1. Neurology Case
Kyle Carpenter PGY III

2. History of Present Illness
60 year old left handed male
Chief complaint- difficult speaking, frequent falls
On his first visit his wife noted that for past 2 years the patient’s language and vocabulary had suffered
He was having trouble recalling words that he wanted to say
e.g. he was formerly a mechanic and was having trouble remembering names of tools
His short term memory had also progressively worsened during this same time
Also for about one year prior had been falling frequently (1- 2 times per week)
Difficulty swallowing and crying spells for no apparent
He was no longer paying bills or driving

3. Past medical history Social Hypertension Diabetes (A1C of 8.9%)
Hyperlipidemia
GERD
Depression
Social
Stopped smoking and drinking 20 years prior
Surgery
CTS in 2011
Kidney stone

4. Exam Mental status Speech Cranial Nerves
Can name correct city, and year but not month or day
Naming intact.
2/3 object at 5min recall
Comprehension intact but perseverates
Speech
Fluent but with severe word finding difficulty
Only 8 objects on “D” test (12 is normal)
Decreased emotion in speech
Cranial Nerves
Intact
Orbicularis oculi 5/5
Tongue strength is normal

5. Exam NF NE Motor Reflexes Gait Cerebellar Sensory Tone is normal
Atrophy of FDI
Exam
Reflexes
3+ in bilaterally UE
3+ Patella
0 Ankle
Downgoing toes
Gait
Wide based, slow, unable to walk heel to toe
Cerebellar
FNF intact but slo
Sensory
Difficult to assess but likely intact to all modalities
Right
Left NF 5 NE SA 4 EF EE WF WE HF 4+ HE KF KE DF PF

6. Second Visit CT head showed moderate cortical atrophy
Seen in clinic three months later
Almost completely anomic. 1-2 words at the most
Unable to answer orientation questions
Could follow 1 step commands but nothing more complicated
Confined to a wheelchair, diffuse weakness
Further atrophy of hands, arms, legs
Fasciculations seen in leg and arm muscles
Further testing was done

7. Where?
What?

8. Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

9. FTD-ALS
Each disease is typically diagnosed separately
15% of ALS patients have FTD
10% of FTD patients
Slightly more common in men than women
Cognitive symptoms typically occur first but motor symptoms can occur before or simultaneously
Interval is 3 months to 7 years with mean of 2 years
Survival is worse in FTD-ALS patients than ALS without dementia
A proposed classification scheme
ALSci (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 signs
Progressive weakness that can begin in legs, arms or bulbar region
Atrophy and fasciculation (LMN)
Hyperreflexia, upgoing toes, jaw jerk (UMN)
EMG shows active denervation and reinnervation
First described in 1869 by Charcot
Marie in 1892 reported on behavioral changes in ALS patients
Entrenched in Neurology that body wasted and mind was spared
In late 80s Stan Appel and Forbes Norris developed clinics devoted to ALS clinics
This concept spread to major centers allowing Neurologists to develop large ALS patient populations
Reports were generated linking ALS and dementia
Criteria for FTD were published in 1998 and ALS and FTD were linked

11. FRONTOTEMPORAL DEMENTIA
Symptoms
Insidious onset with slow progression
Age 50-60
Types
Behavioral variant (bvFTD)
Disinhibition, apathy, behavior changes (next slide)
Primary Progressive Aphasia
Decreased expression of language, anomia
Relative preservation of comprehension
Semantic Dementia (now considered a variant of PPA)
Fluent grammatically correct speech but empty of content
Loss of executive function early is seen in all three
Typically preservation of short term memory, praxis and visualospatial skills
Diagnosed 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 etiquette
Apathetic type
 Blunted emotions
 Disinterested and withdrawn
 Lack of attention to personal hygiene
 Lack of empathy
Stereotypical type
 Hoarding
 Food fads, overeating
 Ritualistic/repetitive behavior

13. Testing FTD in ALS patients
Can be difficult to test for language disorders due to
bulbar weakness (dysarthria),
hand weakness impairs writing
Cognitive changes can be seen in patients follows in specialty clinics
Comprehension in pulmonary testing
Spelling and grammatical errors
Various studies and questionnaires have used to identify dementia in ALS patients
CANTAB
Computer touch screen and Neurologist opinion
Memory loss 7%, FTD criteria 22%
Caregiver questionnaire
NPI, FBI, CBI, FrSBe
Apathy 56%, stereotypical behaviors 20%, executive dysfunction %, disinhibition 18-27% 11% meet criteria for FTD
CANTAB- Cambridge Neuropsychological Test Automated Battery
NPI- Neuropsychiatric Inventory
FBI- Frontal Behavioral Inventory
CBI- Cambridge Behavioral Inventory
FrSBe- Frontal Systems Behavioral Scale
MMSE- Mini mental Status Exam

14. FTD In ALS
2003 study of 100 patients screened with verbal fluency and MMSE
31 had abnormal fluency (“D” or animal test). 50% of bulbar onset patients had abnormal exam, 25% of limb onset patients
All had normal MMSE
2012 study of 160 patients with formal neuropsych testing
14% met FTD-Neary criteria, 21% had cognitive impairment and 47% were normal
2005 study of 279 patients
15% with FTD, 49% normal cognition, 43% cognitive impairment
ALS patients over time-
52 patients every 4 months showed abnormal at onset did not show decline

15. FTD in ALS
2009 AAN practice parameter acknowledged lack of consensus of screening tool
ALS Cognitive Behavioral Screen- has been validated
15 caregiver questions
8 item physician assessment
5 min
Penn State Screen Battery of Frontal and Temporal Dysfunction Syndrome
20 minutes
Not validated
UCSF Screen Battery
45 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 EMG
5 had definite ALS, 5 had fasciculations on EMG and 1 of these developed definite ALS 1 year later
2008 retrospective study of FTDbv
18 of 61 developed definite ALS

17. Genetics
Various genetic mutations have been linked to both familial ALS and FTD
Familial 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 C9ORF72
Mutations in the SOD1 gene are most common in familial ALS
Two 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 diseases
Progranulin 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. Sources
ALS and Frontotemporal Dysfunction: A Review. Eugene Y. Achi and Stacy A. Rudnicki Neurology Research International Volume 2012 (2012), Article ID 806306, 9 pages doi: /2012/806306
Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–268
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134(pt 9):2456Y2477
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.