Four steps to diagnosis of Alzheimer's disease

Medscape http://www.medscape.com/viewarticle/761284_3

Guideline	Procedures
Step 1: criteria for 'all cause dementia'
Interferes with the ability to function at work or with usual abilities and	History and observation
Represents a decline from previous ability and	Evidence of changes in functioning reported by either patient and/or informant or observed by clinician
Cannot be explained by delirium or major psychiatric disorder
Presence of cognitive impairment	History, observation, neuropsychological testing
	History-taking from a knowledgeable informantObjective mental status testing and/or neuropsychological testingNeuropsychological testing is recommended when history and mental status testing cannot provide a confident diagnosis
The cognitive or behavioural impairment involves a minimum of two domains	History, observation, neuropsychological testing
	Impaired ability to acquire/remember new information (eg, repeating questions, forgetting events or appointments, becoming lost in familiar places)Impaired reasoning and handling of complex tasks, poor judgement (eg, inability to handle finances, poor decision making)Impaired visuospatial abilities (eg, difficulty recognising faces or common objects)Impaired language function (speaking, reading, writing; eg, difficulty thinking of common words while speaking, hesitations in speech)Changes in personality, behaviour, comportment (eg, agitation, apathy, social withdrawal)
Difference between MCI and dementia	History and observation
	The fundamental difference between diagnoses of dementia versus MCI depends upon whether or not there is a significant change in the ability to function at work or in daily activities. This will necessarily require clinical judgment based upon the information provided by the patient and a knowledgeable informant.
Step 2: criteria for 'probable AD dementia'
Meets criteria for dementia	See criteria above for dementia, step 1
Insidious onset: symptoms have a gradual onset over months or years, not sudden over hours or days.	History
	From patient and knowledgeable informant
Clear cut history of worsening of cognition	History, serial neuropsychological testing
	From patient and knowledgeable informant
Initial cognitive deficits are evident and most prominent in one of the following categories	History, neuropsychological testing
Amnestic presentation – the most common presentationNon-amnestic presentations	Amnestic presentationImpairment of learning and recall of recently learned information
(1) Language presentation	Deficit in at least one other cognitive areaNon-amnestic presentations
(2) Visuospatial presentation	Language: most prominent deficits are word finding, but should also be deficits in other cognitive areas
(3) Executive dysfunction	Visuospatial: most prominent deficits are spatial cognition, but should also be deficits in other cognitive areasExecutive: most prominent deficits are reasoning, judgment and problem solving, but should also be deficits in other cognitive areas
Diagnosis of AD should not be made when there is evidence of another dementing illness	History, neuropsychological testing, imaging studies, laboratory studies
	Disorders to rule out include:Vascular cognitive impairment/vascular dementiaDementia with Lewy bodiesFrontal-temporal dementia – behavioural variantPrimary progressive aphasiaEvidence of neurological disease or non-neurological condition or medication that could have a substantial effect on cognition
Step 3: criteria for 'probable AD dementia with increased level of certainty'
Meets criteria for AD dementia	See criteria above for AD dementia, step 2
Probable AD dementia with documented decline	History, serial neuropsychological testing
	Evidence of progressive cognitive decline on subsequent evaluations from
	knowledgeable informant orcognitive testing (either formal neuropsychological evaluation or standardised mental status examinations)
Probable AD dementia in a carrier of a causative AD genetic mutation	Laboratory studies
	Presence of an early-onset familial genetic mutation
	APP, PSEN1, or PSEN2
	(Note that the apolipoprotein E ε 4 allele was not considered specific enough to meet criteria)
Step 4: evaluate the 'biomarker probability of AD aetiology'
Evaluate for atrophy of temporal (medial, basal, and lateral) and medial parietal cortex and other biomarkers when available and clinically useful	Biomarkers
	Although the use of biomarkers is not recommended routinely, they are available to the clinician when desiredThere are two categories of biomarkers, those associated with Aβ protein deposition and those associated with downstream neurodegeneration (see Table 1) We recommend routine review of CT and MRI patterns of atrophy, a marker of downstream neurodegenerationPresence of one biomarker category makes the 'biomarker probability of AD aetiology' 'intermediate;' both categories must be positive for a 'high' probability. The 'lowest' probability is present if both categories are negative

