Presentation on theme: "Clinical Phenomenology and Neuroimaging Correlates in ALS-FTD"— Presentation transcript:
1 Clinical Phenomenology and Neuroimaging Correlates in ALS-FTD Catherine Lomen-Hoerth, MD, PhDAssociate Professor of NeurologyUniversity of California, San Francisco
2 Clinical Features Upper motor neuron findings Slow speech Brisk gag and jaw jerk, brisk limb reflexesSpasticityHoffman’s or Babinski signsLower motor neuron findingsAtrophyFasciculationsweaknessALS is a clinical diagnosis with a combination of progressive upper and lower motor neuron findings (see Figure 1). Upper motor neuron findings include slow speech, brisk gag and jaw jerk, brisk reflexes, spasticity, and Hoffman’s or Babinski signs. Lower motor neuron findings include atrophy, fasciculations, and weakness. Patients may also have a pure upper motor neuron syndrome, typically termed primary lateral sclerosis (PLS) when the EMG is normal and symptoms have been present for over 3 years. A pure lower motor neuron syndrome is typically termed progressive muscular atrophy (PMA) variant of ALS. Either PLS or PMA may evolve over time to ALS and have a progression typical of ALS. At other times, PLS or PMA patients may have a more slowly progressive course.
4 Survival in FTD with co-morbid ALS Hodges et al yrs FTD vs. 2.4yrs ALS-FTDRoberson et al yrs FTD vs. 2yrs ALS-FTDHu et al patients with ALS-FTD67 months survival if FTD symptoms first28 months survival if ALS symptoms first19 months if simultaneous ALS-FTD onsetRoberson et. al. (45) have shown that patients with FTD and co-morbid ALS on average live only 2 years after diagnosis compared with FTD patients who live years after diagnosis. This is in comparison to Alzheimer’s Disease where patients may live 20 years or more after the diagnosis. Similar findings were found by Hu, et. al. (46), in a cohort of 87 patients with FTD-ALS. Even with mild disease, where ALS patients have cognitive and behavioral impairments not severe enough to qualify as a diagnosis of FTD, survival is impacted. Olney (47) showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone. He determined that this difference was likely due to compliance with treatment recommendations such as PEG and BiPAP, since these recommendations were followed only 1/3 of the time compared with 2/3 of the time with patients who were cognitively and behaviorally normal, as seen in table 4.
5 FTLD is not new in ALS Old descriptions FTLD behaviors Withdrawn due to depressionStubbornSeeking control in some area of lifeAnger outbursts due to frustration of ALSDenialLanguage problems due to dysarthriaFTLD behaviorsApatheticDis-inhibitedPoor judgementEasily frustratedQuick to angerLack of insightLanguage difficultyWord findingSpellingAphasia
6 Prevalence of Cog/Beh Impairment Among ALS Patients 22% Lomen-Hoerth et al 200345% Ringholz et al 200527% Robinson et al 200630% Rippon et al 200648% Murphy et al 200725% Rusina et al 2010As you can see, up to approximately 45% of patients demonstrate cognitive decline throughout the disease process and 15% actually meet criteria for Frontotemporal Dementia (FTD)At least half a dozen studies now show a significant percentage of pts display cognitive and behavioral changes that affect their day to day functioning. Few of these patients have what neurologists in dementia clinics would diagnose as a full blown FTD syndrome, but they do display the clinical and neuoanatomical features of a spectrum of FTD.
7 Standardized Neuropsychological measures used in peer reviewed studies of ALS dementia Frequency of useExec FunctioningLanguageMemoryIQVisuospatialUsed in > 5 studiesWCST;Digits Bkwds; Category fluency; Stroop IntFAS/COWAT;Written verbal fluency test; BNTNART/AMNART; Ravens Colored Matrices; WAIS-IIIUsed in 2-5 studiesSymbol Digit Modalities Test;VSAT;Trails A&B; Design FluencyPyramids and Palm Trees Test; Graded Naming TestKendrick Object Learning Test; Rey Aud Verbal Learning Test; CVLT-II; RMT; Logical Memory TestBenton Judgment of Line Orientation; MfVPT; Block Design; Rey figureWCST=Wisconsin Card Sort (59); Digits Backwds=Digits Backwards subtest of the Wechsler Adult Intelligence test (60); Category fluency subtest of the DKEFS (61); Stroop Interference subtest of the Dellis-Kaplan Executive Functioning Test (61); Symbol Digit Modalities Test (62); VSAT: Verbal Serial Attention Test (63); BNT=Boston Naming Test (64); FAS/COWAT=Controlled Oral Word Association Test(65); Written Verbal Fluency Test=Abrahams(35); Category Fluency=Subtest of Dellis-Kaplan Executive Functioning Test (61); WAIS=Wechsler Adult Intelligence test (60); Trails subtest of the Dellis-Kaplan Executive Functioning Test (61); VSAT=Visual; NART=National Adult Reading Test (66); AMNART=American version of the National Adult Reading Test(67); CVLT-II=California Verbal Learning Test(68); RMT=Warrington Recognition Memory Test (69); MfVPT=Motor Free Visual Perception Test (70); Rey Complex Figure Test (71); Rey Auditory Verbal Lerning Test (72); Kendrick Object Learning Test (73); Block Desing Subtest of the WAIS(60); Design Fluency=Subest of the Dellis-Kaplan Executive Functioning Test (61); Stroop Int=Stroop Interference subtest of the Dellis-Kaplan Executive Functioning Test (61); Trails A and B Subtest of the Dellis-Kaplan Executive Functioning Test (61); Logical Memory Test=Subtest of the Wechsler Memory Scale (74); Pyramids and Palmtrees(75); Graded Naming Test(76); Ravens Colored Matrices(77); Benton Judgment of Line Orientation(78)
