Differential Diagnosis in Neurology

16.6. Secondary Dementias

• General characteristics:
  • Vascular dementia:
    • Epidemiological features:
      • Probably the third most common cause of dementia
      • Approximately 10% of dementia is from a vascular cause
      • More common in males than females:
        • Women 75–79 years of age have 1.5% incidence
        • Men > 80 year of age have approximately a 15% incidence
      • Japan has a high prevalence of vascular dementia; >50% of all demented patients
      • Prevalence of dementia is approximately 15% of stroke patients >60 of age
      • Vascular disease mixed with ALZ possibly 30–35% of dementia
  • Single brain lesions (unless strategic locations) in general do not lead to dementia
  • Strategic brain lesions:
    • May affect attention
    • Have a global effect on behavior
  • Protracted time course of months to years is associated with dementia:
    • Characteristics of the lacunar state
    • Global encephalopathy over hours to days:
      • Characteristic of the vasculitis of autoimmune disease
  • Vascular dementia progressive with the exception of:
    • Intracranial hemorrhage
    • Cardiac arrest

Dementia from Strategic Vascular Lesion

• General characteristics:
  • Some patients' mental changes are the presenting or only manifestation of stroke:
    • Approximately 15% of strokes (may have minimal transient motor or sensory symptoms or signs)
    • Small cortical or subcortical infarcts or hemorrhages that are asymptomatic
    • Cognitive deficit determined by location

Middle Cerebral Artery

• Angular gyrus syndrome (posterior division of MCA)
• Acute confusional states:
  • R > L MCA
  • Infarctions of:
    • Middle frontal gyrus
    • Middle temporal gyrus
    • Inferior parietal lobule
    • Head of the left caudate nucleus
    • Right temporo-parietal-occipital cortex
  • Possible global deficit of selective attention causes confusion:
    • Clinical deficits:
      • Inattentive to relevant stimuli
      • Distractible
      • Arousal is intact
      • Lack of concern for the illness
      • Disorientation
      • Anomia
      • Inability to maintain coherent thought
      • Restless agitated and at times aggressive
  • Most acute confusional states last:
    • Days to weeks
    • Occasionally they are permanent

Anterior Cerebral Artery

• ACA branch occlusions with dementia:
  • Fronto polar artery
  • Callosomarginal artery
  • Neuroanatomical structures destroyed:
    • Orbital cortex
    • Mediofrontal cortex
  • Clinical signs:
    • Mental inertia (abulia)
    • Indifference and apathy
    • Emotional blunting
    • Infarct causes subtle deficits of:
      • Divergent thinking
      • Temporal organization
      • Executive and planning strategies
    • Behavior may be triggered by environmental stimuli:
      • Imitation behavior
      • Utilization behavior

Posterior Cerebral Artery

• Infarction of varying degree in:
  • Occipital lobe
  • Mediotemporal areas
  • Midline mesencephalon
  • Thalamic nuclei
• Occipital lobe lesions and behavior:
  • Color vision (lingual fusiform gyrus)
  • Color naming
  • Alexia without agraphia (visual field deficit in the left occipital lobe; concomitant damage of the corpus callosum)
  • Visual distortions and hallucinations (perceived in the hemianopic or entire VF)
  • Bilateral lesions:
    • Visual agnosia
    • Cortical blindness
• Medial temporal lobe infarction:
  • Severe amnestic deficit:
    • Often bilateral involvement
    • Severe hippocampal formation damage
    • Never occurs in isolation; it occurs with anoxia, ischemia of cardiac arrest or severe hypotension (heart or abdominal surgery)

Subcortical Infarction

• Thalamic vascular disease and dementia:
  • Intralaminar artery infarction from P1 (first division of the posterior cerebral artery)
  • Single artery supplying both territories of the intralaminar artery (the thalamic peduncle of Percheron)
  • Small arteries of the posterior communicating artery:
    • Supply the anterior thalamus
• Clinical features:
  • Bilateral involvement:
    • Disturbance of consciousness
    • Ocular and eye movement deficits (vertical gaze) from midbrain lesions
    • Unilateral infarction of the thalamus:
      • Inattention
      • Motor neglect
      • Anterograde amnesia
      • Left sided lesions (aphasia):
        • Fluent paraphasic speech
        • Perseverative speech
        • Anomia
        • Spared repetition
      • Right sided lesion:
        • Hemineglect

