Curr Treat Options Neurol (2014) 16:282 DOI 10.1007/s11940-013-0282-1
MOVEMENT DISORDERS (O SUCHOWERSKY, SECTION EDITOR)
Diagnosis and Treatment of Corticobasal Degeneration Melissa J. Armstrong, MD, MSc Address Division of Movement Disorders, Department of Neurology, University of Maryland School of Medicine, 110 S. Paca Street, 3rd Floor, Baltimore, MD 21201, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Movement Disorders Keywords Corticobasal degeneration (CBD) I Corticobasal syndrome (CBS) I Tauopathy I Neurodegenerative disease I Atypical parkinsonism I Diagnostic criteria I Treatment I Motor symptoms I Behavioral symptoms I Cognitive symptoms
Opinion statement Corticobasal degeneration is a pathologic entity. Presenting clinical phenotypes include corticobasal syndrome (CBS), frontal behavioral spatial syndrome, aphasia, progressive supranuclear palsy-like syndrome (PSPS), and a predominantly cognitive phenotype often mistaken for Alzheimer’s disease (AD). Treatment of CBD is symptomatic, particularly given recently negative neuroprotective studies. Given the relentless progression in CBD, all interested patients should be offered the opportunity to enroll in clinical neuroprotective trials as they arise. For symptomatic therapy, treatment options are necessarily based on evidence from other disorders given the lack of studies in CBD. In patients with CBS and PSPS, parkinsonism is treated with levodopa/carbidopa. This generally has modest and transient benefits at best and often results in no improvement. Botulinum toxin injections are the treatment of choice for limb dystonia. Clonazepam and levetiracetam are commonly used for myoclonus. Physical therapy is an important part of motor treatment, particularly for fall prevention strategies and assist device assessment. Whether medications such as cholinesterase inhibitors or memantine have any role in CBD is unclear given the various responses described in related phenotypes and diseases. Treating the behavioral symptoms associated with CBD is critical in an attempt to treat symptoms for which we have good pharmacologic interventions and to hopefully improve quality of life. General supportive care is important, including assessing for sores related to dystonia or immobility, monitoring dysphagia, and identifying needs for support services. Finally, as with other relentlessly progressive neurodegenerative diseases, it is critical to provide family and caregiver support and to assess for when palliative care services will serve the patient best.
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Introduction CBD is a pathologic disorder [1] resulting from abnormal aggregation of hyperphosphorylated tau isoforms with four conserved repeat sequences (4R tau). Prior to 2013, CBD diagnostic criteria all reflected only one presenting phenotype, corticobasal syndrome (CBS), once thought pathognomonic for CBD. CBS is a motor presentation with asymmetric parkinsonism, dystonia, and myoclonus accompanied by higher cortical features including apraxia, alien limb phenomena, cortical sensory loss, and cognitive changes. It is now recognized that CBS is only one presenting phenotype of CBD, reflected in updated clinical research diagnostic criteria for CBD (cr-CBD) published in 2013 [2••]. The new criteria attempt to characterize the multiple phenotypes of CBD to facilitate in-life recognition of this pathologic diagnosis. This is in contrast to diagnosing CBS, which is a clinical syndrome with multiple underlying pathologies including CBD but also progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), and frontotemporal lobar degeneration (FTLD) [3–10]. Phenotypes included in the new criteria include CBS, frontal behavioral spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). A dementing phenotype often misdiagnosed as AD is also a common presentation of CBD, but was not included in the new criteria given that this picture is much more likely to represent AD than CBD simply given the large difference in prevalence [2••]. These new criteria, while better reflecting our current understanding of CBD, are not without limitations. They remain unvalidated and will likely result in false-positive diagnoses given each phenotype’s association with multiple underlying pathologies. They will need refinement, particularly as research identifies clinical clues that predict underlying pathology or relevant biomarkers. There is no currently established role for ancillary testing in diagnosing CBD. Imaging may be useful to in-
vestigate other causes of presenting symptoms, such as signs of prion disease on magnetic resonance imaging (MRI) in patients with CBS and rapidly progressing dementia or amyloid imaging to suggest underlying AD. Voxel based morphometry (VBM) analysis of MRI atrophy patterns may be predictive of underlying pathology in CBS patients [11, 12•], but these findings cannot yet be applied to routine clinical diagnosis. In a disease correctly predicted antemortem in only 25 %–56 % of cases [4, 6, 7, 10, 13–15], how, then, do we discuss treatment options? Treatment in CBD focuses on two approaches: (1) research studies targeting the underlying tauopathy, and (2) symptomatic management. Recent pilot studies of tau-based therapies for patients with CBS and PSPS, however, have been discouraging. A pilot trial of lithium (NCT00703677) enrolled only 17 patients and most subjects did not tolerate the study drug. A pilot study of davunetide (NCT01056965) in patients with CBS, PSPS, progressive non-fluent aphasia, and frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 was recently halted because of a reported lack of benefit. CBD is a relentlessly progressive neurodegeneration with a mean disease duration of 6.6 years (SD 2.4, range 2.0–12.5) [13, 16]. Because of this, interested patients should be referred for participation in disease-modifying clinical trials when available. The mainstays of clinical treatment are symptomatic and supportive therapies. In this context, the underlying pathology is less important than the symptoms and the clinical phenotype becomes as important as pathology. Most treatments used to treat the symptoms in CBD and its associated phenotypes—particularly CBS—are largely based on Class IV evidence of case series, case reports, expert opinion, and anecdotal descriptions. Data regarding treatment of other phenotypes such as naPPA and FBS (which has some overlap with FTD presentations) are also scarce.
