heimer’s disease are between ages 65 and 74 years, 53% are between ages 75 and 84 years,
and 40% are 85 years and older. The percentage  of dementias attributable to Alzheimer’s
disease ranges from about 60% to over 90%, depending on the setting and diagnostic cri-
teria. Mild NCD due to Alzheimer’s disease is likely to represent a substantial fraction of
mild cognitive impairment (MCI) as well.
Development and Course
Major or mild NCD due to Alzheimer’s disease progresses gradually, sometimes with
brief plateaus, through severe dementia to death. The mean duration of survival after di-


Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease 613
agnosis is approximately 10 years, reflecting th e advanced age of the majority of individ-
uals rather than the course of the disease; some individuals can live with the disease for as
long as 20 years. Late-stage individuals are eventually mute and bedbound. Death most
commonly results from aspiration in those who survive through the full course. In mild
NCD due to Alzheimer’s disease, impairments increase over time, and functional status
gradually declines until symptoms reach the threshold for the diagnosis of major NCD.
The onset of symptoms is usually in the eighth and ninth decades; early-onset forms
seen in the fifth and sixth decades are often related to known causative mutations. Symp-
toms and pathology do not differ markedly at different onset ages. However, younger in-
dividuals are more likely to survive the full course of the disease, while older individuals
are more likely to have numerous medical co morbidities that affect the course and man-
agement of the illness. Diagnostic complexity is  higher in older adults because of the in-
creased likelihood of comorbid me dical illness and mixed pathology.
Risk and Prognostic Factors
Environmental. Traumatic brain injury increases risk  for major or mild NCD due to Alz-
heimer’s disease.
Genetic and physiological. Age is the strongest risk factor for Alzheimer’s disease. The
genetic susceptibility polymorphism apolipoprotein E4 increases risk and decreases age
at onset, particularly in homozygous individu als. There are also extremely rare causative
Alzheimer’s disease genes. Individuals with Down’s syndrome (trisomy 21) develop Alz-
heimer’s disease if they survive to midlife. Multiple vascular risk factors influence risk for


heimer’s disease if they survive to midlife. Multiple vascular risk factors influence risk for
Alzheimer’s disease and may act by increasing  cerebrovascular pathology or also through
direct effects on Alzheimer pathology.
Culture-Related Diagnostic Issues
Detection of an NCD may be more difficult in  cultural and socioeconomic settings where
memory loss is considered normal in old age, where older adults face fewer cognitive de-
mands in everyday life, or where very low educational levels pose greater challenges to
objective cognitive assessment.
Diagnostic Markers
Cortical atrophy, amyloid-predominant neuritic plaques, and tau-predominant neurofibril-
lary tangles are hallmarks of the pathological diagnosis of Alzheimer’s disease and may be
confirmed via postmortem histopathological examination. For early-onset cases with auto-
somal dominant inheritance, a mutation in on e of the known causative Alzheimer’s disease
genes—amyloid precursor protein (APP), presen ilin 1 (PSEN1), or presenilin 2 (PSEN2)—
may be involved, and genetic testing for such mutations is commercially available, at least
for PSEN1. Apolipoprotein E4 cannot serve as a diagnostic marker because it is only a risk
factor and neither necessary nor sufficient for disease occurrence.
Since amyloid beta-42 deposition in the br ain occurs early in the pathophysiological
cascade, amyloid-based diagnostic tests such  as amyloid imaging on brain positron emis-
sion tomography (PET) scans and reduced leve ls of amyloid beta-42 in the cerebrospinal
fluid (CSF) may have diagnostic value. Signs of neuronal injury, such as hippocampal and
temporoparietal cortical atrophy on a magnetic resonance image scan, temporoparietal


temporoparietal cortical atrophy on a magnetic resonance image scan, temporoparietal
hypometabolism on a fluorodeoxyglucose PET sc an, and evidence for elevated total tau
and phospho-tau levels in CSF,  provide evidence of neuronal  damage but are less specific
for Alzheimer’s disease. At present, these biomarkers are not fully validated, and many
are available only in tertiary care settings. However, some of them, along with novel bio-
markers, will likely move into wider clinical practice in the coming years.


614 Neurocognitive Disorders
Functional Consequences of Major or Mild
Neurocognitive Disorder Du e to Alzheimer’s Disease
The prominence of memory loss can cause significant difficulties relatively early in the
course. Social cognition (and thus social func tioning) and procedural memory (e.g., danc-
ing, playing musical instruments) may be relatively preserved for extended periods.
Differential Diagnosis
Other neurocognitive disorders. Major and mild NCDs due to other neurodegenera-
tive processes (e.g., Lewy body disease, fron totemporal lobar degene ration) share the in-
sidious onset and gradual decline caused by Alzheimer’s disease but have distinctive core
features of their own. In major or mild vascular NCD, th ere is typically history of stroke
temporally related to the onset of cognitive impairment, and infarcts or white matter hy-
perintensities are judged sufficient to accoun t for the clinical picture. However, particu-
larly when there is no clear hi story of stepwise decline, ma jor or mild vascular NCD can
share many clinical features with Alzheimer’s disease.
Other concurrent, active neurological or systemic illness. Other neurological or sys-
temic illness should be considered if there is an appropriate temporal relationship and
severity to account for the clinical picture. At the mild NCD level, it may be difficult to dis-
tinguish an Alzheimer’s disease etiology from that of another medical condition (e.g., thy-
roid disorders, vitamin B12 deficiency).
Major depressive disorder. Particularly at the mild NCD level, the differential diagnosis
also includes major depression. The presence of depression may be associated with re-
duced daily functioning and poor concentration that may resemble an NCD, but improve-
ment with treatment of depression may be  useful in making the distinction.
Comorbidity


ment with treatment of depression may be  useful in making the distinction.
Comorbidity
Most individuals with Alzheimer’s disease are elderly and have multiple medical conditions
that can complicate diagnosis and influence th e clinical course. Major or mild NCD due to
Alzheimer’s disease commonly co-occurs with cerebrovascular disease, which contributes
to the clinical picture. When a comorbid condition contribute s to the NCD in an individual
with Alzheimer’s disease, then NCD due to multiple etiologies should be diagnosed.
Major or Mild Frontotemporal
Neurocognitive Disorder
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The disturbance has insidious onset and gradual progression.
C. Either (1) or (2):
1. Behavioral variant:
a. Three or more of the following behavioral symptoms:
i. Behavioral disinhibition.
ii. Apathy or inertia.
iii. Loss of sympathy or empathy.
iv. Perseverative, stereotyped or compulsive/ritualistic behavior.
v. Hyperorality and dietary changes.
b. Prominent decline in social cognition and/or executive abilities.


Major or Mild Frontotemporal Neurocognitive Disorder 615
2. Language variant:
a. Prominent decline in language ability, in the form of speech production, word
finding, object naming, grammar, or word comprehension.
D. Relative sparing of learning and memory and perceptual-motor function.
E. The disturbance is not better explained by cerebrovascular disease, another neurode-
generative disease, the effects of a substance, or another mental, neurological, or sys-
temic disorder.
Probable frontotemporal neurocognitive disorder  is diagnosed if either of the following
is present; otherwise, possible frontotemporal neurocognitive disorder  should be di-
agnosed:
1. Evidence of a causative frontotemporal neur ocognitive disorder genetic mutation, from
either family history or genetic testing.
2. Evidence of disproportionate frontal and/or temporal lobe involvement from neuroim-
aging.
Possible frontotemporal neurocognitive disorder  is diagnosed if there is no evidence
of a genetic mutation, and neuroimaging has not been performed.
Coding note: For probable major neurocognitive disorder due to frontotemporal lobar de-
generation, with behavioral disturbance, code first 331.19 (G31.09) frontotemporal dis-
ease, followed by 294.11 (F02.81)  probable major neurocognitive disorder due to
frontotemporal lobar degeneration, with behavioral disturbance. For probable major neu-
rocognitive disorder due to frontotemporal  lobar degeneration, without behavioral distur-
bance, code first 331.19 (G31.09) frontotemporal disease, followed by 294.10 (F02.80)
probable major neurocognitive disorder due to frontotemporal lobar degeneration, without


probable major neurocognitive disorder due to frontotemporal lobar degeneration, without
behavioral disturbance.
For possible major neurocognitive disorder due to frontotemporal lobar degeneration, code
331.9 (G31.9)  possible major neurocognitive disorder due to frontotemporal lobar degen-
eration. ( Note:  Do not use the additional code for frontote mporal disease. Behavioral distur-
bance cannot be coded but should still be indicated in writing.)
For mild neurocognitive disorder due to frontotemporal lobar degeneration, code 331.83
(G31.84).  (Note:  Do not use the additional code for frontotemporal disease. Behavioral
disturbance cannot be coded but should still be indicated in writing.)
Diagnostic Features
Major or mild frontotemporal neurocognitive  disorder (NCD) comprises a number of syn-
dromic variants characterized by the progressi ve development of behavioral and personality
change and/or language impairment. The behavioral variant and three language variants (se-
mantic, agrammatic/nonfluent, and logopenic) ex hibit distinct patterns of brain atrophy and
some distinctive neuropathology. The criteria must be met for either the behavioral or the lan-
guage variant to make the diagnosis, but many  individuals present with features of both.
Individuals with behavioral-variant major or mild frontotemporal NCD present with
varying degrees of apathy or disinhibition. They may lose interest in socialization, self-
care, and personal responsibilities, or displa y socially inappropriate behaviors. Insight is
usually impaired, and this often delays medical consultation. The first referral is often to a
psychiatrist. Individuals may develop changes in  social style, and in religious and political


psychiatrist. Individuals may develop changes in  social style, and in religious and political
beliefs, with repetitive movements, hoarding, changes in ea ting behavior, and hyperoral-
ity. In later stages, loss of sphincter contro l may occur. Cognitive decline is less prominent,
and formal testing may show relatively few deficits in the early stages. Common neuro-
cognitive symptoms are lack of planning and organization, distractib ility, and poor judg-
ment. Deficits in executive function, such  as poor performance on tests of mental


