variety of features including parkinsonism, 2626 dystonia, neuropsychiatric abnormalities, and retinal degeneration. Cognitive disorders and cerebellar dysfunction may also be seen. Presentation is usually in childhood, but adult cases have been described. Multiple genes have been identified to date. Pantothenate kinase–associated neurodegeneration (PKAN) formerly known as Hallervorden-Spatz disease and caused by a mutation in the PANK2 gene is the most common form of NBIA, accounting for about 50% of cases. Onset is usually in early childhood and is manifest as a combination of dystonia, parkinsonism, and spasticity. MRI shows a characteristic low signal abnormality in the center of the globus pallidus on T2-weighted scans known as the “eye of the tiger”


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InternalMed_Harrison. as a combination of dystonia, parkinsonism, and spasticity. MRI shows a characteristic low signal abnormality in the center of the globus pallidus on T2-weighted scans known as the “eye of the tiger” sign caused by iron accumulation. Numerous other gene mutations have been described associated with iron accumulation including mutations in PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17. One must be cautious, however, not to assume that all cases with iron accumulation in the basal ganglia represent an NBIA, because iron accumulation in specific basal ganglia regions is normal, and excess iron accumulation may occur in the basal ganglia region as a consequence of neurodegeneration of multiple causes unrelated to a defect in iron metabolism.


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InternalMed_Harrison. Acanthocytosis, some hereditary spinocerebellar atrophies and spastic parapareses, and HD can also present with parkinsonian features associated with involuntary movements. Diagnosis in these cases is best established with genetic testing.


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InternalMed_Harrison. Virtually all movement disorders including tremor, tics, dystonia, myoclonus, chorea, ballism, and parkinsonism can be psychogenic in origin. Tremor affecting the upper limbs is the most common psychogenic movement disorder. Psychogenic movements can result from a somatoform or conversion disorder, malingering (e.g., seeking financial gain), or a factitious disorder (e.g., seeking psychological gain). Psychogenic movement disorders are common (estimated to be 2–3% of patients seen in a movement disorder clinic), more frequent in women, disabling for the patient and family, and expensive for society (estimated $20 billion annually). Clinical features suggesting a psychogenic movement disorder include an acute onset and a pattern of abnormal movement that is inconsistent with a known movement disorder. Diagnosis is based on the nonorganic quality of the movement, the absence of findings of an organic disease process, and positive features that specifically point to a psychogenic illness


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InternalMed_Harrison. disorder. Diagnosis is based on the nonorganic quality of the movement, the absence of findings of an organic disease process, and positive features that specifically point to a psychogenic illness such as variability and distractibility. For example, the magnitude of a psychogenic tremor is increased with attention and diminishes or even disappears when the patient is distracted by being asked to perform a different task or is unaware that he or she is being observed. Other positive features suggesting a psychogenic problem include a tremor frequency that is variable or that entrains with the frequency of a designated movement in the contralateral limb, and a positive response to placebo medication. Associated features can include nonanatomic sensory findings, give-way weakness, astasia-abasia (an odd, gyrating gait; Chap. 32), and multiple somatic complaints with no underlying pathology (somatoform disorder). Comorbid psychiatric problems such as anxiety, depression, and emotional


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InternalMed_Harrison. (an odd, gyrating gait; Chap. 32), and multiple somatic complaints with no underlying pathology (somatoform disorder). Comorbid psychiatric problems such as anxiety, depression, and emotional trauma may be present but are not necessary for the diagnosis of a psychogenic movement disorder to be made. Psychogenic movement disorders can occur as an isolated entity or in association with an underlying organic problem. The diagnosis can often be made based on clinical features alone, and unnecessary tests or medications can be avoided. Underlying psychiatric problems may be present and should be identified and treated, but many patients with psychogenic movement disorders have no obvious psychiatric pathology. Psychotherapy and hypnosis may be of value for patients with conversion reaction, and cognitive behavioral therapy may be helpful for patients with somatoform disorders. Patients with hypochondriasis, factitious disorders, and malingering have a poor prognosis.