Treatment Pharmacologic treatment of motor symptoms &
Motor symptoms of CBD and CBS consist of parkinsonism, limb dystonia, and myoclonus. These symptoms are managed symptomatically using pharmacologic treatments developed for other disor-
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ders such as Parkinson’s disease (PD). The aim of these treatments is to reduce disability where possible and to decrease associated symptoms such as pain, particularly in the context of dystonia. The parkinsonism in CBD/CBS is treated with levodopa, typically with minimal response. Transient mild to moderate benefits are described, however [6, 16–18, all Class IV]. Dyskinesias may rarely occur even in pathologically-confirmed CBD patients [6, 19]. Other treatments for parkinsonism such as other dopaminergic therapies, benzodiazepines and anticholinergics, are usually unhelpful [17, Class IV] and may be associated with side effects such as worsened cognition. Dystonia is most successfully treated with targeted botulinum toxin injections [17, 20–22, all Class IV]. Botulinum toxin injections for dystonia in CBS can be used to reduce pain, improve hygeiene, prevent secondary contractures, and on occasion, improve limb function early in the disease course. Oral agents such as benzodiazepines, anticholinergic agents, or muscle relaxants are sometimes tried [17, 21, all Class IV], but these are rarely effective. Botulinum toxin injections are the mainstay of care. Myoclonus is typically most responsive to benzodiazepines, particularly clonazepam [17, 18, 23, all Class IV]. Levetiracetam may also be beneficial [24, 25, both Class IV]. Use of other agents such as gabapentin and valproic acid is described [23, Class IV].
Levodopa/carbidopa (immediate release) Standard dosage
Contraindications Main drug interactions Main side effects
Levodopa/carbidopa is given in the 100/25 mg immediate release formulation and can be started at a half tablet 3 times daily, increasing to a starting dose of one tablet 3 times daily. Ideal administration is 30– 60 minutes prior to meals. For patients with an inadequate response, the dose should be gradually increased to 1000 mg daily (total), the necessary dose for an adequate trial. Some patients only respond to higher doses of levodopa. If there is no benefit on a total dose of 1000 mg or more daily, the medication can be gradually weaned. Discontinuation should be gradual as the dose reduction can reveal an unrecognized modest benefit. There are no common contraindications to levodopa/carbidopa use. None. Levodopa/carbidopa is generally well tolerated. The most common side effects include nausea (which can be addressed by taking the medication with food), orthostatic hypotension, confusion, and hallucinations. Dyskinesias are rarely reported even in CBD (as described above).
Botulinum toxin injections Standard dosage
Botulinum toxin A: 100–400 Units; botulinum toxin B: 5000– 25,000 Units. There is no evidence to support using one formulation of botulinum toxin over another. Dose is variable and determined by clinical response.
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None, though caution should be used if injecting patients for cervical dystonia in the context of dysphagia. Dystonia in CBS and CBD more commonly affects the limbs than the neck.
Complications
Botulinum toxin may cause temporary excessive weakness, but this is rarely a major problem when treating limb dystonia in CBS because in most individuals with CBS, the limb is already functionless and the injections are targeting pain and improved hygiene.
Standard dosage
Clonazepam is generally started at a low dose such as 0.25 mg daily given the risks of sedation. It can be gradually increased to doses of 0.5–1.0 mg three times per day when being used to treat myoclonus. The maximum dose of 2.0 mg three times per day is rarely used.
Contraindications
Clonazepam should be used with caution with other sedative-hypnotic agents. Other listed contraindications include acute narrow angle glaucoma and significant liver disease.
Clonazepam
Main drug interactions Main side effects Special points
Clonazepam should be used with caution with other sedative-hypnotic agents. Adverse effects include drowsiness, behavior changes, imbalance, trouble with coordination, and dizziness. Clonazepam is a controlled substance in the US.
Levetiracetam
Standard dosage
Contraindications Main drug interactions Main side effects
Levetiracetam for myoclonus is typically started at a dose of 250 mg twice daily. It can be gradually increased up to a maximum dose of 1500 mg twice daily. None. Concomitant use of levetiracetam and carbamazepine can increase the risk of carbamazepine toxicity. Behavior changes, irritability, fatigue, loss of appetite, dizziness, headache.
Nonpharmacologic treatment of motor symptoms &
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Like the other atypical parkinsonisms, patients with CBS and CBD do not respond to current deep brain stimulation (DBS) surgeries/targets. Published reports of CBS patients receiving DBS are rare [26], but unpublished reports, consensus, and the fact that levodopa-resistant symptoms do not respond to DBS targets all indicate that DBS should not be used in patients with CBS. Rare reports suggest that select CBS patients may benefit from physical therapy [23, 27, Class IV], with ongoing benefit for 10 years described in one patient with CBS/PSPS features receiving hour-long
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physical therapy sessions twice weekly [28, Class IV]. While extensive research evidence is lacking, physical, occupational, and speech therapies are important components of a well-rounded approach to CBD patients. Early in the disease course, therapy may help improve or maintain mobility and is important for assessing the need for assistance devices (eg, walkers) to improve gait and potentially decrease fall risk. Later in the disease course, involvement of therapists is critical for home safety assessments and appropriate wheelchair provision (eg, to prevent pressure ulcers) and to instruct caregivers on range of motion exercises.
Pharmacologic treatment of cognitive symptoms &
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Acetylcholinesterase inhibitors (AChEIs) are sometimes tried in CBS and CBD patients based on anecdotal experience [23, Class IV]. The potentially beneficial role of AChEIs in CBS has biological plausibility given recent evidence of a cholinergic deficit in CBS as measured by [11C] N-methylpiperdn-4-yl acetate PET [29]. AChEIs, particularly galantamine, have some efficacy in PD and Dementia with Lewy Bodies (DLB) [30]. However, a study of donepezil in FTD patients described worsening in four of twelve patients treated with the AChEI [31]. In addition, a recent study of discontinuation of donepezil in patients with FTD showed improvements in behavioral symptoms and caregiver burden when the medication was stopped [32]. A small trial of patients with behavioral variant FTD and PPA found no benefit of galantamine for the patients with behavioral variant FTD but there was a trend towards efficacy in the aphasia subgroup [33]. Follow-up studies have not been performed. It seems likely that the response to AChEIs in phenotypes associated with CBD relates to the underlying pathology; this would explain why some patients respond to these medications and others do not. It is unknown whether patients with CBD pathology respond to AChEI therapy. Given the current uncertainty in correctly identifying the pathologic diagnosis in patients presenting with CBS and other phenotypes associated with CBD, it may be reasonable to try AChEIs given that patients with certain underlying pathologies like AD may experience some improvement. The role of memantine in CBS and CBD is unstudied and undefined. In an evidence-based review of treatment of cognition in PD, memantine is still considered investigational in this context [30]. Multiple studies of memantine in patients with FTD—including randomized controlled trials—showed no benefit [34–37]. While this does not preclude a possible benefit in patients with CBS/CBD, it suggests those patients with an FTD-like presentation, such as those presenting with the FBS phenotype, may be unlikely to respond. Because AD is the underlying pathology for some patients presenting with CBS, it is possible that this subset might benefit from memantine (ie, those patients with AD rather than CBD pathology). Additionally, pilot studies suggest that there may be a role for
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memantine in treating primary progressive aphasia [36, 38], but more research is needed. Psychostimulants are used in some reports of CBS and CBD treatment [23, Class IV], but there is no consensus on their clinical utility and some clinics have observed no benefit when attempting their use.