616 Neurocognitive Disorders
flexibility, abstract reasoning, and response inhibition, are present, but learning and mem-
ory are relatively spared, and perceptual-mot or abilities are almost always preserved in
the early stages.
Individuals with language-variant major or mild frontotemporal NCD present with pri-
mary progressive aphasia with gradual onse t, with three subtypes commonly described:
semantic variant, agrammatic/n onfluent variant, and logopenic variant, and each variant
has distinctive features and corresponding neuropathology.
“Probable” is distinguished from “possibl e” frontotemporal NCD by the presence of
causative genetic factors (e.g., mutations in the gene coding for microtubule-associated pro-
tein tau) or by the presence of distinctive at rophy or reduced activity in frontotemporal re-
gions on structural or functional imaging.
Associated Features Supporting Diagnosis
Extrapyramidal features may be prominent in  some cases, with an overlap with syn-
dromes such as progressive supranuclear pa lsy and corticobasal dege neration. Features of
motor neuron disease may be present in some  cases (e.g., muscle atrophy, weakness). A
subset of individuals develop visual hallucinations.
Prevalence
Major or mild frontotemporal NCD is a common  cause of early-onset NCD in individuals
younger than 65 years. Population prevalen ce estimates are in th e range of 2–10 per
100,000. Approximately 20%–25% of cases of  frontotemporal NCD occur in individuals
older than 65 years. Frontotemporal NCD accoun ts for about 5% of all cases of dementia in


unselected autopsy series. Prevalence estima tes of behavioral variant and semantic lan-
guage variant are higher among males, and prevalence estimates of nonfluent language
variant are higher among females.
Development and Course
Individuals with major or m ild frontotemporal NCD commonly present in the sixth de-
cade of life, although the age at onset varies from the third to the ninth decades. The dis-
ease is gradually progressive, with median  survival being 6–11 years after symptom onset
and 3–4 years after diagnosis. Survival is shorter and decline is faster in major or mild fron-
totemporal NCD than in typical Alzheimer’s disease.
Risk and Prognostic Factors
Genetic and physiological. Approximately 40% of individuals with major or mild fron-
totemporal NCD have a family history of early-onset NCD, and approximately 10% show an
autosomal dominant inheritance pattern. A number of genetic factors have been identified,
such as mutations in the gene  encoding the microtubule asso ciated protein tau (MAPT), the
granulin gene (GRN), and the C9ORF72 gene. A number of families with causative muta-
tions have been identified (see the section “D iagnostic Markers” for th is disorder), but many
individuals with known familial transmission do not have a known mutation. The presence
of motor neuron disease is associated  with a more rapi d deterioration.
Diagnostic Markers
Computed tomography (CT) or structural magnetic resonance imaging (MRI) may show
distinct patterns of atrophy. In behavioral-variant major or mild  frontotemporal NCD,
both frontal lobes (especially the medial frontal lobes) and the anterior temporal lobes are


both frontal lobes (especially the medial frontal lobes) and the anterior temporal lobes are
atrophic. In semantic language–variant majo r or mild frontotemporal NCD, the middle,
inferior, and anterior temporal lobes are at rophic bilaterally but asymmetrically, with the


Major or Mild Frontotemporal Neurocognitive Disorder 617
left side usually being more affected. Nonfluent la nguage–variant major or mild fronto-
temporal NCD is associated with predominantly left posterior fr ontal-insular atrophy.
The logopenic variant of major or mild fron totemporal NCD is associated with predomi-
nantly left posterior perisylvian or parietal atrophy. Functional imaging demonstrates hy-
poperfusion and/or cortical hypometabolism in the corresponding brain regions, which
may be present in the early stages in the abse nce of structural abno rmality. Emerging bio-
markers for Alzheimer’s disease (e.g., cerebrospinal fluid amyl oid-beta and tau levels, and
amyloid imaging) may help in the differential  diagnosis, but the dist inction from Alzhei-
mer’s disease can remain difficult (the logopeni c variant is in fact often a manifestation of
Alzheimer’s disease).
In familial cases of frontotemporal NCD, the identification of genetic mutations may
help confirm the diagnosis. Mutations associated with frontote mporal NCD include
the genes encoding microtubule-associated protein tau (MAPT) and granulin (GRN),
C9ORF72, transactive response DNA-binding  protein of 43 kDa (TDP-43, or TARDBP),
valosin-containing protein (V CP), chromatin modifying protein 2B (CHMP2B), and fused
in sarcoma protein (FUS).
Functional Consequences of Major or Mild
Frontotemporal Neurocognitive Disorder
Because of the relative early age at onset of the disorder, the disorder oftens affects work-
place and family life. Because of the involvem ent of language and/or behavior, function is


often more severely impaired relatively early in the course . For individuals with the be-
havioral variant, prior to diagnostic clarific ation there may be significant family disrup-
tion, legal involvement, and problems in the workplace because of socially inappropriate
behaviors. The functional impairment due to  behavioral change and language dysfunc-
tion, which can include hyperorality, impuls ive wandering, and other dishinhibited be-
haviors, may far exceed that due to the co gnitive disturbance and may lead to nursing
home placement or institutionalization. Thes e behaviors can be severely disruptive, even
in structured care settings, particularly wh en the individuals are otherwise healthy, non-
frail, and free of othe r medical comorbidities.
Differential Diagnosis
Other neurocognitive disorders. Other neurodegenerative diseases may be distinguished
from major or mild frontotemporal NCD by th eir characteristic features. In major or mild
NCD due to Alzheimer’s disease, decline in learning and memory is an early feature.
However, 10%–30% of patients presenting with  a syndrome suggestive of major or mild
frontotemporal NCD are found at  autopsy to have Alzheimer’s disease pathology. This oc-
curs more frequently in individuals who present with progressi ve dysexecutive syn-
dromes in the absence of behavioral changes or movement disorder or in those with the
logopenic variant.
In major or mild NCD with Lewy bodies, co re and suggestive features of Lewy bodies
must be present. In major or mild NCD due to Parkinson’s disease, spontaneous parkin-
sonism emerges well befo re the cognitive decline. In majo r or mild vascular NCD, depend-
ing on affected brain regions, there may also  be loss of executive ability and behavioral


ing on affected brain regions, there may also  be loss of executive ability and behavioral
changes such as apathy, and this disorder should  be considered in the differential diagno-
sis. However, history of a cerebrovascular event is temporally related to the onset of cog-
nitive impairment in major or mild vascular NCD, and neuroimaging reveals infarctions
or white matter lesions sufficient to account for the clinical picture.
Other neurological conditions. Major or mild frontotemporal NCD overlaps with pro-
gressive supranuclear palsy, corticobasal  degeneration, and motor neuron disease
clinically as well as pathologically. Progressive supranuclear palsy is characterized by


618 Neurocognitive Disorders
supranuclear gaze palsies and axial-predominant parkinsoni sm. Pseudobulbar signs may
be present, and retropulsion is often prom inent. Neurocognitive assessment shows psy-
chomotor slowing, poor working memory, and executive dysfunction. Corticobasal degen-
eration presents with asymmetr ic rigidity, limb apraxia, postural instability, myoclonus,
alien limb phenomenon, and cortical sensory loss. Many individuals wi th behavioral-variant
major or mild frontotemporal NCD show features of motor neuron disease, which tend to
be mixed upper and predominantly lower motor neuron disease.
Other mental disorders and medical conditions. Behavioral-variant major or mild fron-
totemporal NCD may be mistaken for a primary mental disorder, such as major depression,
bipolar disorders, or schizophrenia, and individuals with this variant often present initially
to psychiatry. Over time, the development of  progressive neurocognitive difficulties will
help to make the distinction. A careful medi cal evaluation will help to exclude treatable
causes of NCDs, such as meta bolic disturbances, nutritional deficiencies, and infections.
Major or Mild Neurocognitive Disorder
With Lewy Bodies
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The disorder has an insidious onset and gradual progression.
C. The disorder meets a combination of core diagnostic features and suggestive diagnos-
tic features for either probable or possibl e neurocognitive disorder with Lewy bodies.
For probable major or mild neurocognitive disorder with Lewy bodies,  the indi-
vidual has two core features, or one suggestive  feature with one or more core features.


vidual has two core features, or one suggestive  feature with one or more core features.
For possible major or mild neurocognitive disorder with Lewy bodies,  the individ-
ual has only one core feature, or one or more suggestive features.
1. Core diagnostic features:
a. Fluctuating cognition with pronounced variations in attention and alertness.
b. Recurrent visual hallucinations that are well formed and detailed.
c. Spontaneous features of parkinsonism, with onset subsequent to the develop-
ment of cognitive decline.
2. Suggestive diagnostic features:
a. Meets criteria for rapid eye movement sleep behavior disorder.
b. Severe neuroleptic sensitivity.
D. The disturbance is not better explained by cerebrovascular disease, another neurode-
generative disease, the effects of a substance, or another mental, neurological, or sys-
temic disorder.
Coding note:  For probable major neurocognitive disorder with Lewy bodies, with behav-
ioral disturbance, code first 331.82 (G31.83) Lewy body disease, followed by 294.11
(F02.81)  probable major neurocognitive disorder with Lewy bodies, with behavioral distur-
bance. For probable major neurocognitive disorder with Lewy bodies, without behavioral
disturbance, code first 331.82 (G31.83)  Lewy body disease, followed by 294.10 (F02.80)
probable major neurocognitive disorder with Lewy bodies, without behavioral disturbance.
For possible major neurocognitive disorder with Lewy bodies, code 331.9 (G31.9)  possible
major neurocognitive disorder with Lewy bodies. ( Note:  Do not use the additional code for


Lewy body disease. Behavioral disturbance cannot be coded but should still be indicated
in writing.)


Major or Mild Neurocognitive Disorder With Lewy Bodies 619
For mild neurocognitive disorder with Lewy bodies, code 331.83 (G31.84). ( Note:  Do not
use the additional code for Lewy body disease. Behavioral disturbance cannot be coded
but should still be indicated in writing.)
Diagnostic Features
Major or mild neurocognitive disorder with Lewy bodies (NCDLB), in the case of major
neurocognitive disorder (NCD), corresponds  to the condition known as dementia with
Lewy bodies (DLB). The disorder includes  not only progressive cognitive impairment
(with early changes in complex attention and ex ecutive function rather than learning and
memory) but also recurrent complex visual hallucinations; and concurrent symptoms of
rapid eye movement (REM) sleep behavior diso rder (which can be a very early manifes-
tation); as well as hallucinations in other sensory modalities, depression, and delusions.
The symptoms fluctuate in a pattern that can resemble a delirium, but no adequate under-
lying cause can be found. The variable pres entation of NCDLB symptoms reduces the like-
lihood of all symptoms being observed in a brief clinic visit and necessitates a thorough
assessment of caregive r observations. The use of assessment scales specifically designed to
assess fluctuation may aid in diagnosis. Anot her core feature is spontaneous parkinson-
ism, which must begin after the onset of cognit ive decline; by convention, major cognitive
deficits are observed at least 1 year befo re the motor symptoms. The parkinsonism must
also be distinguished from neuroleptic-induce d extrapyramidal signs.  Accurate diagnosis
is essential to safe treatment planning, as up  to 50% of individuals with NCDLB have se-


vere sensitivity to neuroleptic drugs, and these medications should be used with extreme
caution in managing the psychotic manifestations.
The diagnosis of mild NCDLB is appropriate for individuals who present with the core
or suggestive features at a stage when cognitive or functional impairments are not of suf-
ficient severity to fulfill criteria for major NC D. However, as for all mild NCDs, there will
often be insufficient ev idence to justify any si ngle etiology, and use of the unspecified di-
agnosis is most appropriate.
Associated Features Supporting Diagnosis
Individuals with NCDLB frequently experience  repeated falls and syncope and transient
episodes of unexplained loss of consciousness. Autonomic dysfunction, such as ortho-
static hypotension and urinary incontinen ce, may be observed. Auditory and other
nonvisual hallucinations are common, as are sy stematized delusions, delusional misiden-
tification, and depression.
Prevalence
The few population-based prev alence estimates for NCDLB available range from 0.1% to
5% of the general elderly popu lation, and from 1.7% to 30.5 % of all dementia cases. In
brain bank (autopsy) series, the pathological lesions known as Lewy bodies are present in
20%–35% of cases of dementia. The male-to- female ratio is approximately 1.5:1.
Development and Course
NCDLB is a gradually progressive disorder with  insidious onset. However, there is often
a prodromal history of confusional episodes (delirium) of acute onset, often precipitated
by illness or surgery. The distinction between NCDLB, in which Lewy bodies are primar-


ily cortical in location, and major or mild NC D due to Parkinson’s disease, in which the pa-
thology is primarily in the basal ganglia, is  the order in which th e cognitive and motor
symptoms emerge. In NCDLB, th e cognitive decline is manifest ed early in the course of ill-
ness, at least a year before the onset of mo tor symptoms (see the section “Differential Di-