ANA patterns - list from fpnotebook

http://www.fpnotebook.com/rheum/lab/anstngptrn.htm

I. Rim Pattern

1. Systemic Lupus Erythematosus (Most Specific)

II. Homogenous Pattern

1. Systemic Lupus Erythematosus (Very specific)
2. Further evaluation
   1. Anti-dsDNA
   2. Anti-ssDNA
   3. Anti-Smith

III. Speckled Pattern

1. Most common, least specific
2. Disorders
   1. Systemic Lupus Erythematosus
   2. Mixed Connective Tissue Disease
   3. Scleroderma
   4. Sjogren's Syndrome
3. Further evaluation
   1. Smith Antibody (Anti-Smith)
   2. Ribonucleoprotein Antibody (Anti-RNP)
   3. Scl-70 kD kinetochore (Anti-Topoisomerase I)
   4. Anti-La (Anti-SSB)

IV. Nucleolar Pattern

1. Disorders
   1. Scleroderma
   2. CREST syndrome
2. Further evaluation
   1. Scl-70 kD kinetochore (Anti-Topoisomerase I)
   2. PM-1

V. Diffuse Pattern

1. Non-specific pattern

VI. Centromere Pattern

1. Seen in PSS with CREST syndrome

1998 Consensus Criteria for FTD (Neary et al)

http://www.neurology.org/content/51/6/1546.full#sec-3

The clinical criteria are set out in lists 1 through 4. The criteria for each of the three major clinical syndromes are divided into sections. The clinical profile statement together with the core clinical inclusion and exclusion features provide the necessary foundation for diagnosis. Additional clinical features, neuropsychological investigation, and brain imaging support the clinical diagnosis. Operational definitions of specific features are outlined later. 

Clinical profile. This statement (seen in lists 1 through 3) summarizes the neurobehavioral profile necessary to fulfill criteria for diagnosis. 

Core diagnostic features. These are features (see lists 1 through 3) integral to the clinical syndrome. All features must be present to fulfill the criteria for diagnosis. 

Supportive diagnostic features. 

Clinical. These are features (see lists 1 through 3) that are not present in all patients, or they may be noted only during one phase of the disease. They are therefore not necessary conditions for diagnosis. Supportive features are characteristic, often with high diagnostic specificity, and their presence adds substantial weight to the clinical diagnosis. The diagnosis becomes more likely when more supportive features are present.

Physical. In each of the clinical syndromes physical signs are few in contrast to the prominent mental changes. Parkinsonian signs typically emerge only during late disease. The physical features outlined should be regarded as "supportive" rather than as necessary conditions for diagnosis.

Investigations. Formal neuropsychological assessment, EEG, and brain imaging each can provide support for and strengthen the clinical diagnosis. Such investigatory techniques are not available universally, and ought not to be considered a prerequisite for diagnosis. When neuropsychological assessment is performed, the profile of deficits must demonstrate disproportionate executive dysfunction in FTD or disproportionate language/semantic breakdown in PA and SD. With regard to brain imaging, the patterns of abnormality are characteristic, but not seen invariably. For example, prominent atrophy of the temporal lobes is well visualized by high-resolution MRI, but may be undetected by CT. Failure to demonstrate the prototypic appearances on imaging need not result in diagnostic exclusion.

Supportive features common to each of the clinical syndromes. These features (see list 4) support but are not a necessary condition for FTLD. Onset of disease is most commonly before the age of 65 years, although rare examples of onset in the very elderly have been reported. A positive family history of a similar disorder in a first-degree relative has been reported^2,4 in as many as 50% of patients: Some families have shown mutations on chromosome 17 or linkage to chromosome 3. Motor neuron disease is a recognized albeit uncommon accompaniment to the clinical syndromes of lobar degeneration.^42-47 The development of motor neuron disease in patients presenting with a progressive behavioral or language disorder would strongly support a clinical diagnosis of FTD or PA respectively.

Exclusion features common to each clinical syndrome.  

Clinical. All features (see list 4) must be absent. Early severe amnesia, early spatial disorientation, logoclonic speech with loss of train of thought, and myoclonus are features designed to exclude AD.

Investigations. All features should be absent (when the relevant information is available).