Rivastigmine Standard dosage
The starting capsule dose is 1.5 mg twice daily. After at least 2 weeks, the dose can be increased to 3 mg twice daily if tolerated. The maximum dosage is 6 mg twice daily. With the transdermal system, treatment is started with the 4.6 mg per 24 hours patch. If this is well tolerated, it can be increased to 9 mg per 24 hours after at least 4 weeks.
Contraindications
The only contraindication to transdermal use is a history of application site reactions with the drug. AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Rivastigmine can increase the risk of extrapyramidal effects when used in combination with metoclopramide, but metoclopramide should not be used in patients with parkinsonism regardless given potential worsening of symptoms. Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect).
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, and loss of appetite. These particularly occur during titration. Falls are described as a common side effect. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Donepezil is started at a dose of 5 mg nightly and can be increased to 10 mg nightly after 4 weeks.
Contraindications
AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect).
Donepezil
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, and loss of appetite. Insomnia and muscle cramps are also described. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Galantamine is started at a dose of 4 mg twice daily and can be increased to 8 mg twice daily after 4 weeks. The maximum dose is 12 mg twice daily, which can be considered after at least 4 weeks on the 8 mg twice daily dose. Extended release capsules are started at the dose of 8 mg/day and can be increased to 16 mg/day and then 24 mg/day after at least 4 weeks at each dose.
Galantamine
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Contraindications
AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect). Numerous drugs including certain antidepressants may increase the plasma concentration of galantamine.
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, loss of appetite, and weight loss. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Memantine is started at a dose of 5 mg daily and can be increased by 5 mg each week to a maximum dose of 10 mg BID.
Memantine
Contraindications
None identified.
Main drug interactions
Concurrent use of memantine and nicotine can result in altered plasma levels of both. Use of carbonic anhydrase inhibitors can reduce the clearance of memantine.
Main side effects
Memantine is generally well-tolerated. Confusion, dizziness, and headache are described.
Pharmacologic treatment of behavioral symptoms &
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Clinical experience suggests depression in CBS can be treated with selective serotonin reuptake inhibitors (SSRIs) [23, Class IV]; a case report of severe depression in CBS described beneficial treatment with sertraline [39]. Cognitive behavioral therapy may also be useful [23, Class IV]. Attempts to treat apathy include AChEIs and psychostimulants [23, Class IV], but apathy is difficult to treat effectively. SSRIs can sometimes worsen apathy and this should be monitored when relevant. Anxiety and obsessive-compulsive features are treated with SSRIs [23, Class IV]. Atypical neuroleptics or mood-stabilizing agents are tried for problematic and inappropriate behavior [23, Class IV], though caution is needed when using neuroleptics in patients with parkinsonism. There are also reports of SSRIs helping behavioral symptoms in patients with FTD [40–44], though one small report suggested that paroxetine was unhelpful and might even have caused cognitive worsening [45]. Trazodone was helpful for behavioral symptoms in FTD patients [46], but this study had a small sample size and methodologic limitations making its practice implications unclear [47].
Sertraline Standard dosage
Sertraline is started at a dose of 25–50 mg daily for depression and/or obsessive-compulsive disorder and can be increased by 25–50 mg/day each week to a maximum of 200 mg/day.
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Co-administration with monoamine oxidase inhibitors (MAOIs), particularly MAO-A inhibitors, increases the risk of a serotonin syndrome, which can be fatal. Co-administration with linezolid, pimozide, or disulfiram is contraindicated.
Main drug interactions
See contraindications above. Other drugs with good evidence for an interaction include moclobemide, iproniazid, procarbazine, isocarboxazid, toloxatone, selegeline, and others.
Main side effects
Diarrhea, nausea, constipation, indigestion, headache, somnolence, fatigue, insomnia, tremor, dizziness, agitation, sexual dysfunction.
Special points
When initiating antidepressants in general, patients should be monitored for clinical worsening, behavior changes, and suicidality. Sertraline should be tapered gradually if discontinuation is planned. Withdrawal reactions can include emotional lability, irritability, nervousness, agitation, dizziness, and headache.
Standard dosage
Paroxetine is started at a dose of 20 mg daily for a typical dose of 20–40 mg/ day, with a single dose in the morning.
Contraindications
Paroxetine should not be used in combination with an MAOIs (including linezolid), pimozide, or thioridazine. Caution should be used with triptans and select other drugs.
Main drug interactions
Risk of a serotonin syndrome in combination with other SSRIs or SNRIs. Paroxetine is metabolized by cytochrome CYP2D6 and can interact with other medications metabolized by this system. Caution should be used with triptans. Concomitant use with NSAID or anticoagulants may increase bleeding risk.
Paroxetine
Main side effects
Special points
Asthenia, loss of appetite, nausea, diarrhea, constipation, insomnia, somnolence, headache, dizziness, dry mouth, sweating, sexual dysfunction. When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Paroxetine has a high risk of a withdrawal reaction and should be tapered gradually if discontinuation is planned.