620 Neurocognitive Disorders
agnosis” for this disorder). Disease course may be characterized by occasional plateaus
but eventually progresses through severe deme ntia to death. Average duration of survival
is 5–7 years in clinical series. Onset of symptoms is typically observed from the sixth
through the ninth decades of life, with most cases having their onset when affected indi-
viduals are in their mid-70s.
Risk and Prognostic Factors
Genetic and physiological. Familial aggregation may occur, and several risk genes have
been identified, but in most cases of NCDLB, there is no family history.
Diagnostic Markers
The underlying neurodegenerative disease is  primarily a synucleinopathy due to alpha-
synuclein misfolding and aggregation. Cognitiv e testing beyond the use of a brief screen-
ing instrument may be necessary to define de ficits clearly. Assessment scales developed to
measure fluctuation can be useful. The associated condition REM sl eep behavior disorder
may be diagnosed through a formal sleep study or identified by questioning the patient or
informant about relevant symptoms. Neurolep tic sensitivity (challenge) is not recom-
mended as a diagnostic marker but raises suspicion of NCDLB if it occurs. A diagnosti-
cally suggestive feature is low striatal dopa mine transporter uptake on single photon
emission computed tomography  (SPECT) or positron emission tomography (PET) scan.
Other clinically useful markers potentially include relative preservation of medial tempo-
ral structures on computed tomography (C T)/magnetic resonance imaging (MRI) brain
scan; reduced striatal dopamine transporter uptake on SPECT/PET scan; generalized low
uptake on SPECT/PET perfusion scan with re duced occipital activity; abnormal (low up-


take) MIBG myocardial scintigraphy suggest ing sympathetic denervation; and prominent
slow-wave activity on the electroencephalo gram with temporal lobe transient waves.
Functional Consequences of Major or Mild
Neurocognitive Disord er With Lewy Bodies
Individuals with NCDLB are more  functionally impaired than would be expected for their
cognitive deficits when contrasted to individuals with other neurodegenerative diseases,
such as Alzheimer’s disease. This is largely a result of motor and autonomic impairments,
which cause problems with toileting, transfer ring, and eating. Sleep disorders and prom-
inent psychiatric symptoms may also add to functional di fficulties. Consequently, the qual-
ity of life of individuals with NCDLB is often significantly worse than that of individuals
with Alzheimer’s disease.
Differential Diagnosis
Major or mild neurocognitive diso rder due to Parkinson’s disease. A key differenti-
ating feature in clinical diagnosis is the tempor al sequence in which the parkinsonism and
the NCD appear. For NCD due to Parkinson’s disease, the individual must develop cog-
nitive decline in the context of established Parkinson’s disease; by convention, the decline
should not reach the stage of major NCD until at least 1 year after Parkinson’s is diagnosed.
If less than a year has passed since the onset of motor symptoms, the diagnosis is NCDLB.
This distinction is clearer at the major NCD level than at the mild NCD level.
The timing and sequence of parkinsonism an d mild NCD may be more difficult to de-
termine because the onset and clinical presentation can be ambiguous, and unspecified
mild NCD should be diagnosed if the othe r core and suggestive features are absent.


Major or Mild Vascular Neurocognitive Disorder 621
Comorbidity
Lewy body pathology frequent ly coexists with Alzheimer’s disease and cerebrovascular
disease pathology, particularly among the olde st age groups. In Alzheimer’s disease, there
is concomitant synuclein pathology in 60% of cases (if amygdala-restricted cases are in-
cluded). In general, there is a higher rate of Lewy body pathology in individuals with de-
mentia than in older individuals without dementia.
Major or Mild Vascular Neurocognitive Disorder
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The clinical features are consistent with a vascular etiology, as suggested by either of
the following:
1. Onset of the cognitive deficits is temporally related to one or more cerebrovascular
events.
2. Evidence for decline is prominent in complex attention (including processing
speed) and frontal-executive function.
C. There is evidence of the presence of cere brovascular disease from history, physical
examination, and/or neuroimaging consider ed sufficient to account for the neurocog-
nitive deficits.
D. The symptoms are not better explained by another brain disease or systemic disorder.
Probable vascular neurocognitive disorder  is diagnosed if one of the following is pres-
ent; otherwise possible vascular neurocognitive disorder  should be diagnosed:
1. Clinical criteria are supported by neuroimaging evidence of significant parenchymal in-
jury attributed to cerebrovascula r disease (neuroimaging-supported).
2. The neurocognitive syndrome is temporally related to one or more documented cere-
brovascular events.
3. Both clinical and genetic (e.g., cerebral aut osomal dominant arteriopathy with subcortical


infarcts and leukoencephalopathy) evidence of cerebrovascular disease is present.
Possible vascular neuroc ognitive disorder  is diagnosed if the clinical criteria are met
but neuroimaging is not available and the tem poral relationship of the neurocognitive syn-
drome with one or more cerebrovascular events is not established.
Coding note:  For probable major vascular neurocognitive disorder, with behavioral dis-
turbance, code 290.40 (F01.51). For probable major vascular neurocognitive disorder,
without behavioral disturbance, code 290.40 (F01.50). For possible major vascular neuro-
cognitive disorder, with or without behavioral disturbance, code 331.9 (G31.9).  An addi-
tional medical code for the cerebrovascular disease is not needed.
For mild vascular neurocognitive disorder, code 331.83 (G31.84). ( Note:  Do not use an
additional code for the vascular disease. Behavioral disturbance cannot be coded but
should still be indicated in writing.)
Diagnostic Features
The diagnosis of major or mild  vascular neurocognitive diso rder (NCD) requires the es-
tablishment of an NCD (Criterion A) and the determination that cere brovascular disease is
the dominant if not exclusive pathology that accounts for the cognitive deficits (Criteria B
and C). Vascular etiology may range from large vessel stroke to micr ovascular disease; the


622 Neurocognitive Disorders
presentation is therefore very heterogeneous, stemming from the types of vascular lesions
and their extent and location. The lesions may be focal, multifocal, or diffuse and occur in
various combinations.
Many individuals with major or mild vascul ar NCD present with multiple infarctions,
with an acute stepwise or fluctuating dec line in cognition, and intervening periods of
stability and even some improvement. Others may have gradual onset with slow pro-
gression, a rapid development of deficits follo wed by relative stabilit y, or another complex
presentation. Major or mild vascular NCD wi th a gradual onset an d slow progression is
generally due to small vessel disease leading to lesions in the white matter, basal ganglia,
and/or thalamus. The gradual progression in these cases is often punctuated by acute
events that leave subtle neurological deficits. The cognitive deficits in these cases can be at-
tributed to disruption of cortical-subcortical  circuits, and complex attention, particularly
speed of information processing, and exec utive ability are likely to be affected.
Assessing for the presence of sufficient cerebrovascular disease relies on history, phys-
ical examination, and neuroimaging (Criterion  C). Etiological certainty requires the dem-
onstration of abnormalities on neuroimaging. The lack of neuroimaging can result in
significant diagnostic inaccuracy by overlooking “silent” brain infarction and white mat-
ter lesions. However, if the neurocognitive im pairment is temporally associated with one
or more well-documented  strokes, a probable diagnosis can be made in the absence of neu-
roimaging. Clinical evidence of cerebrovascular disease includes documented history of
stroke, with cognitive decline temporally assoc iated with the event, or physical signs con-


stroke, with cognitive decline temporally assoc iated with the event, or physical signs con-
sistent with stroke (e.g., hemi paresis; pseudobulbar syndrome , visual field defect). Neuro-
imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) evidence of
cerebrovascular disease comprises one or more of the following: one or more large vessel
infarcts or hemorrhages, a strategically placed  single infarct or hemorrhage (e.g., in angu-
lar gyrus, thalamus, basal forebrain), two or mo re lacunar infarcts outside the brain stem,
or extensive and confluent white matter lesions. The latter is often termed small vessel dis-
ease or subcortical ischemic changes  on clinical neuroimaging evaluations.
For mild vascular NCD, history of a single stroke or extensive white matter disease is gen-
erally sufficient. For major vascular NCD, two or more strokes, a strate gically placed stroke,
or a combination of white matter disease and one or more lacunes is  generally necessary.
The disorder must not be better explained by another disorder. For example, promi-
nent memory deficit early in the course mi ght suggest Alzheimer' s disease, early and
prominent parkinsonian features would suggest Parkinson's disease, and a close associa-
tion between onset and depression would suggest depression.
Associated Features Supporting Diagnosis
A neurological assessmen t often reveals history of stroke  and/or transient ischemic epi-
sodes, and signs indicative of brain infarctions. Also commonly associated are personality
and mood changes, abulia, depression, and emotional lability. The development of late-
onset depressive symptoms accompanied by psychomotor slowing and executive dys-


onset depressive symptoms accompanied by psychomotor slowing and executive dys-
function is a common presentation among olde r adults with progressive small vessel isch-
emic disease (“vascular depression”).
Prevalence
Major or mild vascular NCD is the second most common cause of NCD after Alzheimer’s
disease. In the United States, population prevalence estimates for vascular dementia range
from 0.2% in the 65–70 years age group to 16%  in individuals 80 years and older. Within
3 months following stroke, 20%–30% of individuals are diagnosed with dementia. In neu-


from 0.2% in the 65–70 years age group to 16%  in individuals 80 years and older. Within
3 months following stroke, 20%–30% of individuals are diagnosed with dementia. In neu-
ropathology series, the prevalence of vascular  dementia increases from 13% at age 70 years
to 44.6% at age 90 years or older, in comp arison with Alzheimer’s disease (23.6%–51%) and
combined vascular dementia and Alzheimer’s disease (2%–46.4%). Higher prevalence has


