2 History of Present Illness 60 year old left handed maleChief complaint- difficult speaking, frequent fallsOn his first visit his wife noted that for past 2 years the patient’s language and vocabulary had sufferedHe was having trouble recalling words that he wanted to saye.g. he was formerly a mechanic and was having trouble remembering names of toolsHis short term memory had also progressively worsened during this same timeAlso for about one year prior had been falling frequently (1- 2 times per week)Difficulty swallowing and crying spells for no apparentHe was no longer paying bills or driving
3 Past medical history Social Hypertension Diabetes (A1C of 8.9%) HyperlipidemiaGERDDepressionSocialStopped smoking and drinking 20 years priorSurgeryCTS in 2011Kidney stone
4 Exam Mental status Speech Cranial Nerves Can name correct city, and year but not month or dayNaming intact.2/3 object at 5min recallComprehension intact but perseveratesSpeechFluent but with severe word finding difficultyOnly 8 objects on “D” test (12 is normal)Decreased emotion in speechCranial NervesIntactOrbicularis oculi 5/5Tongue strength is normal
5 Exam NF NE Motor Reflexes Gait Cerebellar Sensory Tone is normal Atrophy of FDIExamReflexes3+ in bilaterally UE3+ Patella0 AnkleDowngoing toesGaitWide based, slow, unable to walk heel to toeCerebellarFNF intact but sloSensoryDifficult to assess but likely intact to all modalitiesRightLeftNF5NESA4EFEEWFWEHF4+HEKFKEDFPF
6 Second Visit CT head showed moderate cortical atrophy Seen in clinic three months laterAlmost completely anomic. 1-2 words at the mostUnable to answer orientation questionsCould follow 1 step commands but nothing more complicatedConfined to a wheelchair, diffuse weaknessFurther atrophy of hands, arms, legsFasciculations seen in leg and arm musclesFurther testing was done
8 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
9 FTD-ALSEach disease is typically diagnosed separately15% of ALS patients have FTD10% of FTD patientsSlightly more common in men than womenCognitive symptoms typically occur first but motor symptoms can occur before or simultaneouslyInterval is 3 months to 7 years with mean of 2 yearsSurvival is worse in FTD-ALS patients than ALS without dementiaA proposed classification schemeALSci (cognitively impaired)ALSbi (behaviorally impaired)ALS-FTD (meet Neary Criteria)FTD-MND (patients who have motor neuron loss at autopsy but no clinical signs)ALS-dementia (Alzheimer's or vascular)M. J. Strong, G. M. Grace, M. Freedman, et al., “Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis,”Amyotrophic Lateral Sclerosis, vol. 10, no. 4, pp. 131–146, 2009.
10 Amyotrophic Lateral Sclerosis ALS used interchangeably with ‘Motor Neuron Disease’ and ‘Lou Gehrig's Disease’Diagnosed clinically with a mixture of upper motor neuron signs and lower motor neuron signsProgressive weakness that can begin in legs, arms or bulbar regionAtrophy and fasciculation (LMN)Hyperreflexia, upgoing toes, jaw jerk (UMN)EMG shows active denervation and reinnervationFirst described in 1869 by CharcotMarie in 1892 reported on behavioral changes in ALS patientsEntrenched in Neurology that body wasted and mind was sparedIn late 80s Stan Appel and Forbes Norris developed clinics devoted to ALS clinicsThis concept spread to major centers allowing Neurologists to develop large ALS patient populationsReports were generated linking ALS and dementiaCriteria for FTD were published in 1998 and ALS and FTD were linked
11 FRONTOTEMPORAL DEMENTIA SymptomsInsidious onset with slow progressionAge 50-60TypesBehavioral variant (bvFTD)Disinhibition, apathy, behavior changes (next slide)Primary Progressive AphasiaDecreased expression of language, anomiaRelative preservation of comprehensionSemantic Dementia (now considered a variant of PPA)Fluent grammatically correct speech but empty of contentLoss of executive function early is seen in all threeTypically preservation of short term memory, praxis and visualospatial skillsDiagnosed via Neary Criteria (other criteria have been suggested)