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InternalMed_Harrison. Roger N. Rosenberg APPROACH TO THE PATIENT:


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InternalMed_Harrison. Symptoms and signs of ataxia consist of gait impairment, unclear (“scanning”) speech, visual blurring due to nystagmus, hand incoordination, and tremor with movement. These result from the involvement of the cerebellum and its afferent and efferent pathways, including the spinocerebellar pathways, and the frontopontocerebellar pathway originating in the rostral frontal lobe. True cerebellar ataxia must be distinguished from ataxia associated with vestibular nerve or labyrinthine disease, as the latter results in a disorder of gait associated with a significant degree of dizziness, light-headedness, or the perception of movement (Chap. 28). True cerebellar ataxia is devoid of these vertiginous complaints and is clearly an unsteady gait due to imbalance. Sensory disturbances can also on occasion simulate the imbalance of cerebellar disease; with sensory ataxia, imbalance dramatically worsens when visual input is removed (Romberg sign). Rarely, weakness of proximal leg muscles mimics


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InternalMed_Harrison. occasion simulate the imbalance of cerebellar disease; with sensory ataxia, imbalance dramatically worsens when visual input is removed (Romberg sign). Rarely, weakness of proximal leg muscles mimics cerebellar disease. In the patient who presents with ataxia, the rate and pattern of the development of cerebellar symptoms help to narrow the diagnostic possibilities (Table 450-1). A gradual and progressive increase in symptoms with bilateral and symmetric involvement suggests a genetic, metabolic, immune, or toxic etiology. Conversely, focal, unilateral symptoms with headache and impaired level of consciousness accompanied by ipsilateral cranial nerve palsies and contralateral weakness imply a space-occupying cerebellar lesion.


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InternalMed_Harrison. Progressive and symmetric ataxia can be classified with respect to onset as acute (over hours or days), subacute (weeks or months), or chronic (months to years). Acute and reversible ataxias include those caused by intoxication with alcohol, phenytoin, lithium, barbiturates, and other drugs. Intoxication caused by toluene exposure, gasoline sniffing, glue sniffing, spray painting, or exposure to methyl mercury or bismuth are additional causes of acute or subacute ataxia, as is treatment with cytotoxic chemotherapeutic drugs such as fluorouracil and paclitaxel. Patients with a postinfectious syndrome (especially after varicella) may develop gait ataxia and mild dysarthria, both of which are reversible (Chap. 458). Rare infectious causes of acquired ataxia include poliovirus, coxsackievirus, echovirus, Epstein-Barr virus, toxoplasmosis, Legionella, and Lyme disease.


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InternalMed_Harrison. The subacute development of ataxia of gait over weeks to months (degeneration of the cerebellar vermis) may be due to the combined effects of alcoholism and malnutrition, particularly with deficiencies of vitamins B1 and B12. Hyponatremia has also been associated with ataxia. Paraneoplastic cerebellar ataxia is associated with a number of different tumors (and autoantibodies) such as breast and ovarian cancers (anti-Yo), small-cell lung cancer (anti-PQ-type voltage-gated calcium channel), and Hodgkin’s disease (anti-Tr) (Chap. 122). Another paraneoplastic syndrome associated with myoclonus and opsoclonus occurs with breast (anti-Ri) and lung cancers and neuroblastoma. Elevated serum anti-glutamic acid decarboxylase (GAD) antibodies have been associated with a progressive ataxic syndrome affecting speech and gait. For all of these paraneoplastic ataxias, the neurologic syndrome may be the presenting symptom of the cancer. Another immune-mediated progressive ataxia is associated with


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InternalMed_Harrison. affecting speech and gait. For all of these paraneoplastic ataxias, the neurologic syndrome may be the presenting symptom of the cancer. Another immune-mediated progressive ataxia is associated with antigliadin (and antiendomysium) antibodies and the human leukocyte antigen (HLA) DQB1*0201 haplotype; in some affected patients, biopsy of the small intestine reveals villus atrophy consistent with gluten-sensitive enteropathy (Chap. 349). Finally, subacute progressive ataxia may be caused by a prion disorder,


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InternalMed_Harrison. Intoxication: alcohol, lithium, phenytoin, barbiturates (positive history and toxicology screen) Acute viral cerebellitis (CSF supportive of acute viral infection) Postinfection syndrome Intoxication: mercury, solvents, gasoline, glue; cytotoxic chemotherapeutic, hemotherapeutic drugs Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging. especially when an infectious etiology, such as transmission from contaminated human growth hormone, is responsible (Chap. 453e). Chronic symmetric gait ataxia suggests an inherited ataxia (discussed below), a metabolic disorder, or a chronic infection. Hypothyroidism must always be considered as a readily treatable and reversible form of gait ataxia. Infectious diseases that can present with ataxia are meningovascular syphilis and tabes dorsalis due to degeneration of the posterior columns and spinocerebellar pathways in the spinal cord.