Caudate Lesions

• Disruption of caudate frontal lobe circuits
• Left caudate head:
  • Acute agitation
  • Thalamic aphasia:
    • Disruption of fibers to AV and DM thalamic nuclei
• Frontal lobe syndrome

Multi-Infarct Dementia

• Most common form of vascular dementia
• Accrued defects in:
  • Supratentorial nuclei and white matter
  • Basal ganglia
  • Subcortical white matter
  • Internal capsule
  • Lesions are bilateral
• Clinical features:
  • Patients older than 50: men > women
  • Episodic focal deficit that include:
    • Hemiparesis
    • Hemisensory deficit
    • Aphasia
    • Dysarthria
    • Confusion
    • Ataxia
    • Diplopia
    • Dizziness
  • Partial recovery; usually minimal residual from each episode
  • Cognitive deficits occur early or late:
    • Dependent in location of the lesions
  • Prior to cognitive decline:
    • Gait disturbance
    • Urinary incontinence
  • Concomitant medical problems in most patients:
    • HCVD
    • CHF
    • Diabetes mellitus
    • Intermittent claudication
    • Angina
    • Myocardial infarction
    • Generalized vascular disease
    • Valvular disease

Primary Accumulation of Deep Subcortical Lesion Cause

• Slowed psychomotor processing
• Decreased attention
• Decreased concentration
• Poor memory
• Inertia

Associated Neurological Signs of Deep Subcortical Lesions

• Pyramidal tract dysfunction
• Spasticity
• Parkinsonism
• Pseudobulbar palsy
• Hypomimia
• Instability of gait

Accumulation of Cortical Lesions Causes

• Aphasia
• Visuospatial deficits
• Apraxia
• Amnesia

Mixed Cortical and Subcortical Lesions

• Insight infrequently preserved

Both Cortical and Subcortical Lesions

• Minimal Ischemic Deficits
  • May have abrupt onset
  • Step wise deterioration
  • Nocturnal confusion
  • Depression
  • Fluctuating course

MRI Evaluation of Multi-Infarct Dementia

• Infarctions in multiple cortical areas
• Lacunar infarction of the basal ganglia, thalamus, internal capsule, centrum semiovale
• T2 weighted lesions around the ventricles ("ventricular capping")
• Large strategic infarcts
• Periventricular white matter lesions prominent on T2 weighted images
• Ventricular enlargement
• Loss of between 50 ml to 100 ml of brain tissue is necessary for multi infarct dementia:
  • If dementia is present with less than this amount of tissue loss there is concomitant AD

Dementia of Lacunar Infarction

• "État e lacuniere"
• The degree of dementia accompanies the degree of white matter destruction
• Associated closely with HCVD
• Numerous microscopic infarcts in the cortex cause cortical granular atrophy

Inherited Vascular Diseases Associated with Dementia

• CADASIL
• HCHWA (Icelandic)
• HCHWA (Danish)
• HCHWA (British)
• HERNS
• Moya-Moya disease
• Hereditary hemorrhagic telangiectasia
• Fibromuscular dysplasia
• PXE (pseudoxanthoma elasticum)
• Homocystinuria

Vascular Dementia Compared to AD

• Less severe memory deficit
• More severe frontal lobe deficits:
  • Apathy
  • Lack of initiative
  • Executive dysfunction
• Incontinence
• Gait disturbance
• Clinical progression and duration of dementia is more variable

Binswanger's Disease

• General characteristics:
  • Diffuse white matter damage of vascular etiology
  • Deficient blood supply leading to blood vessel wall damage
• Clinical features:
  • Progressive longstanding dementia
  • Subacute neurologic symptoms and signs
  • Patients are 50–70 years old
  • Males and females are equally affected
  • Usually hypertensive patients
  • Occipital preponderance
• Pathology:
  • Brain weight is normal
  • Often associated with atherosclerosis of large vessels
  • Enlargement of lateral and third ventricle
  • Periventricular white matter myelin pallor
  • Lacunes in deep gray matter of the pons
  • Minor degrees of cortical infraction
  • Myelin changes are most severe in:
    • Frontal lobe
    • Parietal and occipital lobe
    • Bilateral distribution usually symmetrical
    • Increased size of Virchow–Robin spaces
    • Deficient blood supply due to vessel wall changes HCVD
• Imaging evaluation:
  • Lateral ventricular enlargement more prominent posteriorly