12 Table 1: Behavioral features in FTLD Disinhibited type Increased interest in sexual activity Lack of judgment Swearing Violation of personal space Impulsive buying Paranoia Criminal activity Grandiose thinking Ignoring social etiquetteApathetic type Blunted emotions Disinterested and withdrawn Lack of attention to personal hygiene Lack of empathyStereotypical type Hoarding Food fads, overeating Ritualistic/repetitive behavior
13 Testing FTD in ALS patients Can be difficult to test for language disorders due tobulbar weakness (dysarthria),hand weakness impairs writingCognitive changes can be seen in patients follows in specialty clinicsComprehension in pulmonary testingSpelling and grammatical errorsVarious studies and questionnaires have used to identify dementia in ALS patientsCANTABComputer touch screen and Neurologist opinionMemory loss 7%, FTD criteria 22%Caregiver questionnaireNPI, FBI, CBI, FrSBeApathy 56%, stereotypical behaviors 20%, executive dysfunction %, disinhibition 18-27% 11% meet criteria for FTDCANTAB- Cambridge Neuropsychological Test Automated BatteryNPI- Neuropsychiatric InventoryFBI- Frontal Behavioral InventoryCBI- Cambridge Behavioral InventoryFrSBe- Frontal Systems Behavioral ScaleMMSE- Mini mental Status Exam
14 FTD In ALS2003 study of 100 patients screened with verbal fluency and MMSE31 had abnormal fluency (“D” or animal test). 50% of bulbar onset patients had abnormal exam, 25% of limb onset patientsAll had normal MMSE2012 study of 160 patients with formal neuropsych testing14% met FTD-Neary criteria, 21% had cognitive impairment and 47% were normal2005 study of 279 patients15% with FTD, 49% normal cognition, 43% cognitive impairmentALS patients over time-52 patients every 4 months showed abnormal at onset did not show decline
15 FTD in ALS2009 AAN practice parameter acknowledged lack of consensus of screening toolALS Cognitive Behavioral Screen- has been validated15 caregiver questions8 item physician assessment5 minPenn State Screen Battery of Frontal and Temporal Dysfunction Syndrome20 minutesNot validatedUCSF Screen Battery45 minutes, includes ALS specific FBI and depression screen
16 ALS in FTD patients Studies have had varied results 2002 study of 36 FTD patients with detailed neuromuscular exam and EMG5 had definite ALS, 5 had fasciculations on EMG and 1 of these developed definite ALS 1 year later2008 retrospective study of FTDbv18 of 61 developed definite ALS
17 GeneticsVarious genetic mutations have been linked to both familial ALS and FTDFamilial cases are far outnumbered by sporadic cases in both disorders (10% of ALS and 40% of FTD)Three most important genes associated with FTD are microtubule associated protein tau (MAPT), progranulin and C9ORF72Mutations in the SOD1 gene are most common in familial ALSTwo studies in 2012 found a mutation in the C9ORF72 gene that occurred in both ALS and FTD.This was the first genetic link between the two diseasesProgranulin and C9ORF72 mutations can deposition of TAR-DNA binding protein 43 (TDP-43)TDP-43 is an ubiquinated protein that has been found to accumulate in both ALS and FTD
18 SourcesALS and Frontotemporal Dysfunction: A Review. Eugene Y. Achi and Stacy A. Rudnicki Neurology Research International Volume 2012 (2012), Article ID 806306, 9 pages doi: /2012/806306Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–268Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134(pt 9):2456Y2477M. J. Strong, G. M. Grace, M. Freedman, et al., “Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis,”Amyotrophic Lateral Sclerosis, vol. 10, no. 4, pp. 131–146, 2009.