Major or Mild Vascular Neurocognitive Disorder 623
been reported in African Americans compared with Caucasians, and in East Asian countries
(e.g., Japan, China). Prevalence is  higher in males than in females.
Development and Course
Major or mild vascular NCD can occur at an y age, although the prevalence increases ex-
ponentially after age 65 years. In older indivi duals, additional pathologies may partly ac-
count for the neurocognitive de ficits. The course may vary fr om acute onset with partial
improvement to stepwise decline to progressive decline, with fluctuations and plateaus of
varying durations. Pure subcortical major or  mild vascular NCD can have a slowly pro-
gressive course that simulates major or mild NCD due to Alzheimer’s disease.
Risk and Prognostic Factors
Environmental. The neurocognitive outcomes of vascular brain injury are influenced by
neuroplasticity factors such as education, physical exercise, and mental activity.
Genetic and physiological. The major risk factors for major or mild vascular NCD are the
same as those for cerebrovascular disease, incl uding hypertension, diab etes, smoking, obesity,
high cholesterol levels, high homocysteine levels, other risk factors for atherosclerosis and ar-
teriolosclerosis, atrial fibrillati on, and other conditions increasing  the risk of cerebral emboli.
Cerebral amyloid angiopathy is an important risk factor in which amyloid deposits occur
within arterial vessels. Another key risk factor is the hereditary condition cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL.
Diagnostic Markers
Structural neuroimaging, using MRI or CT, ha s an important role in the diagnostic pro-


cess. There are no other established biomar kers of major or mild vascular NCD.
Functional Consequences of
Major or Mild Vascular Neurocognitive Disorder
Major or mild vascular NCD is commonly asso ciated with physical deficits that cause ad-
ditional disability.
Differential Diagnosis
Other neurocognitive disorders. Since incidental brain infarctions and white matter le-
sions are common in older individuals, it is important to consider other possible etiologies
when an NCD is present. A history of memory  deficit early in the course, and progressive
worsening of memory, language, executive function, and perceptual-motor abilities in the
absence of corresponding focal lesions on br ain imaging, are suggestive of Alzheimer’s
disease as the primary diagnosis. Potential bi omarkers currently being validated for Alz-
heimer’s disease, such as cerebrospinal fluid levels of beta-amyloid and phosphorylated
tau, and amyloid imaging, may prove to be helpful in the differential diagnosis. NCD with
Lewy bodies is distinguished fr om major or mild vascular NCD by its core features of fluc-
tuating cognition, visual hallu cinations, and spontaneous parkinsonism. While deficits in
executive function and language occur in majo r or mild vascular NC D, the insidious onset
and gradual progression of behavioral features or language impairment are characteristic
of frontotemporal NCD and are no t typical of vascular etiology.
Other medical conditions. A diagnosis of major or mild vascular NCD is not made if
other diseases (e.g., brain tumor, multiple sc lerosis, encephalitis, toxic or metabolic disor-
ders) are present and are of su fficient severity to account for the cognitive impairment.


624 Neurocognitive Disorders
Other mental disorders. A diagnosis of major or mild vascular NCD is inappropriate if
the symptoms can be entirely attributed to  delirium, although delirium may sometimes be
superimposed on a preexisting major or mild vascular NCD, in which case both diagnoses
can be made. If the criteria for major depressive disorder are met and the cognitive impair-
ment is temporally related to the likely onse t of the depression, major or mild vascular
NCD should not be diagnosed. However, if the NCD preceded the development of the de-
pression, or the severity of the cognitive impairment is out of proportion to the severity of
the depression, both should be diagnosed.
Comorbidity
Major or mild NCD due to Alzheimer’s dise ase commonly co-occurs with major or mild
vascular NCD, in which case both diagnoses should be made. Major or mild vascular NCD
and depression frequently co-occur.
Major or Mild Neurocognitive Disorder
Due to Traumatic Brain Injury
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. There is evidence of a traumatic brain injury—that is, an impact to the head or other
mechanisms of rapid movement or displacement of the brain within the skull, with one
or more of the following:
1. Loss of consciousness.
2. Posttraumatic amnesia.
3. Disorientation and confusion.
4. Neurological signs (e.g., neuroimaging demonstrating injury; a new onset of sei-
zures; a marked worsening of a preexisting seizure disorder; visual field cuts; an-
osmia; hemiparesis).
C. The neurocognitive disorder presents imm ediately after the occurrence of the trau-
matic brain injury or immediately after recovery of consciousness and persists past the


matic brain injury or immediately after recovery of consciousness and persists past the
acute post-injury period.
Coding note:  For major neurocognitive disorder due to traumatic brain injury, with behavioral
disturbance: For ICD-9-CM, first code 907.0 late effect of intracranial injury without skull frac-
ture, followed by 294.11 major neurocognitive disorder due to traumatic brain injury, with be-
havioral disturbance. For ICD-10-CM, first code S06.2X9S  diffuse traumatic brain injury with
loss of consciousness of unspecified duration, sequela; followed by F02.81  major neurocog-
nitive disorder due to traumatic brain injury, with behavioral disturbance.
For major neurocognitive disorder due to traumatic brain injury, without behavioral distur-
bance: For ICD-9-CM, first code 907.0 late effect of intracranial injury without skull fracture,
followed by 294.10 major neurocognitive disorder due to traumatic brain injury, without be-
havioral disturbance. For ICD-10-CM, first code S06.2X9S  diffuse traumatic brain injury with
loss of consciousness of unspecified duration, sequela; followed by F02.80  major neurocog-
nitive disorder due to traumatic brain injury, without behavioral disturbance.
For mild neurocognitive disorder due to traumatic brain injury, code 331.83 (G31.84).
(Note:  Do not use the additional code for traumatic brain injury. Behavioral disturbance
cannot be coded but should still be indicated in writing.)


Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury 625
Specifiers
Rate the severity of the neuroc ognitive disorder (NCD), not the underlying traumatic brain
injury (see the section “Development and Course” for this disorder).
Diagnostic Features
Major or mild NCD due to traumatic brain injury (TBI) is caused by an impact to the head,
or other mechanisms of rapid movement or di splacement of the brain within the skull, as
can happen with blast injuries. Traumatic brain injury  is defined as brain trauma with spe-
cific characteristics that include at least one of the following: loss of consciousness, post-
traumatic amnesia, diso rientation and confusion, or, in more severe cases, neurological
signs (e.g., positive neuroimaging, a new onset of seizures or a marked worsening of a pre-
existing seizure disorder, visual field cuts, anosmia, hemiparesi s) (Criterion B). To be at-
tributable to TBI, the NCD must  present either immediately after the brain injury occurs or
immediately after the individu al recovers consciousness afte r the injury and persist past
the acute post-injury period (Criterion C).
The cognitive presentation is variable. Difficulties in the domains of complex attention,
executive ability, learning, an d memory are common as well as slowing in speed of infor-
mation processing and disturbances in social cognition. In more seve re TBI in which there
is brain contusion, intracranial hemorrhage, or  penetrating injury, there may be additional
neurocognitive deficits, such as aphasia, neglect, and constructional dyspraxia.
Associated Features Supporting Diagnosis
Major or mild NCD due to TBI may be accompanied by disturbances in emotional function


Major or mild NCD due to TBI may be accompanied by disturbances in emotional function
(e.g., irritability, easy frus tration, tension and anxiety, affective lability); personality
changes (e.g., disinhibition, apathy, suspic iousness, aggression); physical disturbances
(e.g., headache, fatigue, slee p disorders, vertigo or dizziness, tinnitus or hyperacusis, pho-
tosensitivity, anosmia, reduced tolerance to psychotropic medication s); and, particularly
in more severe TBI, neurolog ical symptoms and signs (e.g., seizures, hemiparesis, visual
disturbances, cranial nerve deficits) an d evidence of orthopedic injuries.
Prevalence
In the United States, 1.7 million TBIs occur a nnually, resulting in 1.4 million emergency de-
partment visits, 275,000 hospitalizations, and 52,000 deaths. About 2% of the population
lives with TBI-associated disabi lity. Males account for 59% of TBIs in the United States.
The most common etiologies of TBI in the Unit ed States are falls, vehicular accidents, and
being struck on the head. Collisions and blows to the head that occur in the course of con-
tact sports are increasingly re cognized as sources of mild TB I, with a concern that repeated
mild TBI may have cumulatively persisting sequelae.
Development and Course
The severity of a TBI is rated at the time of injury/initial assessment as mild, moderate, or
severe according to the thresholds in Table 2.
The severity rating of the TBI itself does not necessarily correspon d to the severity of
the resulting NCD. The course of recovery fr om TBI is variable, depending not only on the


specifics of the injury but also  on cofactors, such as age, prior history of brain damage, or
substance abuse, that may favor or impede recovery.


626 Neurocognitive Disorders
Neurobehavioral symptoms tend to be most severe in the immediate aftermath of the
TBI. Except in the case of severe TBI, the typi cal course is that of complete or substantial
improvement in associated neurocognitive, neurological, and psyc hiatric symptoms and
signs. Neurocognitive symptoms associated with mild TBI tend to resolve within days to
weeks after the injury with complete resoluti on typical by 3 months. Other symptoms that
may potentially co-occur with the neurological  symptoms (e.g., depression, irritability,
fatigue, headache, photosensitivity, sleep dist urbance) also tend to resolve in the weeks
following mild TBI. Substantial subsequent deterioration in these areas should trigger con-
sideration of additional diagnoses. However,  repeated mild TBI may be associated with
persisting neurocognitive disturbance.
With moderate and severe TBI, in addition to persistence of neurocognitive deficits,
there may be associated neurophysiological, emotional, and behavi oral complications.
These include seizures (particula rly in the first year), photosen sitivity, hyperacu sis, irritabil-
ity, aggression, depression, sl eep disturbance, fatigue, apat hy, inability to resume occu-
pational and social functioning at pre-injury level, and deterioration in interpersonal
relationships. Moderate and seve re TBI have been associated with increased risk of depres-
sion, aggression, and possibly  neurodegenerative diseases such as Alzheimer’s disease.
The features of persisting majo r or mild NCD due to TBI will vary by age, specifics of
the injury, and cofactors. Persisting TBI-related impairment in an infant or child may be re-
flected in delays in reaching developmental mi lestones (e.g., language acquisition), worse


flected in delays in reaching developmental mi lestones (e.g., language acquisition), worse
academic performance, and possibly impaired  social development. Among older teenag-
ers and adults, persisting symptoms may incl ude various neurocognitive deficits, irrita-
bility, hypersensitivity to light and sound, e asy fatigability, and mood changes, including
depression, anxiety, hostility, or apathy. In older individuals with depleted cognitive re-
serve, mild TBI is more  likely to result in incomplete recoveries.
Risk and Prognostic Factors
Risk factors for traumatic brain injury. Traumatic brain injury rates vary by age, with
the highest prevalence among individuals younge r than 4 years, older adolescents, and in-
dividuals older than 65 years. Falls are the mo st common cause of TBI, with motor vehicle
accidents being second. Sports concussions are frequent causes of TBI in older children,
teenagers, and young adults.
Risk factors for neurocognitive disorder after traumatic brain injury. Repeated con-
cussions can lead to persistent NCD and neur opathological evidence of traumatic enceph-
alopathy. Co-occurring intoxication with a substance may incr ease the severity of a TBI
from a motor vehicle accident, but whether into xication at the time of injury worsens neu-
rocognitive outcome is unknown.
Course modifiers. Mild TBI generally resolves within a few weeks to months, although res-
olution may be delayed or incomplete in the context of repeated TB I. Worse outcome fromTABLE 2 Severity ratings for tr aumatic brain injury
Injury characteristic Mild TBI Moderate TBI Severe TBI
Loss of consciousness <30 min 30 minutes–24 hours >24 hours
Posttraumatic amnesia <24 ho urs 24 hours–7 days >7 days