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InternalMed_Harrison. Acute focal ataxia commonly results from cerebrovascular disease, usually ischemic infarction or cerebellar hemorrhage. These lesions typically produce cerebellar symptoms ipsilateral to the injured cerebellum and may be associated with an impaired level of consciousness due to brainstem compression and increased intracranial pressure; ipsilateral pontine signs, including sixth and seventh nerve palsies, may be present. Focal and worsening signs of acute ataxia should also prompt consideration of a posterior fossa subdural hematoma, bacterial abscess, or primary or metastatic cerebellar tumor. Computed tomography (CT) or magnetic resonance imaging (MRI) studies will reveal clinically significant processes of this type. Many of these lesions represent true neurologic emergencies, as sudden herniation, either rostrally through the tentorium or caudal herniation of cerebellar tonsils through the foramen magnum, can occur and is usually devastating. Acute surgical decompression may be


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InternalMed_Harrison. herniation, either rostrally through the tentorium or caudal herniation of cerebellar tonsils through the foramen magnum, can occur and is usually devastating. Acute surgical decompression may be required (Chap. 330). Lymphoma or progressive multifocal leukoencephalopathy (PML) in a patient with AIDS may present with an acute or subacute focal cerebellar syndrome. Chronic etiologies of progressive ataxia include multiple sclerosis (Chap. 458) and congenital lesions such as a Chiari malformation (Chap. 456) or a congenital cyst of the posterior fossa (Dandy-Walker syndrome).


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InternalMed_Harrison. These may show autosomal dominant, autosomal recessive, or maternal (mitochondrial) modes of inheritance. A genomic classification (Chap. 451e) has now largely superseded previous ones based on clinical expression alone. Although the clinical manifestations and neuropathologic findings of cerebellar disease dominate the clinical picture, there may also be characteristic changes in the basal ganglia, brainstem, spinal cord, optic nerves, retina, and peripheral nerves. In large families with dominantly inherited ataxias, many gradations are observed from purely cerebellar manifestations to mixed cerebellar and brainstem disorders, cerebellar and basal ganglia syndromes, and spinal cord or peripheral nerve disease. Rarely, dementia is present as well. The clinical picture may be homogeneous within a family with dominantly inherited ataxia, but sometimes most affected family members show one characteristic syndrome, while one or several members have an entirely different phenotype.


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InternalMed_Harrison. The autosomal spinocerebellar ataxias (SCAs) include SCA types 1 through 36, dentatorubropallidoluysian atrophy (DRPLA), and episodic ataxia (EA) types 1 to 7 (Chap. 451e). SCA1, SCA2, SCA3 (Machado-Joseph disease [MJD]), SCA6, SCA7, and SCA17 are caused by CAG triplet repeat expansions in different genes. SCA8 is due to an untranslated CTG repeat expansion, SCA12 is linked to an untranslated CAG repeat, and SCA10 is caused by an untranslated pentanucleotide repeat. The clinical phenotypes of these SCAs overlap. The genotype has become the gold standard for diagnosis and classification. CAG encodes glutamine, and these expanded CAG triplet repeat expansions result in expanded polyglutamine proteins, termed ataxins, that produce a toxic gain of function with autosomal dominant inheritance. Although the phenotype is variable for any given disease gene, a pattern of neuronal loss with gliosis is produced that is relatively unique for each ataxia. Immunohistochemical and biochemical


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InternalMed_Harrison. Although the phenotype is variable for any given disease gene, a pattern of neuronal loss with gliosis is produced that is relatively unique for each ataxia. Immunohistochemical and biochemical studies have shown cytoplasmic (SCA2), neuronal (SCA1, MJD, SCA7), and nucleolar (SCA7) accumulation of the specific mutant polyglutamine-containing ataxin proteins. Expanded polyglutamine ataxins with more than ~40 glutamines are potentially toxic to neurons for a variety of reasons including: high levels of gene expression for the mutant polyglutamine ataxin in affected neurons; conformational change of the aggregated protein to a β-pleated structure; abnormal transport of the ataxin into the nucleus (SCA1, MJD, SCA7); binding to other polyglutamine proteins, including the TATA-binding transcription protein and the CREB-binding protein, impairing their functions; altering the efficiency of the ubiquitin-proteasome system of protein turnover; and inducing neuronal apoptosis. An earlier age of


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InternalMed_Harrison. protein and the CREB-binding protein, impairing their functions; altering the efficiency of the ubiquitin-proteasome system of protein turnover; and inducing neuronal apoptosis. An earlier age of onset (anticipation) and more aggressive disease in subsequent generations are due to further expansion of the CAG triplet repeat and increased polyglutamine number in the mutant ataxin. The most common disorders are discussed below.