Normal Pressure Hydrocephalus

• General characteristics:
  • Epidemiology
    • Probably 2–3% of dementias
    • Occurs in sixth and seventh decade
    • Two specific groups of NPH patients:
      • Secondary to a disease or injury:
        • Predisposes to obstruction of CSF flow or reabsorption
        • Predisposing causes:
          • Subarachnoid hemorrhage
          • Head injury
          • Meningitis
          • Aqueductal stenosis (that obstructs)
          • Syringomyelia
          • Basilar
  • Ventricular enlargement causes:
    • Stretch of the long descending corticospinal leg fibers that are periventricular (increased reflexes and gait apraxia)
    • Bladder fibers:
      • Paracentral lobule fibers to the frontal lobe become dysfunctional
    • Cognitively important fibers that are affected:
      • Cortico-cortical
      • Transcallosal
• Clinical features in sequence of development:
  • Gait disturbance
  • Dementia (subcortical in type):
    • Slowing of information processing
    • Decreased attentiveness
    • Poor concentration
    • Apathy
    • Poor abstract thought
    • Memory relatively well preserved
  • Falling backwards
  • Urinary incontinence
• Pathology:
  • Normal brain weight
  • Well preserved cortical ribbon
  • Minimally thinned corpus callosum
  • Mild pallor of periventricular white matter
  • Often constant:
    • Vascular pathology
    • Alzheimer's pathology
• Imaging evaluation:
  • Severely dilated lateral and IIIrd ventricles
  • Absence of significant cortical atrophy
  • Dilated temporal horn out of proportion to the others ventricles
  • Transventricular edema
  • Altered CSF flow through the cerebral aqueduct

Metabolic Disease Associated with Dementia

• Mitochondrial cytopathies:
  • MELAS
  • KSS
  • MNGIE
  • Leigh's disease
  • LHON
  • COX dehydrogenase
  • PDHC
  • Cytochrome oxidase deficiency

Renal Failure

• General characteristics:
  • Patients on hemodialysis
  • Lessened in frequency with aluminum free dialysates
• Clinical features:
  • Slowly progressive course
  • Occasionally remittent
  • Dysarthria
  • Myoclonus
  • Seizures
  • Dysphasia
• EEG:
  • Paroxysmal sharp waves and polyspike wave forms

Uremic Encephalopathy

• General characteristics:
  • HCVD
  • Anemia
  • Blood uremia nitrogen > 60 mg/dl
  • Parathyroid hormone may be involved in the cognitive changes of uremia
• Clinical features:
  • Cognitive defects in all spheres
  • Memory deficits
  • Process fluctuates
• Pathologic features:
  • Subdural hemorrhage in 1–3% of patient
  • Generalized and variable neuronal loss
  • Perivascular necrosis and demyelination
  • Neuroanatomical areas of involvement:
    • Cerebral cortex
    • Subcortical nuclei of the brainstem
    • Cerebellum
  • Alzheimer type 2 astrocytes are prominent

Liver Failure with Dementia

• General characteristics:
  • Probably directly related to serum ammonia level
  • Liver has direct effect on Alzheimer type II glia
• Clinical features:
  • Acquired hepatolenticular degeneration:
    • Occurs in patients with several episodes of hepatic encephalopathy; usually cirrhotic patients
    • Subcortical dementia
    • Falling backwards
    • Parkinsonism
    • Severe dysarthria
    • Choreoathetosis
• Pathology:
  • Patchy cortical laminar or pseudo laminar necrosis
  • Polymicrocavitation at the corticomedullary junction and the striatum
  • Diffuse Alzheimer's type 2 astrocytosis
  • Neuronal loss in the cortex, cerebellum and basal ganglia