Posttraumatic amnesia <24 ho urs 24 hours–7 days >7 days
Disorientation and confusion
at initial assessment
(Glasgow Coma Scale
Score)13–15 (not below 13
at 30 minutes)9–12 3–8


Substance/Medication-Induced Major or Mild Neurocognitive Disorder 627
moderate to severe TBI is associated with older ag e (older than 40 years) and initial clinical pa-
rameters, such as low Glasgow Coma Scale score; worse motor function; pupillary nonreac-
tivity; and computed tomography (CT) evidence of brain injury (e.g., petechial hemorrhages,
subarachnoid hemorrhage, midline shift, obliteration of third ventricle).
Diagnostic Markers
Beyond neuropsycholog ical testing, CT scanning may reveal petechial hemorrhages,
subarachnoid hemorrhage, or evidence of contusion. Magn etic resonance image scanning
may also reveal hyperintensities suggestive of microhemorrhages.
Functional Consequences of Major or Mild
Neurocognitive Disorder Due to Traumatic Brain Injury
With mild NCD due to TBI, individuals may re port reduced cognitive efficiency, difficulty
concentrating, and lessened abilit y to perform usual activities. With major NCD due to TBI, an
individual may have di fficulty in independent living an d self-care. Prominent neuromotor
features, such as severe incoordination, ataxia , and motor slowing, may be present in major
NCD due to TBI and may add to functional diffi culties. Individuals with TBI histories report
more depressive symptoms, and these can amp lify cognitive complaints and worsen func-
tional outcome. Additionally, loss of emotional control, including aggre ssive or inappropriate
affect and apathy, may be present after more se vere TBI with greater neurocognitive impair-
ment. These features may compound difficulti es with independent living and self-care.
Differential Diagnosis


Differential Diagnosis
In some instances, severity of neurocognitive symptoms ma y appear to be inconsistent
with the severity of the TBI. After previously  undetected neurologic al complications (e.g.,
chronic hematoma) are excluded , the possibility of diagnoses such as somatic symptom
disorder or factitious disorder need to be considered. Posttraumatic stress disorder (PTSD)
can co-occur with the NCD and have overlappi ng symptoms (e.g., difficulty concentrat-
ing, depressed mood, aggressiv e behavioral disinhibition).
Comorbidity
Among individuals with substa nce use disorders, the neurocognitive effects of the sub-
stance contribute to or compound the TBI-as sociated neurocognitive change. Some symp-
toms associated with TBI may overlap with sy mptoms found in cases of PTSD, and the two
disorders may co-occur, especia lly in military populations.
Substance/Medication-Induced
 Major or Mild Neurocognitive Disorder
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The neurocognitive impairments do not occur exclusively during the course of a delir-
ium and persist beyond the usual duration of intoxication and acute withdrawal.
C. The involved substance or medication and duration and extent of use are capable of
producing the neurocognitive impairment.
D. The temporal course of the neurocognitive deficits is consistent with the timing of sub-
stance or medication use and abstinence (e.g., the deficits remain stable or improve
after a period of abstinence).


628 Neurocognitive Disorders
E. The neurocognitive disorder is not attributable to another medical condition or is not
better explained by another mental disorder.
Coding note:  The ICD-9-CM and ICD-10-CM codes for the [specific substance/medica-
tion]-induced neurocognitive disorders are indi cated in the table below. Note that the ICD-
10-CM code depends on whether or not there is a comorbid substance use disorder present
for the same class of substance. If a mild substance use disorder is comorbid with the sub-
stance-induced neurocognitive disorder, the 4th position character is “1,” and the clinician
should record “mild [substance] use disorder” before the substance-induced neurocognitive
disorder (e.g., “mild inhalant use disorder wi th inhalant-induced major neurocognitive disor-
der”). If a moderate or severe  substance use disorder is comorbid with the substance-
induced neurocognitive disorder, the 4th position character is “2,” and the clinician should
record “moderate [substance] use disorder” or “severe [substance] use disorder,” depending
on the severity of the comorbid substance use disorder. If there is no comorbid substance
use disorder, then the 4th position character is “9,” and the clinician should record only the
substance-induced neurocognitive disorder. For some classes of substances (i.e., alcohol;
sedatives, hypnotics, anxiolytics), it is not permissible to code a comorbid mild substance
use disorder with a substance-induced neurocog nitive disorder; only a comorbid moderate
or severe substance use disorder, or no substance use disorder, can be diagnosed. Behav-


or severe substance use disorder, or no substance use disorder, can be diagnosed. Behav-
ioral disturbance cannot be coded but should still be indicated in writing.
ICD-10-CM
ICD-9-CMWith use
disorder,
mildWith use
disorder,
moderate or
severeWithout use
disorder
Alcohol (major neurocognitive
disorder), nonamnestic-
confabulatory type291.2 NA F10.27 F10.97
Alcohol (major neurocognitive
disorder), amnestic-
confabulatory type291.1 NA F10.26 F10.96
Alcohol (mild neurocognitive
disorder)291.89 NA F10.288 F10.988
Inhalant (major neurocognitive
disorder)292.82 F18.17 F18.27 F18.97
Inhalant (mild neurocognitive
disorder)292.89 F18.188 F18.288 F18.988
Sedative, hypnotic, or anxiolytic
(major neurocognitive disorder)292.82 NA F13.27 F13.97
Sedative, hypnotic, or anxiolytic
(mild neurocognitive disorder)292.89 NA F13.288 F13.988
Other (or unknown) substance
(major neurocognitive disorder)292.82 F19.17 F19.27 F19.97
Other (or unknown) substance
(mild neurocognitive disorder)292.89 F19.188 F19.288 F19.988


Substance/Medication-Induced Major or Mild Neurocognitive Disorder 629
Specify if:
Persistent:  Neurocognitive impairment continues to be significant after an extended
period of abstinence.
Recording Procedures
ICD-9-CM. The name of the substance/medication-i nduced neurocogniti ve disorder be-
gins with the specific substance/medication (e.g ., alcohol) that is presumed to be causing
the neurocognitive symptoms. Th e diagnostic code is selected from the table included in
the criteria set, which is based on the drug clas s. For substances that do not fit into any of
the classes, the code for “other substance” should be used; and in cases in which a substance
is judged to be an etiological factor but the sp ecific class of substance is unknown, the cat-
egory “unknown substance” should be used.
The name of the disorder (i.e., [specific su bstance]-induced major neurocognitive dis-
order or [specific substance]-induced mild neurocognitive disorder) is followed by the
type in the case of alcohol (i.e., nonamnestic-confabulatory type, amnestic-confabulatory
type), followed by specification of duration (i .e., persistent). Unlike the recording procedures
for ICD-10-CM, which combine the substanc e/medication-induced disorder and sub-
stance use disorder into a single code, for ICD-9-CM a separate diagnostic code is given for
the substance use disorder. For example, in th e case of persistent amnestic-confabulatory
symptoms in a man with a severe alcohol use disorder, the diagnosis is 291.1 alcohol-
induced major neurocognitive d isorder, amnestic-confabulatory type, persistent. An addi-


tional diagnosis of 303.90 severe alcohol use diso rder is also given. If the substance/medi-
cation-induced neurocognitive disorder occurs without a comorbid substance use disorder
(e.g., after a sporadic heavy use of inhalants) , no accompanying substance use disorder is
noted (e.g., 292.82 inhalant-induced mild neurocognitive disorder).
ICD-10-CM. The name of the substance/medicati on-induced neurocognitive disorder
begins with the specific substance (e.g., alcoho l) that is presumed to be causing the neuro-
cognitive symptoms. The diagnostic code is sele cted from the table included in the criteria
set, which is based on the drug class and pres ence or absence of a comorbid substance use
disorder. For substances that do  not fit into any of the cla sses, the code for “other sub-
stance” should be used; and in cases in which a substance is judged to be an etiological fac-
tor but the specific class of substance is unknown, the category “unknown substance”
should be used.
When recording the name of the disorder, the comorbid substa nce use disorder (if any) is
listed first, followed by the word “with,” followe d by the name of the disorder (i.e., [specific
substance]-induced major neurocognitive diso rder or [specific substance]-induced mild
neurocognitive disorder), follow ed by the type in the case of  alcohol (i.e., nonamnestic-con-
fabulatory type, amnestic-confabulatory type),  followed by specification of duration (i.e.,
persistent). For example, in the case of pers istent amnestic-confabulatory symptoms in a


man with a severe alcohol use disorder, the di agnosis is F10.26 severe alcohol use disorder
with alcohol-induced major neur ocognitive disorder, amnestic -confabulatory type, persis-
tent. A separate diagnosis of the comorbid severe  alcohol use disorder is not given. If the
substance-induced neurocognitive disorder occurs without a comorbid substance use dis-
order (e.g., after a sporadic heavy use of inha lants), no accompanying substance use disor-
der is noted (e.g., F18.98 8 inhalant-induced mild neurocognitive disorder).
Diagnostic Features
Substance/medication-induced major or mild  NCD is characterized by neurocognitive
impairments that persist beyond the usual du ration of intoxication and acute withdrawal
(Criterion B). Initially, these manifestations can reflect slow recovery of brain functions


impairments that persist beyond the usual du ration of intoxication and acute withdrawal
(Criterion B). Initially, these manifestations can reflect slow recovery of brain functions
from a period of prolonged su bstance use, and improvements in neurocognitive as well as