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InternalMed_Harrison. SCA1 was previously referred to as olivopontocerebellar atrophy, but genomic data have shown that that entity represents several different genotypes with overlapping clinical features. Symptoms and Signs SCA1 is characterized by the development in early or middle adult life of progressive cerebellar ataxia of the trunk and limbs, impairment of equilibrium and gait, slowness of voluntary movements, scanning speech, nystagmoid eye movements, and oscillatory tremor of the head and trunk. Dysarthria, dysphagia, and


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InternalMed_Harrison. FIGURE 450-1 Sagittal magnetic resonance imaging (MRI) of the brain of a 60-year-old man with gait ataxia and dysarthria due to spinocerebellar ataxia type 1 (SCA1), illustrating cerebellar atrophy (arrows). (Reproduced with permission from RN Rosenberg, P Khemani, in RN Rosenberg, JM Pascual [eds]: Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th ed. London, Elsevier, 2015.) oculomotor and facial palsies may also occur. Extrapyramidal symptoms include rigidity, an immobile face, and parkinsonian tremor. The reflexes are usually normal, but knee and ankle jerks may be lost, and extensor plantar responses may occur. Dementia may be noted but is usually mild. Impairment of sphincter function is common, with urinary and sometimes fecal incontinence. Cerebellar and brainstem atrophy are evident on MRI (Fig. 450-1).


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InternalMed_Harrison. Marked shrinkage of the ventral half of the pons, disappearance of the olivary eminence on the ventral surface of the medulla, and atrophy of the cerebellum are evident on gross postmortem inspection of the brain. Variable loss of Purkinje cells, reduced numbers of cells in the molecular and granular layer, demyelination of the middle cerebellar peduncle and the cerebellar hemispheres, and severe loss of cells in the pontine nuclei and olives are found on histologic examination. Degenerative changes in the striatum, especially the putamen, and loss of the pigmented cells of the substantia nigra may be found in cases with extrapyramidal features. More widespread degeneration in the central nervous system (CNS), including involvement of the posterior columns and the spinocerebellar fibers, is often present.


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InternalMed_Harrison. SCA1 encodes a gene product, called ataxin-1, which is a novel protein of unknown function. The mutant allele has 40 CAG repeats located within the coding region, whereas alleles from unaffected individuals have ≤36 repeats. A few patients with 38–40 CAG repeats have been described. There is a direct correlation between a larger number of repeats and a younger age of onset for SCA1. Juvenile patients have higher numbers of repeats, and anticipation is present in subsequent generations. Transgenic mice carrying SCA1 developed ataxia and Purkinje cell pathology. Nuclear localization, but not aggregation, of ataxin-1 appears to be required for cell death initiated by the mutant protein.


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InternalMed_Harrison. SCA2 Symptoms and Signs Another clinical phenotype, SCA2, has been described in patients from Cuba and India. Cuban patients probably are descendants of a common ancestor, and the population may be the largest homogeneous group of patients with ataxia yet described. The age of onset ranges from 2–65 years, and there is considerable clinical variability within families. Although neuropathologic and clinical findings are compatible with a diagnosis of SCA1, including slow saccadic eye movements, ataxia, dysarthria, parkinsonian rigidity, optic disc pallor, mild spasticity, and retinal degeneration, SCA2 is a unique form of cerebellar degenerative disease. The gene in SCA2 families also contains CAG repeat expansions coding for a polyglutamine-containing protein, ataxin-2. Normal alleles contain 15–32 repeats; mutant alleles have 35–77 repeats.


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InternalMed_Harrison. The gene in SCA2 families also contains CAG repeat expansions coding for a polyglutamine-containing protein, ataxin-2. Normal alleles contain 15–32 repeats; mutant alleles have 35–77 repeats. MJD was first described among the Portuguese and their descendants in New England and California. Subsequently, MJD has been found in families from Portugal, Australia, Brazil, Canada, China, England, France, India, Israel, Italy, Japan, Spain, Taiwan, and the United States. In most populations, it is the most common autosomal dominant ataxia.