Thyroid Failure with Dementia

• General characteristics:
  • Myxedema madness
  • Hashimoto's encephalopathy
  • Apathetic hyperthyroidism
• Clinical features of myxedema:
  • Lethargic; bradyphemic
  • Subcortical dementia
  • Associated neurologic findings:
    • Proximal myopathy
    • Ataxia (Purkinje cell loss)
    • Hearing loss
    • Occasional facial pain (mucopolysaccharide invasion of the Vth nerves)
    • Bilateral carpal and tarsal tunnel syndromes
    • Sensorimotor neuropathy
    • Delayed relaxation phase of reflexes
• General medical features:
  • Interstitial deposition of hydrophilic muccopolysiarides with retention of:
    • Fluid
    • Sodium
    • No increased ADH
  • Scleromyxedema:
    • Generalized papular eruption
    • Dermal fibroblast proliferation
    • Monoclonal paraproteinemia
    • Clinical features:
      • High fever
      • Seizures
      • Coma
      • Dermatoneuro syndrome
    • Laboratory evaluation:
      • Increased CSF protein and IgG
      • Increased interleukin-6 (IL6) driving the encephalopathy

Addison's Disease

• General characteristics:
  • Most due to autoimmune disease
  • Rarely the Tbc or adrenoleukodystrophy in the USA
  • Associated autoimmune diseases:
    • B12 deficiency
    • Thyroid deficiency
    • Autoimmune neuropathy
    • MG
    • Peripheral neuropathy
    • Diabetes mellitus
• Clinical features:
  • Personality change
  • Apathy
  • Cognitive impairment
  • Flexed posture
  • Thin muscles (type II atrophy)
  • Severe fatigue; asthenia
  • Increased K⁺ in association with hyponatremia
  • Depressed reflexes

Vitamin B12/Folic Acid Deficiency

• General characteristics:
  • Neurological signs and symptoms:
    • Precipitated by nitrous oxide anesthesia
    • Folate administration if both B12 and folate are deficient
    • May occur with low normal levels in some patients
• Clinical features:
  • Apathy
  • Gradual intellectual deterioration
  • Associated neurological features:
    • Loss of cranial nerve I
    • Optic neuropathy
    • Subacute combined degeneration of the spinal cord
    • Ataxia
  • Folic acid deficiency:
    • Usually mild cognitive impairment
    • Associated with mania (megaloblastic mania)

Chronic Hypoglycemia

• General characteristics:
  • Multiple episodes of seizures and coma lead to the neurological sequela
• Clinical features:
  • Gradual deterioration of intellectual function
  • Associated with:
    • Motor neuropathy
    • Ataxia
    • Involuntary movements
• Pathology:
  • Neuroanatomical areas of neuronal loss:
    • Neocortex layers III–VI
    • Purkinje cell loss
    • Globus pallidus internus (Gpi)
    • Anterior horn cell

Calcium Metabolism (Hyper)

• General characteristics:
  • Usually cognitive deficits at 13 mg/dl
  • Metastatic disease, hyperthyroidism, hyperparathyroidism are the major etiologies; immobilization in young patients with rapid bone turnover
• Clinical features:
  • Lethargy progressing to stupor
  • Early stages poor cognitive function
  • Associated neurological findings:
    • Absent reflexes
    • Profound lethargy
    • Absent bowel sounds
  • In association with hyperparathyroidism:
    • Muscle aches and cramps
    • Rare pseudo ALS syndrome:
      • Fasciculating tongue
      • Hyperactive reflexes
      • Muscle weakness (proximal)

Hypocalcemia

• General characteristics:
  • Often seen in uremic states
  • Hereditary and acquired hypoparathyroidism
  • Vitamin D deficiency
  • Acute pancreatitis
• Clinical features:
  • Cognitive impairment
  • Neuromuscular irritability:
    • Chvostek's & Trousseau's sign
    • Hyperactive reflexes
  • Seizures
  • Asterixis
  • Basal ganglia dysfunction and calcification

Cushing's Syndrome (Iatrogenic or Organic)

• General characteristics:
  • Primarily: iatrogenic; either steroid administration; adrenalectomy
  • Sterol hydroxylase 22 deficiency
  • Adrenal tumors
• Clinical features:
  • Behavioral change:
    • Steroid psychosis
    • Mania
    • Depression
  • Subcortical dementia (with withdrawal)
  • Proximal myopathy
  • Pseudo tumor cerebri (with withdrawal)