Fluvoxamine
Standard dosage Contraindications Main drug interactions
Main side effects
Fluvoxamine is started at 50 mg daily with a therapeutic range of 100– 300 mg/day (divided into BID dosing if 9100 mg/day). Co-administration of MAOIs (including linezolid), tizanidine, thioridazine, alosetron, pimozide, or ramelteon. See contraindications. Fluvoxamine inhibits several cytochrome P450 isoenzymes and thus can interact with other drugs metabolized via these enzymes (eg, warfarin and others). Caution should be used with triptans. Asthenia, nausea, somnolence or insomnia, dizziness, nervousness, anxiety, diarrhea, indigestion, dry mouth, tremor, sweating, sexual dysfunction. Sexual side effects may be less pronounced than with other SSRIs.
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Page 9 of 12, 282 When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Risk of discontinuation syndrome.
Citalopram
Standard dosage Contraindications
Citalopram is started at 20 mg daily; may increase to maximum dose of 40 mg daily after 1 week. Co-administration of MAOIs (including linezolid) and pimozide.
Main drug interactions
See contraindications. In addition, citalopram causes dose-dependent QT prolongation (particularly doses 940 mg/day) and ECG monitoring is recommended when co-administering drugs that may also prolong the QT interval. Caution should be used with triptans. Concomitant use with NSAID or anticoagulants may increase bleeding risk.
Main side effects
Side effects are less common compared with other SSRIs. Nausea, dry mouth, constipation, diarrhea, dizziness, headache, somnolence, tremor, increased sweating, and sexual dysfunction can occur.
Special points
When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Risk of discontinuation syndrome.
Standard dosage
Trazodone is started at a dose of 25 to 50 mg BID-TID (up to 150 mg total per day as a starting dose). This can be increased by 50 mg/day every 3– 4 days to a maximum dose of 400 mg daily.
Trazodone
Contraindications
Co-administration of MAOIs (including linezolid, theoretical risk) and saquinavir/ritonavir.
Main drug interactions
See contraindications. Trazodone is metabolized by the CYP3A4 system and thus levels may be altered by drugs affecting this enzyme system. Caution should be used with triptans. Caution should also be used with other medications that have the potential to cause QT prolongation.
Main side effects
Nausea, dry mouth, headache, dizziness, somnolence, fatigue, constipation, diarrhea, nervousness, dream disorders, blurry vision, hypotension.
Special points
Risk of discontinuation syndrome. Trazodone can be prescribed in lower doses at night for insomnia. The sedating side effects of trazodone can be beneficial in agitated or restless patients.
Other: supportive care, caregiver support, and palliative care &
Clinicians should make sure that all treatable symptoms are addressed, such as constipation. They should also assess in-home needs, such as hospital beds, commodes, wheelchairs, etc. For CBD patients with hand dystonia, clinicians must assess for wounds on the palms resulting from clenched fists. For CBD patients who are unable to ambulate, assessing for bed sores and pressure ulcers are an important part of care by both the neurologist and primary care physician. It is critical to not be fatalistic in the care of CBD patients but rather make sure all care is opti-
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mized for both symptomatic and supportive management. Symptoms of dysphagia should be assessed regularly as this can contribute to morbidity and mortality [16]. Patients with dysphagia should be referred for swallowing evaluations. Early dysphagia may be treatable with therapy recommendations and/or changes in food consistency. As the disease progresses, clinicians should discuss with patients and caregivers about wishes regarding PEG tube placement. The decision regarding whether or not to pursue PEG is a complex one and the full discussion is outside the scope of this article. In addition to physical and occupational therapy as discussed above, patients with language dysfunction may benefit from speech therapy [48, 49]. Caregivers play a critical role in assisting patients with CBD regardless of clinical phenotype. As with other degenerative diseases and dementia, providing adequate education, support, and resources for caregivers and families is one of the most important interventions physicians and clinics provide. Caregiver burden should be routinely assessed at clinic visits and there should be a low threshold for social work referrals to assist with long term planning, in-home services, home safety assessments, etc. Because CBD is a relentlessly progressive condition without cure and with limited therapeutic options, palliative care services are an important consideration when managing patients with CBD.
Compliance with Ethics Guidelines Conflict of Interest Melissa J. Armstrong receives some salary support from Abbvie (as a local PI for the LCIG study), has served on an advisory board for Eli Lilly and Company, has served as a consultant for the American Academy of Neurology, and has had travel expenses covered by the Movement Disorders Society. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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2.••
Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496–503. This article describes the clinical features and phenotypes of
Curr Treat Options Neurol (2014) 16:282 over 200 patients with pathologically-confirmed CBD and proposes new clinical research diagnostic criteria reflecting the identified phenotypes. While the criteria will require validation and revision, they are the first to incorporate CBD phenotypes other than just CBS 3. Bhatia KP, Lee MS, Rinne JO, et al. Corticobasal degeneration look-alikes. Adv Neurol. 2000;82:169–82. 4. Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology. 1999;53(4):795–800. 5. Josephs KA, Petersen RC, Knopman DS, et al. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology. 2006;66(1):41–8. 6. Ling H, O'Sullivan SS, Holton JL, et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain. 2010;133(Pt 7):2045–57. 7. Litvan I, Agid Y, Goetz C, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology. 1997;48(1):119–25. 8. Hu WT, Rippon GW, Boeve BF, et al. Alzheimer's disease and corticobasal degeneration presenting as corticobasal syndrome. Mov Disord. 2009;24(9):1375–9. 9. Shelley BP, Hodges JR, Kipps CM. Is the pathology of corticobasal syndrome predictable in life? Mov Disord. 2009;24(11):1593–9. 10. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain. 2002;125(Pt 4):861–70. 11. Whitwell JL, Jack Jr CR, Boeve BF, et al. Imaging correlates of pathology in corticobasal syndrome. Neurology. 2010;75(21):1879–87. 12.• Lee SE, Rabinovici GD, Mayo MC, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol. 2011;70(2):327–40. This clinicopathological study describes clinical syndromes and imaging findings of patients with pathologically-proven CBD and also atrophy patterns of patients presenting with CBS. This is one of two recent imaging studies of patients with these conditions 13. Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology. 2007;68(16):1274–83. 14. Grimes DA, Lang AE, Bergeron CB. Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology. 1999;53(9):1969–74. 15. Boeve B. Corticobasal degeneration: the syndrome and the disease. In: Litvan I, editor. Atypical Parkinsonian Disorders: Clinial and Research Aspects. New Jersey: Humana Press; 2005. p. 309–34. 16. Wenning GK, Litvan I, Jankovic J, et al. Natural history and survival of 14 patients with
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Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Amer J Geriatr Psychiatry. 2007;15(1):84–7. Kimura T, Takamatsu J. Pilot study of pharmacological treatment for frontotemporal dementia: risk of donepezil treatment for behavioral and psychological symptoms. Geriatr Gerontol Int. 2013;13(2):506–7. Kertesz A, Morlog D, Light M, et al. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord. 2008;25(2):178–85. Diehl-Schmid J, Förstl H, Perneczky R, et al. A 6month, open-label study of memantine in patients with frontotemporal dementia. Int J Geriatr Psychiatry. 2008;23(7):754–9. Vercelletto M, Boutoleau-Bretonnière C, Volteau C, et al. Memantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis. 2011;23(4):749–59. Boxer AL, Lipton AM, Womack K, et al. An open-label study of memantine treatment in 3 types of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord. 2009;23(3):211–7. Boxer AL, Knopman DS, Kaufer DI, et al. Memantine in patients with frontotemporal lobar degeneration: a multi-centreer, randomized, double-blind, placebocontrolled trial. Lancet Neurol. 2013;12(2):149–56. Johnson NA, Rademaker A, Weintraub S, et al. Pilot trial of memantine in primary progressive aphasia. Alzheimer Dis Assoc Disord. 2010;24(3):308. Hargrave R, Rafal R. Depression in corticobasal degeneration. Psychosomatics. 1998;39(5):481–2. Mendez MF. Frontotemporal dementia: therapeutic interventions. Front Neurol Neurosci. 2009;24:168–78.