9 Defining cognitive sub-types in ALS* Terminology Clinical CharacteristicsALS – FTDALS-bvFTDALS patient meeting either the Neary criteria or Hodge’s criteria for FTDALS-PNFAALS patient meeting Neary criteria for PNFAALS-SDALS patient meeting Neary criteria for SDALSbiALS patient meeting at least 2 non-overlapping supportive diagnostic features from either the Neary criteria or Hodge’s criteria for FTDALSciEvidence of cognitive impairment at or below the 5th percentile on at least two distinct tests of cognition that are sensitive to executive functioning*Table from Strong et al., 2009
11 Incidence of FTLD in ALS AD 4%Behavior Abnormal 17%Executive Dysfunction 9%Not normal,Not FTLD 26%FTLD 22%AD 4%FTLD 22%Normal 48%Normal 48%The 26% that is not normal but also not FTD is being redefined as Executive Dysfunction (9%), Behavior Abnormalities (17%)
12 Brief ALS Screening Exams 5-10 Minute ExamsTargeted populationStrengthsWeaknessesLengthALS-Cognitive Brhavioral Screen (ALS-CBS; Woolley et al 2010ALS-specific; Public domainSpecifically designed for ALS population; Some controls for dysarthria, motor weaknessEarly in the standardization process<10 minMontreal Cognitive Assessment (MoCA; Nasreddine et al 2005General population; Public domain for non-commercial useWell- standardized; in common use; measures frontal lobe functioningNot specifically designed to tap ALS-specific deficits; no controls for dysarthria, motor weakness10 minWritten Fluency; Abrahams et al 2000Specifically designed for ALS population; Controls for dysarthria, motor weaknessEarly stages of standardization; no behavioral component10 min
13 30 Minute ALS Screening Exams Penn State Exam; Flaherty-Craig 2009General population; CopyrightedNational norms, including measure of judgment and problem solvingNot specifically designed to tap ALS-specific deficits; no controls for dysarthria, motor weakness20-30 minAddenbrookACE-R; Mioshi et al 2006Well- standardized; in common use; measures frontal lobe functioning30 minUCSF Screening ExamALS-specific; Public domainSpecifically designed for ALS population; Controls for dysarthria, motor weakness; includes in- depth behavior interviewBehavioral measure requires staff time to interview caregiver
14 UCSF Screening Battery We also use Susan Woolley’s ALS-CBS. The cognitive portion contains a variety of exec functioning tasks making up a total of 20 points and a behavioral quesionnniare with 18 questions for the caregiver.
15 Mimics of cognitive and behavioral impairment in ALS Depression or other underlying psych disorderPseudobulbar affectHypoxia or hypercapneaEducational level/baseline intellectual functioningPresence of bulbar palsy or paralysis limiting testingAdvanced diseaseTreatable mimics of cognitive and behavioral functionIt is absolutely critical to exclude mimics of cognitive and behavioral dysfunction. Most mimics are treatable, and even reversible with therapy. For example, severe depression is uncommon in ALS, but when present, does improve with antidepressant therapy and/or counseling. Importantly, survival is impacted when depression, stress, or other measures of psychological distress are measured (48), because patients with ALS with high co-morbid psychological distress have greater mortality than those with low psychological distress. Screening with the depression screen of choice, such as the Beck Depression Inventory (49) or Geriatric Depression Scale (50) is important whenever there are concerns about cognitive and behavioral function.It is important to exclude and treat pseudobulbar affect (PBA)—easy laughing and crying—which is sometimes confused with depression but is a very different condition. Patients with PBA do not necessarily feel depressed but they do have trouble with excessive emotional expression that they are unable to control. The CNS LS is a common screen used to diagnosis this condition and is a simple series of 7 questions (51). Other, more in-depth measures of PBA also exist (49, 52, 53). The treatments most typically used include low dose amitriptyline or a serotonin reuptake inhibitor (SSRI). More recently the combination of dextromethorphan and quinidine, which will likely be approved by the FDA in late 2010, has demonstrated positive results in an ALS clinical trial (54).Many of the medications to treat symptoms of ALS can cause sedation and confusion such as the antispasticity medications of valium, baclofen, and zanaflex. Sleep aids and sedating antidepressants may have unwanted sedating after-effects the next day. Riluzole, which is the only FDA approved drug to slow disease progression in ALS, causes sleepiness and confusion in some patients, particularly older patients. It is recommend to reduce the dose of any potentially offending medication, and to consider a drug holiday for a week or two to see if improvement is noted.Retaining CO2 or having low oxygenation can dramatically affect