630 Neurocognitive Disorders
brain imaging indicators may be seen over ma ny months. If the diso rder continues for an
extended period, persistent  should be specified. The give n substance and its use must be
known to be capable of causing the observed impairments (Criterion C). While nonspecific
decrements in a range of cognitive abilities can occur with nearly any substance of abuse
and a variety of medications, some patterns occur more frequently  with selected drug
classes. For example, NCD due to sedative, hypno tic, or anxiolytic drugs (e.g., benzodiaz-
epines, barbiturates) ma y show greater disturbances in memory than in other cognitive
functions. NCD induced by alcohol frequently  manifests with a co mbination of impair-
ments in executive-function and memory and learning domains. Th e temporal course of
the substance-induced NCD must be consistent  with that of use of the given substance
(Criterion D). In alcohol-induced amnestic confabulatory (Korsakoff ’s) NCD, the features
include prominent amnesia (severe difficulty learning new information with rapid forget-
ting) and a tendency to confabulate. These ma nifestations may co-occur with signs of thi-
amine encephalopathy (Wernicke’s encephalopathy) with associated features such as
nystagmus and ataxia. Ophthalmoplegia of Wernicke’s encephalopathy is typically charac-
terized by a lateral gaze paralysis.
In addition to or independent of the mo re common neurocognitive symptoms related
to methamphetamine use (e.g., difficulties wi th learning and memory; executive func-
tion), methamphetamine use can also be associat ed with evidence of vascular injury (e.g.,


focal weakness, unilateral incoordination, as ymmetrical reflexes). The most common neu-
rocognitive profile approximates that seen in vascular NCD.
Associated Features Supporting Diagnosis
Intermediate-duration NC D induced by drugs with central nervous system depressant effects
may manifest with added symptoms of increased irritability, anxiety, sleep disturbance, and
dysphoria. Intermediate-duration NCD induced by stimulant drugs may manifest with re-
bound depression, hypersomnia, and apathy. In severe forms of substance/medication-
induced major NCD (e.g., associ ated with long-term alcohol use), there may be prominent
neuromotor features, such as incoordination, ataxia, and motor slowing. There may also be
loss of emotional control, including aggres sive or inappropriat e affect, or apathy.
Prevalence
The prevalence of these conditions is not know n. Prevalence figures for substance abuse are
available, and substance/medica tion-induced major or mild NCDs are more likely in those
who are older, have longer use, and have other risk factors such as nutritional deficits.
For alcohol abuse, the rate of mild NCD of intermediate duration is approximately 30%–
40% in the first 2 months of abstinence. Mild NCD may persist, particularly in those who do
not achieve stable abstinence until after age 50 years. Major NCD is rare and may result from
concomitant nutritional deficits, as in al cohol-induced amnestic  confabulatory NCD.
For individuals quitting cocaine, metham phetamine, opioids, phencyclidine, and sed-
ative, hypnotics, or anxiolytics, substance/medication-induced mild NCD of intermediate
duration may occur in one-third or more, and there is some evidence that these substances


duration may occur in one-third or more, and there is some evidence that these substances
may also be associated with persistent mild  NCD. Major NCD associated with these sub-
stances is rare, if it occurs at  all. In the case of methamph etamine, cerebr ovascular disease
can also occur, resulting in diffuse or focal brain injury that  can be of mild or major neu-
rocognitive levels. Solvent expo sure has been linked to both major and mild NCD of both
intermediate and persistent duration.
The presence of NCD induced by cannabis and various hallucinogens is controversial.
With cannabis, intoxication is  accompanied by various neur ocognitive disturbances, but
these tend to clear with abstinence.


Substance/Medication-Induced Major or Mild Neurocognitive Disorder 631
Development and Course
Substance use disorders tend to commence du ring adolescence and peak in the 20s and
30s. Although longer history of severe substa nce use disorder is associated with greater
likelihood of NCD, the relationships are not straightforward, with substantial and even
complete recovery of neurocognitive func tions being common among individuals who
achieve stable abstinence prior to age 50 ye ars. Substance/medication-induced major or
mild NCD is most likely to become persistent in individuals who continue abuse of sub-
stances past age 50 years, presumably becaus e of a combination of lessened neural plas-
ticity and beginnings of other age-related br ain changes. Earlier commencement of abuse,
particularly of alcohol, may lead to defects in later neural development (e.g., later stages of
maturation of frontal circuitries), which may have effects on social cognition as well as
other neurocognitive abilities.  For alcohol-induced NCD, there may be an additive effect
of aging and alcohol-induced brain injury.
Risk and Prognostic Factors
Risk factors for substance/medication-induced  NCDs include older age, longer use, and
persistent use past age 50 years. In additi on, for alcohol-induced NCD, long-term nutri-
tional deficiencies, liver disease, vascular r isk factors, and cardiovascular and cerebrovas-
cular disease may contribute to risk.
Diagnostic Markers
Magnetic resonance imaging (MRI) of individuals with chronic alcohol abuse frequently
reveals cortical thinning, white matter loss, and enlargement of sulci and ventricles. While
neuroimaging abnormalities are more common in  those with NCDs, it is possible to ob-


serve NCDs without neuroimaging abnormalitie s, and vice versa. Specialized techniques
(e.g., diffusion tensor imaging) may reveal damage to specific white matter tracts. Mag-
netic resonance spectroscopy may reveal reduction in N-acetylaspartate, and increase in
markers of inflammation (e.g., myoinositol) or white matter injury (e.g., choline). Many of
these brain imaging changes and neurocogniti ve manifestations reverse following suc-
cessful abstinence. In individuals with meth amphetamine use disorder, MRI may also re-
veal hyperintensities suggestive of microhem orrhages or larger areas of infarction.
Functional Consequences of Substance/Medication-
Induced Major or Mild Neurocognitive Disorder
The functional consequences of substance/ medication-induced mild NCD are sometimes
augmented by reduced cognitive efficiency an d difficulty concentrating beyond that seen
in many other NCDs. In addition, at both major and mild levels, substance/medication-
induced NCDs may have associated motor syndro mes that increase the level of functional
impairment.
Differential Diagnosis
Individuals with substance use disorders, substance intoxica tion, and substance withdrawal
are at increased risk for othe r conditions that may independently, or through a compounding
effect, result in neurocognitive  disturbance. These include hi story of traumatic brain injury
and infections that can accompany substance use disorder (e.g., HIV, hepatitis C virus, syph-
ilis). Therefore, presence of substance/medi cation-induced major or mild NCD should be
differentiated from NCDs arising outside the co ntext of substance use, intoxication, and with-
drawal, including these accompanying cond itions (e.g., traumatic brain injury).


632 Neurocognitive Disorders
Comorbidity
Substance use disorders, substance intoxicati on, and substance withdrawal are highly co-
morbid with other mental disorders. Comorb id posttraumatic stre ss disorder, psychotic
disorders, depressive and bi polar disorders, and neurodev elopmental disorders can con-
tribute to neurocognitive impairment in substance users. Traumatic brain injury occurs
more frequently with substance use, complicati ng efforts to determine the etiology of NCD
in such cases. Severe, long-term alcohol use disorder can be associated with major organ
system disease, including cerebrovascular disease and cirrhosis. Amphetamine-induced
NCD may be accompanied by major or mild vascular NCD, also secondary to amphet-
amine use.
Major or Mild Neurocognitive Disorder
 Due to HIV Infection
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. There is documented infection with human immunodeficiency virus (HIV).
C. The neurocognitive disorder is not bette r explained by non-HIV conditions, including
secondary brain diseases such as progre ssive multifocal leukoencephalopathy or
cryptococcal meningitis.
D. The neurocognitive disorder is not attribut able to another medical condition and is not
better explained by a mental disorder.
Coding note: For major neurocognitive disorder due to HIV infection, with behavioral dis-
turbance, code first 042 (B20)  HIV infection, followed by 294.11 (F02.81)  major neurocog-
nitive disorder due to HIV infection, with behavioral disturbance. For major neurocognitive
disorder due to HIV infection, without behavioral disturbance, code first 042 (B20)  HIV in-


fection, followed by 294.10 (F02.80)  major neurocognitive disorder due to HIV infection,
without behavioral disturbance.
For mild neurocognitive disorder due to HIV infection, code 331.83 (G31.84).  (Note:  Do
not use the additional code for HIV infection. Behavioral disturbance cannot be coded but
should still be indicated in writing.)
Diagnostic Features
HIV disease is caused by infection with hu man immunodeficiency virus type-1 (HIV-1),
which is acquired through exposure to bodily fluids of an infected person through injection
drug use, unprotected sexual contact, or acci dental or iatrogenic exposure (e.g., contami-
nated blood supply, needle puncture injury to medical personnel). HIV infects several types
of cells, most particularly immune cells. Over time, the infection can cause severe depletion
of “T-helper” (CD4) lymphocytes, resulting in severe immunocompromise, often leading to
opportunistic infections and neoplasms. This  advanced form of HIV infection is termed
acquired immune deficiency syndrome  (AIDS). Diagnosis of HIV is confirmed by established
laboratory methods such as enzyme-linked immunosorbent assay for HIV antibody with
Western blot confirmation and/or polymera se chain reaction–based assays for HIV.
Some individuals with HIV infection deve lop an NCD, which generally shows a “sub-
cortical pattern” with prominently impaired executive function, slowing of processing
speed, problems with more demanding attentio nal tasks, and difficulty in learning new
information, but fewer problems with recall of  learned information. In major NCD, slow-
ing may be prominent. Language difficulties , such as aphasia, are uncommon, although
reductions in fluency may be observed. HIV pathogenic proc esses can affect any part of


the brain; therefore, other patterns are possible.


Major or Mild Neurocognitive Disorder Due to HIV Infection 633
Associated Features Supporting Diagnosis
Major or mild NCD due to HIV infection is usually more prevalent in individuals with
prior episodes of severe immunosuppression, high viral loads in the cerebrospinal fluid,
and indicators of advanced HIV disease such as anemia and hypoalbuminemia. Individ-
uals with advanced NCD may experience prom inent neuromotor features such as severe
incoordination, ataxia, and moto r slowing. There may be loss of emotional control, includ-
ing aggressive or inappropriate affect or apathy.
Prevalence
Depending on stage of HIV disease, approx imately one-third to over one-half of HIV-
infected individuals have at least mild neuroc ognitive disturbance, but some of these dis-
turbances may not meet the full criteria for mild NCD. An estimated 25% of individuals
with HIV will have signs and symptoms that meet criteria for mild NCD, and in fewer than
5% would criteria for major NCD be met.
Development and Course
An NCD due to HIV infection can resolve, improve, slowly worsen, or have a fluctuating
course. Rapid progression to profound neur ocognitive impairment is uncommon in the
context of currently available combination antiviral treatment; co nsequently, an abrupt
change in mental status in an individual with HIV may prompt an evaluation of other
medical sources for the cognitive change, incl uding secondary infections. Because HIV in-
fection preferentially affects subcortical regi ons over the course of  illness, including deep
white matter, the progression of the disorder follows a “subcortical ” pattern. Since HIV
can affect a variety of brain regions, and the illness can take on many different trajectories


can affect a variety of brain regions, and the illness can take on many different trajectories
depending on associated comorbidities and cons equences of HIV, the overall course of an
NCD due to HIV infection has considerable heterogeneity. A subc ortical neurocognitive
profile may interact with age over the life course, when psychomo tor slowing and motor
impairments such as slowed gait may occur as a consequence of other age-related condi-
tions so that the overall progression ma y appear more pronounced in later life.
In developed countries, HIV disease is primar ily a condition of adults, with acquisition
via risky behaviors (e.g., unprotected sex, inje ction drug use) beginning in late adolescence
and peaking during young and middle adulth ood. In developing countries, particularly
sub-Saharan Africa, where HIV testing and an tiretroviral treatments for pregnant women
are not readily available, perinatal transmis sion is common. The NCD in such infants and
children may present primarily as neurodevelopment al delay. As individuals treated for
HIV survive into older age, additive and in teractive neurocognitive effects of HIV and
aging, including other NCDs (e .g., due to Alzheimer’s dise ase, due to Parkinson’s dis-
ease), are possible.
Risk and Prognostic Factors
Risk and prognostic factors for HIV infection. Risk factors for HIV infection include injec-
tion drug use, unprotected sex, and unprotecte d blood supply and othe r iatrogenic factors.
Risk and prognostic factors for major or mild neurocognitive disorder due to HIV in-
fection. Paradoxically, NCD due to HIV infection ha s not declined significantly with the
advent of combined antiretrov iral therapy, although the most  severe presentations (con-


sistent with the diagnosis of major NCD) ha ve decreased sharply. Contributory factors
may include inadequate control of HIV in the central nervous system (CNS), the evolution
of drug-resistant viral strains, the effects of  chronic long-term systemic and brain inflam-
mation, and the effects of comorb id factors such as aging, drug  abuse, past history of CNS
trauma, and co-infections, such as with the hepatitis C virus. Chronic exposure to antiret-
roviral drugs also raises the po ssibility of neurotoxicity, alth ough this has not been defin-
itively established.