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MOVEMENT DISORDERS (O SUCHOWERSKY, SECTION EDITOR)
Diagnosis and Treatment of Corticobasal Degeneration Melissa J. Armstrong, MD, MSc Address Division of Movement Disorders, Department of Neurology, University of Maryland School of Medicine, 110 S. Paca Street, 3rd Floor, Baltimore, MD 21201, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Movement Disorders Keywords Corticobasal degeneration (CBD) I Corticobasal syndrome (CBS) I Tauopathy I Neurodegenerative disease I Atypical parkinsonism I Diagnostic criteria I Treatment I Motor symptoms I Behavioral symptoms I Cognitive symptoms
Opinion statement Corticobasal degeneration is a pathologic entity. Presenting clinical phenotypes include corticobasal syndrome (CBS), frontal behavioral spatial syndrome, aphasia, progressive supranuclear palsy-like syndrome (PSPS), and a predominantly cognitive phenotype often mistaken for Alzheimer’s disease (AD). Treatment of CBD is symptomatic, particularly given recently negative neuroprotective studies. Given the relentless progression in CBD, all interested patients should be offered the opportunity to enroll in clinical neuroprotective trials as they arise. For symptomatic therapy, treatment options are necessarily based on evidence from other disorders given the lack of studies in CBD. In patients with CBS and PSPS, parkinsonism is treated with levodopa/carbidopa. This generally has modest and transient benefits at best and often results in no improvement. Botulinum toxin injections are the treatment of choice for limb dystonia. Clonazepam and levetiracetam are commonly used for myoclonus. Physical therapy is an important part of motor treatment, particularly for fall prevention strategies and assist device assessment. Whether medications such as cholinesterase inhibitors or memantine have any role in CBD is unclear given the various responses described in related phenotypes and diseases. Treating the behavioral symptoms associated with CBD is critical in an attempt to treat symptoms for which we have good pharmacologic interventions and to hopefully improve quality of life. General supportive care is important, including assessing for sores related to dystonia or immobility, monitoring dysphagia, and identifying needs for support services. Finally, as with other relentlessly progressive neurodegenerative diseases, it is critical to provide family and caregiver support and to assess for when palliative care services will serve the patient best.
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Introduction CBD is a pathologic disorder [1] resulting from abnormal aggregation of hyperphosphorylated tau isoforms with four conserved repeat sequences (4R tau). Prior to 2013, CBD diagnostic criteria all reflected only one presenting phenotype, corticobasal syndrome (CBS), once thought pathognomonic for CBD. CBS is a motor presentation with asymmetric parkinsonism, dystonia, and myoclonus accompanied by higher cortical features including apraxia, alien limb phenomena, cortical sensory loss, and cognitive changes. It is now recognized that CBS is only one presenting phenotype of CBD, reflected in updated clinical research diagnostic criteria for CBD (cr-CBD) published in 2013 [2••]. The new criteria attempt to characterize the multiple phenotypes of CBD to facilitate in-life recognition of this pathologic diagnosis. This is in contrast to diagnosing CBS, which is a clinical syndrome with multiple underlying pathologies including CBD but also progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), and frontotemporal lobar degeneration (FTLD) [3–10]. Phenotypes included in the new criteria include CBS, frontal behavioral spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). A dementing phenotype often misdiagnosed as AD is also a common presentation of CBD, but was not included in the new criteria given that this picture is much more likely to represent AD than CBD simply given the large difference in prevalence [2••]. These new criteria, while better reflecting our current understanding of CBD, are not without limitations. They remain unvalidated and will likely result in false-positive diagnoses given each phenotype’s association with multiple underlying pathologies. They will need refinement, particularly as research identifies clinical clues that predict underlying pathology or relevant biomarkers. There is no currently established role for ancillary testing in diagnosing CBD. Imaging may be useful to in-
vestigate other causes of presenting symptoms, such as signs of prion disease on magnetic resonance imaging (MRI) in patients with CBS and rapidly progressing dementia or amyloid imaging to suggest underlying AD. Voxel based morphometry (VBM) analysis of MRI atrophy patterns may be predictive of underlying pathology in CBS patients [11, 12•], but these findings cannot yet be applied to routine clinical diagnosis. In a disease correctly predicted antemortem in only 25 %–56 % of cases [4, 6, 7, 10, 13–15], how, then, do we discuss treatment options? Treatment in CBD focuses on two approaches: (1) research studies targeting the underlying tauopathy, and (2) symptomatic management. Recent pilot studies of tau-based therapies for patients with CBS and PSPS, however, have been discouraging. A pilot trial of lithium (NCT00703677) enrolled only 17 patients and most subjects did not tolerate the study drug. A pilot study of davunetide (NCT01056965) in patients with CBS, PSPS, progressive non-fluent aphasia, and frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 was recently halted because of a reported lack of benefit. CBD is a relentlessly progressive neurodegeneration with a mean disease duration of 6.6 years (SD 2.4, range 2.0–12.5) [13, 16]. Because of this, interested patients should be referred for participation in disease-modifying clinical trials when available. The mainstays of clinical treatment are symptomatic and supportive therapies. In this context, the underlying pathology is less important than the symptoms and the clinical phenotype becomes as important as pathology. Most treatments used to treat the symptoms in CBD and its associated phenotypes—particularly CBS—are largely based on Class IV evidence of case series, case reports, expert opinion, and anecdotal descriptions. Data regarding treatment of other phenotypes such as naPPA and FBS (which has some overlap with FTD presentations) are also scarce.