both behavior and cognition (55). A sleep study or home nocturnal oximetry study is helpful to diagnose this problem. Typically BiPAP is recommended once the FVC falls below 50% predicted. Obtaining a sleep study before and after BiPAP can identify desaturations and prompt necessary changes in BiPAP settings. Testing maximal inspiratory force (MIF) during spirometry testing can help identify diaphragm weakness, which contributes to difficulty breathing at night when lying flat and can qualify a patient for BiPAP even when the FVC is still above 50% predicted.Fatigue is a difficult problem with ALS and can impact cognition and behavior if sleep is disrupted. Energy conservation and good sleep hygiene are common recommendations. Troubleshooting the underlying cause of fatigue is important, to identify sedating medications, over exertion in the setting of worsening weakness, breathing difficulties, etc. It is important to also exclude any pre-morbid condition affecting cognition or behavior such as a psychiatric condition, head injury, stroke, or other CNS condition.Once these mimics have been excluded and the problem still persists, further testing is warranted. Anxiety, hypochondria, and stress can impact test performance, and it is important that testing be given in a manner to minimize the impact of these problems as well as to accommodate patients with difficulty speaking or using their hands to write. Other diseases that mimic ALS can cause cognitive problems such as certain hereditary conditions like Tay Sachs disease, infectious conditions such as Creutzfeld-Jacob disease, and paraneoplastic syndromes due to cancer. Neuropsychological testing, neuroimaging and blood testing can help distinguish among these conditions.
16 Continuum of Abnormalities Chang et al, Neurology 2005
18 Grey & white matter abnormalities predict neuropsychological testing Statistical Model :Neuropsych Result = lobar GM volume + lobar WM FA + lobar WM MD
19 Does this milder form of FTLD have clinical significance? Two hypothesis:Survival is shorter in patients with ALS-FTLD than ALS aloneCompliance with treatment recommendations is significantly less in patients with ALS-FTLD than ALS aloneOlney R, Murphy J, Forshew D, Garwood E, Miller B, Langmore S, Kohn M, Lomen-Hoerth C, “The effects of executive and behavioral dysfunction on the course of ALS” Neurology 2005; 65:
20 Survival in ALS with co-morbid FTD Olney et al 2005 showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone.Since the Olney publication, subsequent authors have demonstrated similar findings with a shortened survival in ALS patients with co-morbid disease for both mildly impaired and moderately impaired patients, Gordon et al 2010Roberson et. al. (45) have shown that patients with FTD and co-morbid ALS on average live only 2 years after diagnosis compared with FTD patients who live years after diagnosis. This is in comparison to Alzheimer’s Disease where patients may live 20 years or more after the diagnosis. Similar findings were found by Hu, et. al. (46), in a cohort of 87 patients with FTD-ALS. Even with mild disease, where ALS patients have cognitive and behavioral impairments not severe enough to qualify as a diagnosis of FTD, survival is impacted. Olney (47) showed a survival difference of more than a year between patients with co-morbid disease versus ALS alone. He determined that this difference was likely due to compliance with treatment recommendations such as PEG and BiPAP, since these recommendations were followed only 1/3 of the time compared with 2/3 of the time with patients who were cognitively and behaviorally normal, as seen in table 4.
21 NPPV and PEG Compliance NPPV PEGALS-FTLD 25% 28%ALS only 62% 69%zp (one-tail) < 0.02 < 0.03
22 Important Clinical Issues for ALSci and ALSbi Reduced survival ratePoor compliance (poor use of PEG, BiPap)Caregiver distressPoor safety awareness (falls, choking)Inability to manage important decisionsImplications for stem cell therapyBecause these patients have reduced cognitve abilities and changes in their behaviour, this often leads to reduced survival rate. The majority of patients will need a PEG Tube and Bipap, but due to poor insight, they often refuse or do not comply with instructions. Stubbornness or other behavioural traits often cause the caregiver and family much distress. Patients also have poor safety awareness which often leads to choking or falls. Along with all of this is the inability to make important decision, such as planning for financial future
23 Thanks to the UCSF ALS Center Clinical TeamJennifer Coggiola-Speech PathologistMiriam Crennan-Occupational TherapistMira Kletyman-Respiratory TherapistAndrew Lui-Physical TherapistMary Owen-Nurse CoordinatorColleen Meier-Respiratory TherapistVirginia Santos-New Patient CoordinatorMadelon Thomson-Social WorkerMonica Seiber-DietitianResearch TeamClaudia Villierme-Research AssistantMitchell Luu-Medical StudentJolie Chan-Medical StudentJennifer Murphy-Neuropsychologist
24 Thanks to other key collaborators at UCSF Memory & Aging Center at UCSFBruce MillerJoel KramerKatherine RankinMarilu Gorno-TempiniHoward RosenAdam BoxerNeuroradiology at UCSFRoland HenryCynthia Chin