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InternalMed_Harrison. Symptoms and Signs MJD has been classified into three clinical types. In type I MJD (amyotrophic lateral sclerosis-parkinsonism-dystonia type), neurologic deficits appear in the first two decades and involve weakness and spasticity of extremities, especially the legs, often with dystonia of the face, neck, trunk, and extremities. Patellar and ankle clonus are common, as are extensor plantar responses. The gait is slow and stiff, with a slightly broadened base and lurching from side to side; this gait results from spasticity, not true ataxia. There is no truncal titubation. Pharyngeal weakness and spasticity cause difficulty with speech and swallowing. Of note is the prominence of horizontal and vertical nystagmus, loss of fast saccadic eye movements, hypermetric and hypometric saccades, and impairment of upward vertical gaze. Facial fasciculations, facial myokymia, lingual fasciculations without atrophy, ophthalmoparesis, and ocular prominence are common early manifestations.


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InternalMed_Harrison. In type II MJD (ataxic type), true cerebellar deficits of dysarthria and gait and extremity ataxia begin in the second to fourth decades along with corticospinal and extrapyramidal deficits of spasticity, rigidity, and dystonia. Type II is the most common form of MJD. Ophthalmoparesis, upward vertical gaze deficits, and facial and lingual fasciculations are also present. Type II MJD can be distinguished from the clinically similar disorders SCA1 and SCA2. Type III MJD (ataxic-amyotrophic type) presents in the fifth to the seventh decades with a pancerebellar disorder that includes dysarthria and gait and extremity ataxia. Distal sensory loss involving pain, touch, vibration, and position senses and distal atrophy are prominent, indicating the presence of peripheral neuropathy. The deep tendon reflexes are depressed to absent, and there are no corticospinal or extrapyramidal findings.


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InternalMed_Harrison. The mean age of onset of symptoms in MJD is 25 years. Neurologic deficits invariably progress and lead to death from debilitation within 15 years of onset, especially in patients with types I and II disease. Usually, patients retain full intellectual function. The major pathologic findings are variable loss of neurons and glial replacement in the corpus striatum and severe loss of neurons in the pars compacta of the substantia nigra. A moderate loss of neurons occurs in the dentate nucleus of the cerebellum and in the red nucleus. Purkinje cell loss and granule cell loss occur in the cerebellar cortex. Cell loss also occurs in the dentate nucleus and in the cranial nerve motor nuclei. Sparing of the inferior olives distinguishes MJD from other dominantly inherited ataxias.


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InternalMed_Harrison. The gene for MJD maps to 14q24.3-q32. Unstable CAG repeat expansions are present in the MJD gene coding for a polyglutamine-containing protein named ataxin-3, or MJD-ataxin. An earlier age of onset is associated with longer repeats. Alleles from normal individuals have between 12 and 37 CAG repeats, whereas MJD alleles have 60–84 CAG repeats. Polyglutamine-containing aggregates of ataxin-3 (MJD-ataxin) have been described in neuronal nuclei undergoing degeneration. MJD-ataxin codes for a ubiquitin protease, which is inactive due to expanded polyglutamines. Proteosome function is impaired, resulting in altered clearance of proteins and cerebellar neuronal loss.


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InternalMed_Harrison. Genomic screening for CAG repeats in other families with autosomal dominant ataxia and vibratory and proprioceptive sensory loss have yielded another locus. Of interest is that different mutations in the same gene for the α1A voltage-dependent calcium channel subunit (CACNLIA4; also referred to as the CACNA1A gene) at 19p13 result in different clinical disorders. CAG repeat expansions (21–27 in patients; 4–16 triplets in normal individuals) result in late-onset progressive ataxia with cerebellar degeneration. Missense mutations in this gene result in familial hemiplegic migraine. Nonsense mutations resulting in termination of protein synthesis of the gene product yield hereditary paroxysmal cerebellar ataxia or EA. Some patients with familial hemiplegic migraine develop progressive ataxia and also have cerebellar atrophy.


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InternalMed_Harrison. This disorder is distinguished from all other SCAs by the presence of retinal pigmentary degeneration. The visual abnormalities first appear as blue-yellow color blindness and proceed to frank visual loss with macular degeneration. In almost all other respects, SCA7 resembles several other SCAs in which ataxia is accompanied by various noncerebellar findings, including ophthalmoparesis and extensor plantar responses. The genetic defect is an expanded CAG repeat in the SCA7 gene at 3p14-p21.1. The expanded repeat size in SCA7 is highly variable. Consistent with this, the severity of clinical findings varies from essentially asymptomatic to mild late-onset symptoms to severe, aggressive disease in childhood with rapid progression. Marked anticipation has been recorded, especially with paternal transmission. The disease protein, ataxin-7, forms aggregates in nuclei of affected neurons, as has also been described for SCA1 and SCA3/MJD.