Treatment Pharmacologic treatment of motor symptoms &
Motor symptoms of CBD and CBS consist of parkinsonism, limb dystonia, and myoclonus. These symptoms are managed symptomatically using pharmacologic treatments developed for other disor-
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ders such as Parkinson’s disease (PD). The aim of these treatments is to reduce disability where possible and to decrease associated symptoms such as pain, particularly in the context of dystonia. The parkinsonism in CBD/CBS is treated with levodopa, typically with minimal response. Transient mild to moderate benefits are described, however [6, 16–18, all Class IV]. Dyskinesias may rarely occur even in pathologically-confirmed CBD patients [6, 19]. Other treatments for parkinsonism such as other dopaminergic therapies, benzodiazepines and anticholinergics, are usually unhelpful [17, Class IV] and may be associated with side effects such as worsened cognition. Dystonia is most successfully treated with targeted botulinum toxin injections [17, 20–22, all Class IV]. Botulinum toxin injections for dystonia in CBS can be used to reduce pain, improve hygeiene, prevent secondary contractures, and on occasion, improve limb function early in the disease course. Oral agents such as benzodiazepines, anticholinergic agents, or muscle relaxants are sometimes tried [17, 21, all Class IV], but these are rarely effective. Botulinum toxin injections are the mainstay of care. Myoclonus is typically most responsive to benzodiazepines, particularly clonazepam [17, 18, 23, all Class IV]. Levetiracetam may also be beneficial [24, 25, both Class IV]. Use of other agents such as gabapentin and valproic acid is described [23, Class IV].
Levodopa/carbidopa (immediate release) Standard dosage
Contraindications Main drug interactions Main side effects
Levodopa/carbidopa is given in the 100/25 mg immediate release formulation and can be started at a half tablet 3 times daily, increasing to a starting dose of one tablet 3 times daily. Ideal administration is 30– 60 minutes prior to meals. For patients with an inadequate response, the dose should be gradually increased to 1000 mg daily (total), the necessary dose for an adequate trial. Some patients only respond to higher doses of levodopa. If there is no benefit on a total dose of 1000 mg or more daily, the medication can be gradually weaned. Discontinuation should be gradual as the dose reduction can reveal an unrecognized modest benefit. There are no common contraindications to levodopa/carbidopa use. None. Levodopa/carbidopa is generally well tolerated. The most common side effects include nausea (which can be addressed by taking the medication with food), orthostatic hypotension, confusion, and hallucinations. Dyskinesias are rarely reported even in CBD (as described above).
Botulinum toxin injections Standard dosage
Botulinum toxin A: 100–400 Units; botulinum toxin B: 5000– 25,000 Units. There is no evidence to support using one formulation of botulinum toxin over another. Dose is variable and determined by clinical response.
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None, though caution should be used if injecting patients for cervical dystonia in the context of dysphagia. Dystonia in CBS and CBD more commonly affects the limbs than the neck.
Complications
Botulinum toxin may cause temporary excessive weakness, but this is rarely a major problem when treating limb dystonia in CBS because in most individuals with CBS, the limb is already functionless and the injections are targeting pain and improved hygiene.
Standard dosage
Clonazepam is generally started at a low dose such as 0.25 mg daily given the risks of sedation. It can be gradually increased to doses of 0.5–1.0 mg three times per day when being used to treat myoclonus. The maximum dose of 2.0 mg three times per day is rarely used.
Contraindications
Clonazepam should be used with caution with other sedative-hypnotic agents. Other listed contraindications include acute narrow angle glaucoma and significant liver disease.
Clonazepam
Main drug interactions Main side effects Special points
Clonazepam should be used with caution with other sedative-hypnotic agents. Adverse effects include drowsiness, behavior changes, imbalance, trouble with coordination, and dizziness. Clonazepam is a controlled substance in the US.
Levetiracetam
Standard dosage
Contraindications Main drug interactions Main side effects
Levetiracetam for myoclonus is typically started at a dose of 250 mg twice daily. It can be gradually increased up to a maximum dose of 1500 mg twice daily. None. Concomitant use of levetiracetam and carbamazepine can increase the risk of carbamazepine toxicity. Behavior changes, irritability, fatigue, loss of appetite, dizziness, headache.
Nonpharmacologic treatment of motor symptoms &
&
Like the other atypical parkinsonisms, patients with CBS and CBD do not respond to current deep brain stimulation (DBS) surgeries/targets. Published reports of CBS patients receiving DBS are rare [26], but unpublished reports, consensus, and the fact that levodopa-resistant symptoms do not respond to DBS targets all indicate that DBS should not be used in patients with CBS. Rare reports suggest that select CBS patients may benefit from physical therapy [23, 27, Class IV], with ongoing benefit for 10 years described in one patient with CBS/PSPS features receiving hour-long
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physical therapy sessions twice weekly [28, Class IV]. While extensive research evidence is lacking, physical, occupational, and speech therapies are important components of a well-rounded approach to CBD patients. Early in the disease course, therapy may help improve or maintain mobility and is important for assessing the need for assistance devices (eg, walkers) to improve gait and potentially decrease fall risk. Later in the disease course, involvement of therapists is critical for home safety assessments and appropriate wheelchair provision (eg, to prevent pressure ulcers) and to instruct caregivers on range of motion exercises.