Relative diagnostic exclusion features. These are features (see list 4) that caution against but do not firmly exclude a diagnosis of FTLD. A history of alcohol abuse raises the possibility of an alcohol-related basis for a frontal lobe syndrome. However, excessive alcohol intake may also occur in FTD patients as a secondary manifestation of social disinhibition or hyperoral tendencies. The presence of vascular risk factors such as hypertension ought to alert investigators to a possible vascular etiology. Nevertheless, such risk factors are common in the general population and may be present coincidentally in some patients with FTLD, particularly in those of more advanced age.

List 1 The clinical diagnostic features of FTD: Clinical profile

Character change and dirordered social conduct are the dominant features initially and throughout the disease course. Instrumental functions of perception, spatial skills, praxis, and memory are intact or relatively well preserved.

1. 
   
   Core diagnostic features
   
   
   
2. 
   
   Insidious onset and gradual progression
3. 
   
   Early decline in social interpersonal conduct
4. 
   
   Early impairment in regulation of personal conduct
5. 
   
   Early emotional blunting
6. 
   
   Early loss of insight


7. 
   
   Supportive diagnostic features
   
   
   
8. 
   
   Behavioral disorder
   
   
   
   
   1. 
      
      Decline in personal hygiene and grooming
   2. 
      
      Mental rigidity and inflexibility
   3. 
      
      Distractibility and impersistence
   4. 
      
      Hyperorality and dietary changes
   5. 
      
      Perseverative and stereotyped behavior
   6. 
      
      Utilization behavior
   
   
   
9. 
   
   Speech and language
   
   
   
   
   1. 
      
      Altered speech output
      
      
      
      
      1. 
         
         Aspontaneity and economy of speech
      2. 
         
         Press of speech
      
      
      
   2. 
      
      Stereotype of speech
   3. 
      
      Echolalia
   4. 
      
      Perseveration
   5. 
      
      Mutism
   
   
   
10. 
    
    Physical signs
    
    
    
    
    1. 
       
       Primitive reflexes
    2. 
       
       Incontinence
    3. 
       
       Akinesia, rigidity, and tremor
    4. 
       
       Low and labile blood pressure
    
    
    
11. 
    
    Investigations
    
    
    
    
    1. 
       
       Neuropsychology: significant impairment on frontal lobe tests in the absence of severe amnesia, aphasia, or perceptuospatial disorder
    2. 
       
       Electroencephalography: normal on conventional EEG despite clinically evident dementia
    3. 
       
       Brain imaging (structural and/or functional): predominant frontal and/or anterior temporal abnormality
    
    
    

List 2 The clinical diagnostic features of progressive nonfluent aphasia: Clinical profile

Disorder of expressive language is the dominant feature initially and throughout the disease course. Other aspects of cognition are intact or relatively well preserved.

1. 
   
   Core diagnostic features
   
   
   
2. 
   
   Insidious onset and gradual progression
3. 
   
   Nonfluent spontaneous speech with at least one of the following: agrammatism, phonemic paraphasias, anomia


4. 
   
   Supportive diagnostic features
   
   
   
5. 
   
   Speech and language
   
   
   
   
   1. 
      
      Stuttering or oral apraxia
   2. 
      
      Impaired repetition
   3. 
      
      Alexia, agraphia
   4. 
      
      Early preservation of word meaning
   5. 
      
      Late mutism
   
   
   
6. 
   
   Behavior
   
   
   
   
   1. 
      
      Early preservation of social skills
   2. 
      
      Late behavioral changes similar to FTD
   
   
   
7. 
   
   Physical signs: late contralateral primitive reflexes, akinesia, rigidity, and tremor
8. 
   
   Investigations
   
   
   
   
   1. 
      
      Neuropsychology: nonfluent aphasia in the absence of severe amnesia or perceptuospatial disorder
   2. 
      
      Electroencephalography: normal or minor asymmetric slowing
   3. 
      
      Brain imaging (structural and/or functional): asymmetric abnormality predominantly affecting dominant (usually left) hemisphere
   
   
   

List 3 The clinical diagnostic features of semantic aphasia and associative agnosia (SD): Clinical profile

Semantic disorder (impaired understanding of word meaning and/or object identity) is the dominant feature initially and throughout the disease course. Other aspects of cognition, including autobiographic memory, are intact or relatively well preserved.