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InternalMed_Harrison. This form of ataxia is caused by a CTG repeat expansion in an untranslated region of a gene on chromosome 13q21. There is marked maternal bias in transmission, perhaps reflecting contractions of the repeat during spermatogenesis. The mutation is not fully penetrant. Symptoms include slowly progressive dysarthria and gait ataxia beginning at ~40 years of age with a range between 20 and 65 years. Other features include nystagmus, leg spasticity, and reduced vibratory sensation. Severely affected individuals are nonambulatory by the fourth to sixth decades. MRI shows cerebellar atrophy. The mechanism of disease may involve a dominant “toxic” effect occurring at the RNA level, as occurs in myotonic dystrophy.


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InternalMed_Harrison. DRPLA has a variable presentation that may include progressive ataxia, choreoathetosis, dystonia, seizures, myoclonus, and dementia. DRPLA is due to unstable CAG triplet repeats in the open reading frame of a gene named atrophin located on chromosome 12p12-ter. Larger expansions are found in patients with earlier onset. The number of repeats is 49 in patients with DRPLA and ≤26 in normal individuals. Anticipation occurs in successive generations, with earlier onset of disease in association with an increasing CAG repeat number in children who inherit the disease from their father. One well-characterized family in North Carolina has a phenotypic variant known as the Haw River syndrome, now recognized to be due to the DRPLA mutation.


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InternalMed_Harrison. EA types 1 and 2 are two rare dominantly inherited disorders that have been mapped to chromosomes 12p (a potassium channel gene) for type 1 and 19p for type 2. Patients with EA-1 have brief episodes of ataxia with myokymia and nystagmus that last only minutes. Startle, sudden change in posture, and exercise can induce episodes. Acetazolamide or anticonvulsants may be therapeutic. Patients with EA-2 have episodes 2629 of ataxia with nystagmus that can last for hours or days. Stress, exercise, or excessive fatigue may be precipitants. Acetazolamide may be therapeutic and can reverse the relative intracellular alkalosis detected by magnetic resonance spectroscopy. Stop codon, nonsense mutations causing EA-2 have been found in the CACNA1A gene, encoding the voltage-dependent calcium channel subunit (see “SCA6,” above).


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InternalMed_Harrison. AUTOSOMAL RECESSIVE ATAXIAS Friedreich’s Ataxia This is the most common form of inherited ataxia, comprising one-half of all hereditary ataxias. It can occur in a classic form or in association with a genetically determined vitamin E deficiency syndrome; the two forms are clinically indistinguishable. SymptomS AnD SignS Friedreich’s ataxia presents before 25 years of age with progressive staggering gait, frequent falling, and titubation. The lower extremities are more severely involved than the upper ones. Dysarthria occasionally is the presenting symptom; rarely, progressive scoliosis, foot deformity, nystagmus, or cardiopathy is the initial sign.


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InternalMed_Harrison. The neurologic examination reveals nystagmus, loss of fast saccadic eye movements, truncal titubation, dysarthria, dysmetria, and ataxia of trunk and limb movements. Extensor plantar responses (with normal tone in trunk and extremities), absence of deep tendon reflexes, and weakness (greater distally than proximally) are usually found. Loss of vibratory and proprioceptive sensation occurs. The median age of death is 35 years. Women have a significantly better prognosis than men. Cardiac involvement occurs in 90% of patients. Cardiomegaly, symmetric hypertrophy, murmurs, and conduction defects are reported. Moderate mental retardation or psychiatric syndromes are present in a small percentage of patients. A high incidence of diabetes mellitus (20%) is found and is associated with insulin resistance and pancreatic β-cell dysfunction. Musculoskeletal deformities are common and include pes cavus, pes equinovarus, and scoliosis. MRI of the spinal cord shows atrophy (Fig. 450-2).


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InternalMed_Harrison. The primary sites of pathology are the spinal cord, dorsal root ganglion cells, and the peripheral nerves. Slight atrophy of the cerebellum and cerebral gyri may occur. Sclerosis and degeneration occur