Pharmacologic treatment of cognitive symptoms &
&
Acetylcholinesterase inhibitors (AChEIs) are sometimes tried in CBS and CBD patients based on anecdotal experience [23, Class IV]. The potentially beneficial role of AChEIs in CBS has biological plausibility given recent evidence of a cholinergic deficit in CBS as measured by [11C] N-methylpiperdn-4-yl acetate PET [29]. AChEIs, particularly galantamine, have some efficacy in PD and Dementia with Lewy Bodies (DLB) [30]. However, a study of donepezil in FTD patients described worsening in four of twelve patients treated with the AChEI [31]. In addition, a recent study of discontinuation of donepezil in patients with FTD showed improvements in behavioral symptoms and caregiver burden when the medication was stopped [32]. A small trial of patients with behavioral variant FTD and PPA found no benefit of galantamine for the patients with behavioral variant FTD but there was a trend towards efficacy in the aphasia subgroup [33]. Follow-up studies have not been performed. It seems likely that the response to AChEIs in phenotypes associated with CBD relates to the underlying pathology; this would explain why some patients respond to these medications and others do not. It is unknown whether patients with CBD pathology respond to AChEI therapy. Given the current uncertainty in correctly identifying the pathologic diagnosis in patients presenting with CBS and other phenotypes associated with CBD, it may be reasonable to try AChEIs given that patients with certain underlying pathologies like AD may experience some improvement. The role of memantine in CBS and CBD is unstudied and undefined. In an evidence-based review of treatment of cognition in PD, memantine is still considered investigational in this context [30]. Multiple studies of memantine in patients with FTD—including randomized controlled trials—showed no benefit [34–37]. While this does not preclude a possible benefit in patients with CBS/CBD, it suggests those patients with an FTD-like presentation, such as those presenting with the FBS phenotype, may be unlikely to respond. Because AD is the underlying pathology for some patients presenting with CBS, it is possible that this subset might benefit from memantine (ie, those patients with AD rather than CBD pathology). Additionally, pilot studies suggest that there may be a role for
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memantine in treating primary progressive aphasia [36, 38], but more research is needed. Psychostimulants are used in some reports of CBS and CBD treatment [23, Class IV], but there is no consensus on their clinical utility and some clinics have observed no benefit when attempting their use.
Rivastigmine Standard dosage
The starting capsule dose is 1.5 mg twice daily. After at least 2 weeks, the dose can be increased to 3 mg twice daily if tolerated. The maximum dosage is 6 mg twice daily. With the transdermal system, treatment is started with the 4.6 mg per 24 hours patch. If this is well tolerated, it can be increased to 9 mg per 24 hours after at least 4 weeks.
Contraindications
The only contraindication to transdermal use is a history of application site reactions with the drug. AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Rivastigmine can increase the risk of extrapyramidal effects when used in combination with metoclopramide, but metoclopramide should not be used in patients with parkinsonism regardless given potential worsening of symptoms. Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect).
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, and loss of appetite. These particularly occur during titration. Falls are described as a common side effect. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Donepezil is started at a dose of 5 mg nightly and can be increased to 10 mg nightly after 4 weeks.
Contraindications
AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect).
Donepezil
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, and loss of appetite. Insomnia and muscle cramps are also described. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Galantamine is started at a dose of 4 mg twice daily and can be increased to 8 mg twice daily after 4 weeks. The maximum dose is 12 mg twice daily, which can be considered after at least 4 weeks on the 8 mg twice daily dose. Extended release capsules are started at the dose of 8 mg/day and can be increased to 16 mg/day and then 24 mg/day after at least 4 weeks at each dose.
Galantamine
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Contraindications
AChEIs should be used with caution in patients with bradycardia, AV block, and sick sinus syndrome and are often avoided in these populations.
Main drug interactions
Because of their mechanism of action, AChEIs can interact with anticholinergic drugs (antagonistic effect) and cholinergic agents (synergistic effect). Numerous drugs including certain antidepressants may increase the plasma concentration of galantamine.
Main side effects
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, loss of appetite, and weight loss. Cardiac dysrhythmias are a serious side effect.
Standard dosage
Memantine is started at a dose of 5 mg daily and can be increased by 5 mg each week to a maximum dose of 10 mg BID.
Memantine
Contraindications
None identified.
Main drug interactions
Concurrent use of memantine and nicotine can result in altered plasma levels of both. Use of carbonic anhydrase inhibitors can reduce the clearance of memantine.
Main side effects
Memantine is generally well-tolerated. Confusion, dizziness, and headache are described.
Pharmacologic treatment of behavioral symptoms &
& & &
Clinical experience suggests depression in CBS can be treated with selective serotonin reuptake inhibitors (SSRIs) [23, Class IV]; a case report of severe depression in CBS described beneficial treatment with sertraline [39]. Cognitive behavioral therapy may also be useful [23, Class IV]. Attempts to treat apathy include AChEIs and psychostimulants [23, Class IV], but apathy is difficult to treat effectively. SSRIs can sometimes worsen apathy and this should be monitored when relevant. Anxiety and obsessive-compulsive features are treated with SSRIs [23, Class IV]. Atypical neuroleptics or mood-stabilizing agents are tried for problematic and inappropriate behavior [23, Class IV], though caution is needed when using neuroleptics in patients with parkinsonism. There are also reports of SSRIs helping behavioral symptoms in patients with FTD [40–44], though one small report suggested that paroxetine was unhelpful and might even have caused cognitive worsening [45]. Trazodone was helpful for behavioral symptoms in FTD patients [46], but this study had a small sample size and methodologic limitations making its practice implications unclear [47].
Sertraline Standard dosage
Sertraline is started at a dose of 25–50 mg daily for depression and/or obsessive-compulsive disorder and can be increased by 25–50 mg/day each week to a maximum of 200 mg/day.
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Co-administration with monoamine oxidase inhibitors (MAOIs), particularly MAO-A inhibitors, increases the risk of a serotonin syndrome, which can be fatal. Co-administration with linezolid, pimozide, or disulfiram is contraindicated.