1. 
   
   Core diagnostic features
   
   
   
2. 
   
   Insidious onset and gradual progression
3. 
   
   Language Disorder characterized by
   
   
   
   
   1. 
      
      Progressive, fluent, empty spontaneous speech
   2. 
      
      Loss of word meaning, manifest by impaired naming and comprehension
   3. 
      
      Semantic paraphasias and/or
   
   
   
4. 
   
   Perceptual disorder characterized by
   
   
   
   
   1. 
      
      Prosopagnosia: impaired recognition of identity of familiar faces and/or
   2. 
      
      Associative agnosia: impaired recognition of object identity
   
   
   
5. 
   
   Preserved perceptual matching and drawing reproduction
6. 
   
   Preserved single-word repetition
7. 
   
   Preserved ability to read aloud and write to dictation orthographically regular words


8. 
   
   Supportive diagnostic features
   
   
   
9. 
   
   Speech and language
   
   
   
   
   1. 
      
      Press of speech
   2. 
      
      Idiosyncratic word usage
   3. 
      
      Absence of phonemic paraphasias
   4. 
      
      Surface dyslexia and dysgraphia
   5. 
      
      Preserved calculation
   
   
   
10. 
    
    Behavior
    
    
    
    
    1. 
       
       Loss of sympathy and empathy
    2. 
       
       Narrowed preoccupations
    3. 
       
       Parsimony
    
    
    
11. 
    
    Physical signs
    
    
    
    
    1. 
       
       Absent or late primitive reflexes
    2. 
       
       Akinesia, rigidity, and tremor
    
    
    
12. 
    
    Investigations
13. 
    
    Neuropsychology
    
    
    
    
    1. 
       
       Profound semantic loss, manifest in failure of word comprehension and naming and/or face and object recognition
    2. 
       
       Preserved phonology and syntax, and elementary perceptual processing, spatial skills, and day-to-day memorizing
    
    
    
14. 
    
    Electroencephalography: normal
15. 
    
    Brain imaging (structural and/or functional): predominant anterior temporal abnormality (symmetric or asymmetric)

List 4 Features common to clinical syndromes of FTLD (extension of lists 1 through 3)

III. Supportive features

Onset before 65 years: positive family history of similar disorder in first-degree relative

Bulbar palsy, muscular weakness and wasting, fasciculations (associated motor neuron disease present in a minority of patients)

IV. Diagnostic exclusion features

Historical and clinical

1. 
   
   Abrupt onset with ictal events
2. 
   
   Head trauma related to onset
3. 
   
   Early, severe amnesia
4. 
   
   Spatial disorientation
5. 
   
   Logoclonic, festinant speech with loss of train of thought
6. 
   
   Myoclonus
7. 
   
   Corticospinal weakness
8. 
   
   Cerebellar ataxia
9. 
   
   Choreoathetosis

Investigations

1. 
   
   Brain imaging: predominant postcentral structural or functional deficit; multifocal lesions on CT or MRI
2. 
   
   Laboratory tests indicating brain involvement of metabolic or inflammatory disorder such as MS, syphilis, AIDS, and herpes simplex encephalitis

V. Relative diagnostic exclusion features

Typical history of chronic alcoholism

Sustained hypertension

History of vascular disease (e.g., angina, claudication)

2011 FTD Consortium Criteria (FTDC) for bvFTD

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170532/?report=classic

International consensus criteria for behavioural variant FTD (FTDC)

I. Neurodegenerative disease

The following symptom must be present to meet criteria for bvFTD

A. Shows progressive deterioration of behaviour and/or cognition by observation or history (as provided by a knowledgeable informant).

II. Possible bvFTD

Three of the following behavioural/cognitive symptoms (A–F) must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events.