634 Neurocognitive Disorders
Diagnostic Markers
Serum HIV testing is required for the diagnosis.  In addition, HIV charac terization of the cere-
brospinal fluid may be helpful if it reveals a disp roportionately high viral load in cerebrospinal
fluid versus in the plasma. Neuroimaging (i.e.,  magnetic resonance im aging [MRI]) may reveal
reduction in total brain volume, cortical thi nning, reduction in white matter volume, and
patchy areas of abnormal white matter (hyper intensities). MRI or lumbar puncture may be
helpful to exclude a specific medical condition such as cryptococcus infection or herpes en-
cephalitis that may contribute to CNS changes in the context of AIDS. Specialized techniques
such as diffusion tensor imaging may reveal  damage to specific white matter tracts.
Functional Consequences of Major or Mild
Neurocognitive Disorder  Due to HIV Infection
Functional consequences of ma jor or mild NCD due to HIV infection are variable across
individuals. Thus, impaired executive abiliti es and slowed information processing may
substantially interfere with the complex dise ase management decisions required for ad-
herence to the combined antire troviral therapy regimen. The likelihood of comorbid dis-
ease may further create functional challenges.
Differential Diagnosis
In the presence of comorbidities, such as other infections (e.g., hepati tis C virus, syphilis),
drug abuse (e.g., methamphetamine abuse), or  prior head injury or neurodevelopmental
conditions, major or mild NCD due to HIV infe ction can be diagnosed provided there is ev-
idence that infection with HIV has worsened any NCDs due to such preexisting or comorbid
conditions. Among older adults, onset of neur ocognitive decline rela ted to cerebrovascular


conditions. Among older adults, onset of neur ocognitive decline rela ted to cerebrovascular
disease or neurodegeneration (e.g., major or mild NCD due to Alzheimer’s disease) may
need to be differentiated. In general, stable, fluctuating (without progression) or improving
neurocognitive status would favor an HIV et iology, whereas steady or stepwise deter-
ioration would suggest neurodeg enerative or vascular etiolo gy. Because more severe im-
munodeficiency can result in opportunistic in fections of the brain (e.g., toxoplasmosis;
cryptococcosis) and neoplasia (e.g., CNS lymphoma), sudden onset of an NCD or sudden
worsening of that disorder demands acti ve investigation of non-HIV etiologies.
Comorbidity
HIV disease is accompanied by chronic systemic  and neuro-inflammation that can be as-
sociated with cerebrovascular disease and metabolic syndrome. These complications can
be part of the pathogenesis of major or mild NCD due to HIV infectio n. HIV frequently co-
occurs with conditions such as substance use disorders when the substance has been in-
jected and other sexually  transmitted disorders.
Major or Mild Neurocognitive Disorder
 Due to Prion Disease
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. There is insidious onset, and rapid progression of impairment is common.
C. There are motor features of prion disease, such as myoclonus or ataxia, or biomarker
evidence.


Major or Mild Neurocognitive Disorder Due to Prion Disease 635
D. The neurocognitive disorder is not attribut able to another medical condition and is not
better explained by another mental disorder.
Coding note:  For major neurocognitive disorder due to prion disease, with behavioral dis-
turbance, code first 046.79 (A81.9)  prion disease, followed by 294.11 (F02.81)  major
neurocognitive disorder due to prion disease,  with behavioral disturbance. For major neu-
rocognitive disorder due to prion disease, without behavioral disturbance, code first
046.79 (A81.9)  prion disease, followed by 294.10 (F02.80)  major neurocognitive disorder
due to prion disease, without behavioral disturbance.
For mild neurocognitive disorder due to prion disease, code 331.83 (G31.84).  (Note:  Do
not use the additional code for prion disease. Behavioral disturbance cannot be coded but
should still be indicated in writing.)
Diagnostic Features
The classification of major or mild neurocogni tive disorder (NCD) due to prion disease in-
cludes NCDs due to a group of subacute sp ongiform encephalopathies (including Creutz-
feldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-
Scheinker syndrome, and fatal insomnia) ca used by transmissible agents known as prions.
The most common type is sporadic Creutzfeld t-Jakob disease, typically referred to as
Creutzfeldt-Jakob disease (CJD). Variant CJD is  much rarer and is associated with trans-


mission of bovine spongiform encephalopathy,  also called “mad cow disease.” Typically,
individuals with CJD present with neurocognitive deficits , ataxia, and abnormal move-
ments such as myoclonus, chorea, or dystonia; a startle reflex is also common. Typically,
the history reveals rapid progression to major NCD over as little as 6 months, and thus the
disorder is typically seen only at the major le vel. However, many individuals with the dis-
order may have atypical presentations, and the disease can be confirmed only by biopsy or
at autopsy. Individuals with variant CJD may present with a greater preponderance of
psychiatric symptoms, characterized a by lo w mood, withdrawal, and anxiety. Prion dis-
ease is typically not diagnosed without at le ast one of the characteristic biomarker fea-
tures: recognized lesions on magnetic resonance imaging with DWI (diffusion-weighted
imaging) or FLAIR (flu id-attenuated inversion recovery), tau or 14-3-3 protein in cerebro-
spinal fluid, characteristic triphasic waves on electroencephalogram, or, for rare familial
forms, family history or genetic testing.
Prevalence
The annual incidence of sporadic CJD is a pproximately one or two cases per million peo-
ple. Prevalence is unknown but ve ry low given the short survival.
Development and Course
Prion disease may develop at any age in adults—the peak age for the sporadic CJD is ap-
proximately 67 years—although it has been report ed to occur in individuals spanning the
teenage years to late life. Prodromal symptoms  of prion disease may include fatigue, anx-
iety, problems with appetite or sleeping, or difficulties with concentration. After several


iety, problems with appetite or sleeping, or difficulties with concentration. After several
weeks, these symptoms may be followed by incoordination, altered vision, or abnormal
gait or other movements that may be myoclonic,  choreoathetoid, or ballistic, along with a
rapidly progressive dementia. The disease typi cally progresses very rapidly to the major
level of impairment over several months. More rarely, it can progress over 2 years and ap-
pear similar in its course to other NCDs.


636 Neurocognitive Disorders
Risk Factors and Prognosis
Environmental. Cross-species transmission  of prion infections, with agents that are
closely related to the human form, has been demonstrated (e.g., the outbreak of bovine
spongiform encephalopathy inducing variant CJD in the United Kingdom during the mid-
1990s). Transmission by corneal transplantation and by human growth factor injection has
been documented, and anecdotal cases of tran smission to health care workers have been
reported.
Genetic and physiological. There is a genetic component in up to 15% of cases, associ-
ated with an autosoma l dominant mutation.
Diagnostic Markers
Prion disease can be definitively confirmed only by biopsy or at autopsy. Although there are
no distinctive findings on cerebrospinal fluid analysis across the prion diseases, reliable bio-
markers are being developed and include 14-3-3 protein (particularly for sporadic CJD) as
well as tau protein. Magnetic resonance brain imaging is currently considered the most sen-
sitive diagnostic test when DWI is performed, with the most common finding being multi-
focal gray matter hyperintensities in subcortical and cortical regions. In some individuals,
the electroencephalogram reve als periodic sharp, often triphasic and synchronous dis-
charges at a rate of 0.5–2 Hz at some point during the course of the disorder.
Differential Diagnosis
Other major neurocognitive disorders. Major NCD due to prion disease may appear
similar in its course to other NCDs, but prio n diseases are typically distinguished by their
rapid progression and prominent cerebellar and motor symptoms.
Major or Mild Neurocognitive Disorder
Due to Parkinson’s Disease
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.


Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. The disturbance occurs in the setting of established Parkinson’s disease.
C. There is insidious onset and gradual progression of impairment.
D. The neurocognitive disorder is not attribut able to another medical condition and is not
better explained by another mental disorder.
Major or mild neurocognitive disorder  probably due to Parkinson’s disease  should
be diagnosed if 1 and 2 are both met. Major or mild neurocognitive disorder possibly
due to Parkinson’s disease should be diagnosed if 1 or 2 is met:
1. There is no evidence of mixed etiology (i.e., absence of other neurodegenerative or
cerebrovascular disease or another neurological, mental, or systemic disease or con-
dition likely contributing to cognitive decline).
2. The Parkinson’s disease clearly precedes the onset of the neurocognitive disorder.
Coding note: For major neurocognitive disorder probably due to Parkinson’s disease,
with behavioral disturbance, code first 332.0 (G20)  Parkinson’s disease, followed by
294.11 (F02.81)  major neurocognitive disorder probably due to Parkinson’s disease, with
behavioral disturbance. For major neurocognitive disorder probably due to Parkinson’s
disease, without behavioral disturbance, code first 332.0 (G20)  Parkinson’s disease, fol-


Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease 637
lowed by 294.10 (F02.80)  major neurocognitive disorder probably due to Parkinson’s dis-
ease, without behavioral disturbance.
For major neurocognitive disorder possibly due to Parkinson’s disease, code 331.9
(G31.9)  major neurocognitive disorder possibly due to Parkinson’s disease. ( Note:  Do not
use the additional code for Parkinson’s disease. Behavioral disturbance cannot be coded
but should still be indicated in writing.)
For mild neurocognitive disorder due to Parkinson’s disease, code 331.83 (G31.84).
(Note:  Do not  use the additional code for Parkinson’s disease. Behavioral disturbance
cannot be coded but should still be indicated in writing.)
Diagnostic Features
The essential feature of major or mild neurocognitive disorder (NCD) due to Parkinson’s
disease is cognitive decline following the onset of Parkinson’s disease. The disturbance
must occur in the setting of established Parkinson’s disease (Criterion B), and deficits must
have developed gradually (Criterion C). The NCD is viewed as probably due to Parkinson’s
disease when there is no evidence of another disorder that might be contributing to the
cognitive decline and when the Parkinson’s disease clearly precedes onset of the NCD. The
NCD is considered possibly due to Parkinson’s disease either  when there is no evidence of
another disorder that might be contributing to the cognitive decline or when the Parkin-
son’s disease precedes onset of the NCD, but not both.
Associated Features Supporting Diagnosis
Frequently present features include apathy , depressed mood, anxious mood, hallucina-
tions, delusions, personality changes, rapid eye movement sleep behavior disorder, and
excessive daytime sleepiness.
Prevalence


excessive daytime sleepiness.
Prevalence
The prevalence of Parkinson’s disease in the United States steadily increases with age from
approximately 0.5% between ages 65 and 69 to  3% at age 85 years and older. Parkinson’s
disease is more common in males than in females. Among individuals with Parkinson’s
disease, as many as 75% will develop a major NC D sometime in the course of their disease.
The prevalence of mild NCD in Parkinso n’s disease has been estimated at 27%.
Development and Course
Onset of Parkinson’s disease is typically betw een the sixth and ninth decades of life, with
most expression in the early 60s. Mild NCD ofte n develops relatively early in the course of
Parkinson’s disease, whereas major impairme nt typically does not occur until late.
Risk and Prognostic Factors
Environmental. Risk factors for Parkinson’s disease include exposure to herbicides and
pesticides.
Genetic and physiological. Potential risk factors for NC D among individuals with Par-
kinson’s disease include older age at diseas e onset and increasing duration of disease.
Diagnostic Markers
Neuropsychological testing, with a focus on test s that do not rely on motor function, is crit-
ical in detecting the core cogn itive deficits, particularly at the mild NCD phase. Structural
neuroimaging and dopamine transporter scans, such as DaT scans, may differentiate
Lewy body–related dementias (Parkinson’s and dementia wi th Lewy bodies) from non–


638 Neurocognitive Disorders
Lewy body–related dementias (e.g., Alzheimer’s disease) and can sometimes be helpful in
the evaluation of major or mild  NCD due to Parkinson’s disease.
Differential Diagnosis
Major or mild neurocognitive disorder with Lewy bodies. This distinction is based sub-
stantially on the timing and sequence of mo tor and cognitive symptoms. For NCD to be at-
tributed to Parkinson’s diseas e, the motor and other symptoms  of Parkinson’s disease must
be present well before (by convention, at leas t 1 year prior) cognit ive decline has reached
the level of major NCD, whereas in major or mild NCD with Lewy bodies, cognitive symp-
toms begin shortly before, or concurrent wi th, motor symptoms. For mild NCD, the timing
is harder to establish because the diagnosis itse lf is less clear and th e two disorders exist on
a continuum. Unless Parkinson’s disease has been established for some time prior to the
onset of cognitive decline, or typical features  of major or mild NCD with Lewy bodies are
present, it is preferable to diagnose unspecified mild NCD.
Major or mild neurocognitive disorder due to Alzheimer’s disease. The motor features
are the key to distinguishing major or mild NCD due to Parkinson’s disease from major or
mild NCD due to Alzheimer’s disease. However, the two disorders can co-occur.
Major or mild vascular neurocognitive disorder. Major or mild vascular NCD may pre-
sent with parkinsonian features such as psychomotor slowing that may occur as a conse-
quence of subcortical small vessel disease. However, the parkinsonian features typically
are not sufficient for a diagnosis of Parkinson’s disease, and the course of the NCD usually
has a clear association with cerebrovascular changes.


has a clear association with cerebrovascular changes.
Neurocognitive disorder due to another medical condition (e.g., neurodegenerative
disorders). When a diagnosis of major or mild NC D due to Parkinson’s disease is being
considered, the distinction must also be made from other brain diso rders, such as progres-
sive supranuclear palsy, corticobasal degeneration, multiple system atrophy, tumors, and
hydrocephalus.
Neuroleptic-induced parkinsonism. Neuroleptic-induced parkinsonism can occur in
individuals with other NCDs, particularly when dopamine-blocking drugs are prescribed
for the behavioral manifest ations of such disorders
Other medical conditions. Delirium and NCDs due to side effects of dopamine-blocking
drugs and other medical conditio ns (e.g., sedation or impair ed cognition, severe hypothy-
roidism, B12 deficiency) must al so be ruled out.
Comorbidity
Parkinson’s disease may coexist with Alzheimer’ s disease and cerebrovascular disease, espe-
cially in older individuals. The compounding of  multiple pathological features may diminish
the functional abilities of individuals with Pa rkinson’s disease. Moto r symptoms and frequent
co-occurrence of depression or apathy can make functional impairment worse.
Major or Mild Neurocognitive Disorder
 Due to Huntington’s Disease
Diagnostic Criteria
A. The criteria are met for major or mild neurocognitive disorder.
B. There is insidious onset and gradual progression.
C. There is clinically established Huntington’ s disease, or risk for Huntington’s disease
based on family history or genetic testing.


Major or Mild Neurocognitive Disorder Due to Huntington’s Disease 639
D. The neurocognitive disorder is not attribut able to another medical condition and is not
better explained by another mental disorder.
Coding note:  For major neurocognitive disorder due to Huntington’s disease, with behav-
ioral disturbance, code first 333.4 (G10)  Huntington’s disease, followed by 294.11
(F02.81)  major neurocognitive disorder due to Huntington’s disease, with behavioral dis-
turbance. For major neurocognitive disorder due to Huntington’s disease, without behav-
ioral disturbance, code first 333.4 (G10)  Huntington’s disease, followed by 294.10 (F02.80)
major neurocognitive disorder due to Huntington’s disease, without behavioral disturbance.
For mild neurocognitive disorder due to Huntington’s disease, code 331.83 (G31.84).
(Note:  Do not use the additional code for Huntington’s disease. Behavioral disturbance
cannot be coded but should still be indicated in writing.)
Diagnostic Features
Progressive cognitive impairment is a core feature of Huntington ’s disease, with early changes
in executive function (i.e., processing speed, organization, and planni ng) rather than learn-
ing and memory. Cognitive and associated beha vioral changes often precede the emergence
of the typical motor abnormalities of bradykinesia (i.e., slowing of voluntary movement)
and chorea (i.e., involuntary jerking movements). A diagnosis of definite Huntington’s dis-
ease is given in the presence of unequivocal,  extrapyramidal motor ab normalities in an in-
dividual with either a family history of Huntington’s disease or genetic testing showing a
CAG trinucleotide repeat expansion in the HTT gene, located on chromosome 4.


Associated Features Supporting Diagnosis
Depression, irritability, anxiety, obsessive -compulsive symptoms, and apathy are fre-
quently, and psychosis more rarely, associat ed with Huntington’s disease and often pre-
cede the onset of motor symptoms.
Prevalence
Neurocognitive deficits are an eventual ou tcome of Huntington’s disease; the worldwide
prevalence is estimated to be 2.7 per 100,000.  The prevalence of Huntington’s disease in
North America, Europe, and Australia is 5.7 pe r 100,000, with a much lower prevalence of
0.40 per 100,000 in Asia.
Development and Course
The average age at diagnosis of Huntington’s disease is approximately 40 years, although
this varies widely. Age at onset is inversely correlated with CAG expansion length. Juve-
nile Huntington’s disease (ons et before age 20) may present more commonly with brady-
kinesia, dystonia, and rigidity than with the choreic movements characteristic of the adult-
onset disorder. The disease is gradually progre ssive, with median survival approximately
15 years after motor symptom diagnosis.
Phenotypic expression of Huntington’s diseas e varies by presence of motor, cognitive,
and psychiatric symptoms. Psychiatric and co gnitive abnormalities can predate the motor
abnormality by at least 15 years. Initial symp toms requiring care often include irritabity,
anxiety, or depressed mood. Other behavioral  disturbances may include pronounced ap-
athy, disinhibition, impulsivit y, and impaired insight, with apathy often becoming more
progressive over time. Early movement symptoms may involve the appearance of fidget-
iness of the extremitie s as well as mild apraxia  (i.e., difficulty with purposeful movements),


particularly with fine motor tasks. As the disorder progre sses, other motor problems in-
clude impaired gait (ataxia ) and postural instability. Motor impairment eventually affects
speech production ( dysarthria ) such that the speech becomes very difficult to understand,


640 Neurocognitive Disorders
which may result in significant distress resu lting from the communication barrier in the
context of comparatively intact cognition. Advanced motor disease severely affects gait
with progressive ataxia. Eventually individuals become nonambulatory. End-stage motor
disease impairs motor control of eating and swallowing, typically a major contributor to
the death of the individual from aspiration pneumonia.
Risk and Prognostic Factors
Genetic and physiological. The genetic basis of Huntington’s disease is a fully penetrant
autosomal dominant expansion of th e CAG trincleotide, often called a CAG repeat  in the
huntingtin gene. A repeat length of 36 or more  is invariably associated with Huntington’s
disease, with longer repeat lengths associated  with early age at onset. A CAG repeat length
of 36 or more is invariably asso ciated with Huntington’s disease.
Diagnostic Markers
Genetic testing is the primary laboratory test  for the determination of Huntington’s dis-
ease, which is an autosomal dominant disord er with complete penetrance. The trinucleo-
tide CAG is observed to have a repeat ex pansion in the gene that encodes huntingtin
protein on chromosome 4. A di agnosis of Huntington’s disease is not made in the presence
of the gene expansion alone, but the diagno sis is made only after symptoms become man-
ifest. Some individuals with a positive family  history request genetic testing in a presymp-
tomatic stage. Associat ed features may also include neur oimaging changes; volume loss in
the basal ganglia, particularly the caudate nu cleus and putamen, is well known to occur
and progresses over the course of illness. Other structural and functional changes have
been observed in brain imagin g but remain research measures.
Functional Consequences of Major or Mild


Functional Consequences of Major or Mild
Neurocognitive Disorder Du e to Huntington’s Disease
In the prodromal phase of illness and at early diagnosis, occupational decline is most com-
mon, with most individuals repo rting some loss of ability to engage in their typical work.
The emotional, behavioral, and cognitive aspects of Huntington’s disease, such as disin-
hibition and personality changes, are highly associated with functional decline. Cognitive
deficits that contribute most to functional decline may incl ude speed of processing, initi-
ation, and attention rather th an memory impairment. Given that Huntington’s disease on-
set occurs in productive years of life, it may have a very disruptive effect on performance
in the work setting as well as social and fam ily life. As the disease progresses, disability
from problems such as impair ed gait, dysarthria, and impulsive or irritable behaviors may
substantially add to the level of impairment and daily care needs, over and above the care
needs attributable to the cognitive decline.  Severe choreic moveme nts may substantially
interfere with provision of care such  as bathing, dressing, and toileting.
Differential Diagnosis
Other mental disorders. Early symptoms of Huntington’s disease may include instabil-
ity of mood, irritability, or compulsive behaviors that may suggest another mental disor-
der. However, genetic testing or the develo pment of motor symptoms  will distinguish the
presence of Huntington’s disease.
Other neurocognitive disorders. The early symptoms of Huntington’s disease, particu-
larly symptoms of executive dysfunction an d impaired psychomotor speed, may resemble
other neurocognitive disorders (NCDs), such as major or mild vascular NCD.