Main drug interactions
See contraindications above. Other drugs with good evidence for an interaction include moclobemide, iproniazid, procarbazine, isocarboxazid, toloxatone, selegeline, and others.
Main side effects
Diarrhea, nausea, constipation, indigestion, headache, somnolence, fatigue, insomnia, tremor, dizziness, agitation, sexual dysfunction.
Special points
When initiating antidepressants in general, patients should be monitored for clinical worsening, behavior changes, and suicidality. Sertraline should be tapered gradually if discontinuation is planned. Withdrawal reactions can include emotional lability, irritability, nervousness, agitation, dizziness, and headache.
Standard dosage
Paroxetine is started at a dose of 20 mg daily for a typical dose of 20–40 mg/ day, with a single dose in the morning.
Contraindications
Paroxetine should not be used in combination with an MAOIs (including linezolid), pimozide, or thioridazine. Caution should be used with triptans and select other drugs.
Main drug interactions
Risk of a serotonin syndrome in combination with other SSRIs or SNRIs. Paroxetine is metabolized by cytochrome CYP2D6 and can interact with other medications metabolized by this system. Caution should be used with triptans. Concomitant use with NSAID or anticoagulants may increase bleeding risk.
Paroxetine
Main side effects
Special points
Asthenia, loss of appetite, nausea, diarrhea, constipation, insomnia, somnolence, headache, dizziness, dry mouth, sweating, sexual dysfunction. When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Paroxetine has a high risk of a withdrawal reaction and should be tapered gradually if discontinuation is planned.
Fluvoxamine
Standard dosage Contraindications Main drug interactions
Main side effects
Fluvoxamine is started at 50 mg daily with a therapeutic range of 100– 300 mg/day (divided into BID dosing if 9100 mg/day). Co-administration of MAOIs (including linezolid), tizanidine, thioridazine, alosetron, pimozide, or ramelteon. See contraindications. Fluvoxamine inhibits several cytochrome P450 isoenzymes and thus can interact with other drugs metabolized via these enzymes (eg, warfarin and others). Caution should be used with triptans. Asthenia, nausea, somnolence or insomnia, dizziness, nervousness, anxiety, diarrhea, indigestion, dry mouth, tremor, sweating, sexual dysfunction. Sexual side effects may be less pronounced than with other SSRIs.
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Page 9 of 12, 282 When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Risk of discontinuation syndrome.
Citalopram
Standard dosage Contraindications
Citalopram is started at 20 mg daily; may increase to maximum dose of 40 mg daily after 1 week. Co-administration of MAOIs (including linezolid) and pimozide.
Main drug interactions
See contraindications. In addition, citalopram causes dose-dependent QT prolongation (particularly doses 940 mg/day) and ECG monitoring is recommended when co-administering drugs that may also prolong the QT interval. Caution should be used with triptans. Concomitant use with NSAID or anticoagulants may increase bleeding risk.
Main side effects
Side effects are less common compared with other SSRIs. Nausea, dry mouth, constipation, diarrhea, dizziness, headache, somnolence, tremor, increased sweating, and sexual dysfunction can occur.
Special points
When initiating SSRIs, patients should be monitored for clinical worsening, behavior changes, and suicidality. Risk of discontinuation syndrome.
Standard dosage
Trazodone is started at a dose of 25 to 50 mg BID-TID (up to 150 mg total per day as a starting dose). This can be increased by 50 mg/day every 3– 4 days to a maximum dose of 400 mg daily.
Trazodone
Contraindications
Co-administration of MAOIs (including linezolid, theoretical risk) and saquinavir/ritonavir.
Main drug interactions
See contraindications. Trazodone is metabolized by the CYP3A4 system and thus levels may be altered by drugs affecting this enzyme system. Caution should be used with triptans. Caution should also be used with other medications that have the potential to cause QT prolongation.
Main side effects
Nausea, dry mouth, headache, dizziness, somnolence, fatigue, constipation, diarrhea, nervousness, dream disorders, blurry vision, hypotension.
Special points
Risk of discontinuation syndrome. Trazodone can be prescribed in lower doses at night for insomnia. The sedating side effects of trazodone can be beneficial in agitated or restless patients.
Other: supportive care, caregiver support, and palliative care &
Clinicians should make sure that all treatable symptoms are addressed, such as constipation. They should also assess in-home needs, such as hospital beds, commodes, wheelchairs, etc. For CBD patients with hand dystonia, clinicians must assess for wounds on the palms resulting from clenched fists. For CBD patients who are unable to ambulate, assessing for bed sores and pressure ulcers are an important part of care by both the neurologist and primary care physician. It is critical to not be fatalistic in the care of CBD patients but rather make sure all care is opti-
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mized for both symptomatic and supportive management. Symptoms of dysphagia should be assessed regularly as this can contribute to morbidity and mortality [16]. Patients with dysphagia should be referred for swallowing evaluations. Early dysphagia may be treatable with therapy recommendations and/or changes in food consistency. As the disease progresses, clinicians should discuss with patients and caregivers about wishes regarding PEG tube placement. The decision regarding whether or not to pursue PEG is a complex one and the full discussion is outside the scope of this article. In addition to physical and occupational therapy as discussed above, patients with language dysfunction may benefit from speech therapy [48, 49]. Caregivers play a critical role in assisting patients with CBD regardless of clinical phenotype. As with other degenerative diseases and dementia, providing adequate education, support, and resources for caregivers and families is one of the most important interventions physicians and clinics provide. Caregiver burden should be routinely assessed at clinic visits and there should be a low threshold for social work referrals to assist with long term planning, in-home services, home safety assessments, etc. Because CBD is a relentlessly progressive condition without cure and with limited therapeutic options, palliative care services are an important consideration when managing patients with CBD.
Compliance with Ethics Guidelines Conflict of Interest Melissa J. Armstrong receives some salary support from Abbvie (as a local PI for the LCIG study), has served on an advisory board for Eli Lilly and Company, has served as a consultant for the American Academy of Neurology, and has had travel expenses covered by the Movement Disorders Society. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Dickson DW, Bergeron C, Chin SS, et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol. 2002;61(11):935–46.
2.••
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