A. Early* behavioural disinhibition [one of the following symptoms (A.1–A.3) must be present]:

A.1. Socially inappropriate behaviour

A.2. Loss of manners or decorum

A.3. Impulsive, rash or careless actions

B. Early apathy or inertia [one of the following symptoms (B.1–B.2) must be present]:

B.1. Apathy

B.2. Inertia

C. Early loss of sympathy or empathy [one of the following symptoms (C.1–C.2) must be present]:

C.1. Diminished response to other people’s needs and feelings

C.2. Diminished social interest, interrelatedness or personal warmth

D. Early perseverative, stereotyped or compulsive/ritualistic behaviour [one of the following symptoms (D.1–D.3) must be present]:

D.1. Simple repetitive movements

D.2. Complex, compulsive or ritualistic behaviours

D.3. Stereotypy of speech

E. Hyperorality and dietary changes [one of the following symptoms (E.1–E.3) must be present]:

E.1. Altered food preferences

E.2. Binge eating, increased consumption of alcohol or cigarettes

E.3. Oral exploration or consumption of inedible objects

F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions [all of the following symptoms (F.1–F.3) must be present]:

F.1. Deficits in executive tasks

F.2. Relative sparing of episodic memory

F.3. Relative sparing of visuospatial skills

III. Probable bvFTD

All of the following symptoms (A–C) must be present to meet criteria.

A. Meets criteria for possible bvFTD

B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores)

C. Imaging results consistent with bvFTD [one of the following (C.1–C.2) must be present]:

C.1. Frontal and/or anterior temporal atrophy on MRI or CT

C.2. Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or SPECT

IV. Behavioural variant FTD with definite FTLD Pathology

Criterion A and either criterion B or C must be present to meet criteria.

A. Meets criteria for possible or probable bvFTD

B. Histopathological evidence of FTLD on biopsy or at post-mortem

C. Presence of a known pathogenic mutation

V. Exclusionary criteria for bvFTD

Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD.

A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders

B. Behavioural disturbance is better accounted for by a psychiatric diagnosis

C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process

*As a general guideline ‘early’ refers to symptom presentation within the first 3 years

Corneomandibular reflex

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC108345

Seven patients are presented in whom a prominent corneomandibular reflex was observed. These patients all had severe cerebral and/or brain-stem disease with altered states of consciousness. Two additional patients with less prominent and inconsistent corneomandibular reflexes were seen; one had bulbar amyotrophic lateral sclerosis and one had no evidence of brain disease. The corneomandibular reflex, when found to be prominent, reflects an exaggeration of the normal. Therefore one may consider the corneomandibular hyper-reflexia as possibly due to disease of the corticobulbar system.

http://archopht.jamanetwork.com/article.aspx?articleid=627241

The corneomandibular reflex, or von Sölder phenomenon, is an automatic, involuntary movement of the mandible elicited by touching the cornea. This phenomenon is helpful in diagnosis of supranculear lesions of the trigeminal nerve. It simply requires observation of the relaxed and slightly opened jaw when the cornea is stroked with a cotton wisp, and it can be handily included in the testing of corneal sensation. A prominent deviation of the jaw, the result of homolateral contraction of the external pterygoid muscle, constitutes a positive response.

http://archneur.jamanetwork.com/article.aspx?articleid=1674016

Corneomandibular Reflex (Wartenberg Reflex) in Coma - A Rarely Elicited Sign

 A 52-year-old man underwent emergent surgery for a dissecting aneurysm of aorta type A (dissection of ascending, arch, and descending thoracic aorta) and remained intubated. Neurological examination revealed dilatation of the left pupil (6 mm) with no light response. Oculocephalic and oculovestibular reflexes were abolished. There was bilateral Babinski sign and bilateral decerebrate posture after pain stimuli. Stimulation for testing the corneal reflex elicited a normal direct response, an absent consensual response, and a horizontal movement of the mandible to the contralateral side (corneomandibular reflex [Wartenberg reflex]) ( ) on both sides. Neuroimaging showed a massive cerebral infarct. The patient died 7 days after the initial neurological consultation.

Corneomandibular reflex consists of contralateral deviation of the mandible. It is suggested that a supranuclear lesion of the trigeminal nerve provokes an associated movement between the orbicularis oculi and the external pterygoid muscles.

The reflex may be present in acute coma (especially if due to a structural lesion), cerebrovascular disease, multiple sclerosis, Parkinson disease, and amyotrophic lateral sclerosis. In acute unilateral supratentorial lesions such as infarcts or hemorrhages, the reflex is elicited contralaterally. In most cases with bilateral corneomandibular reflex, there have been bilateral brainstem pathological findings or a unilateral hemispheric lesion with secondary pressure on the brainstem.