Differential Diagnosis in Neurology

16.9. Toxic Disorders with Dementia

Aluminum

• General considerations:
  • Role in Alzheimer's disease and dialysis dementia is unlikely to be significant
  • Mechanisms of action in vitro:
    • Increases phosphorylation of heavy and medium weight neurofilament subunits
    • Induces cross linking between neurofilaments
    • Disrupts transcortical processing

Alcohol and Dementia

• General considerations:
  • Wernicke–Korsakoff:
    • Often seen with alcohol abuse
    • Differential diagnosis:
      • Starvation diets
      • Prolonged IV treatment without vitamin supplementation
      • AIDS
      • Gastric stapling
• Clinical features:
  • Classic clinical syndrome of Wernicke–Korsakoff:
    • Ophthalmoplegia
    • Nystagmus
    • Ataxia
    • Encephalopathy
  • Core clinical feature of Korsakoff's psychosis:
    • Amnestic state
    • Deficits in memory:
      • Anterograde episodic memory deficit
      • Normal semantic memory
      • Relatively intact non-declarative memory
    • Normal intelligence and learned behavior
    • Differential diagnosis:
      • Diencephalic tumor or trauma
    • Pathology of Wernicke–Korsakoff (W-K):
      • Lesions are most characteristic in the:
        • Mammillary bodies
        • Periventricular III and IV ventricles
        • Sylvian aqueduct (perisylvian)
        • Hemorrhage noted in 5% of patients
        • Chronic Wernicke–Korsakoff:
          • Shrinkage and discoloration of the mammillary bodies (Fe⁺⁺ deposition from hemorrhage)
      • Korsakoff's psychosis:
        • Medical dorsal nucleus affected most frequently > submedius > lateral dorsal > medial pulvinar
        • Neuropathological changes in:
          • Cortex
          • White matter
          • Diencephalon
          • Cerebellum
          • Brainstem

Marchiafava Bignami Disease

• General considerations:
  • Male alcoholics
  • Originally described male red wine drinkers
  • Rarely seen in non-alcoholics
• Clinical features:
  • Acute form:
    • Seizures
    • Disorder of consciousness
    • Death
  • Chronic form:
    • Progressive dementia
    • Interhemispheric disconnection syndrome
• Pathology:
  • Necrotizing, cystic lesions of the:
    • Corpus callosum
    • Optic chiasm
    • Anterior commissure
    • Centrum semiovale
    • Middle cerebellar peduncles
    • Demyelination with sparing of axons
• MRI evaluation:
  • Diffuse swelling of the corpus callosum

Fetal Alcohol Syndrome

• General considerations:
  • Consumption of alcohol during pregnancy
• Clinical features:
  • Facial and ocular defects (thin and straight upper lip, short frenulum)
  • Intellectual and cognitive deficits
  • Cerebellum dysfunction
  • Hearing loss
• Neuropathology:
  • Microcephaly
  • Hydrocephalus
  • Cerebellar malformation
  • Agenesis of corpus callosum
  • Optic nerve hypoplasia
  • Retinal ganglion cell loss
  • Neuronal micro dysplasia

Methyl Alcohol

• General considerations:
  • Exposure:
    • Sterno ingestion by alcoholics
    • Methanol is metabolized to formic acid
    • Formic acid inhibits cytochrome C oxidase
• Clinical features:
  • Methanol is metabolized to formic acid
  • Formic acid inhibits cytochrome C oxidase
  • Acute exposure:
    • Edema of the optic disk (bloody)
    • Loss of visual acuity
    • Acute coma
    • Dementia (in survivors)
    • Parkinsonism
• Neuropathology:
  • Edema and petechial hemorrhages in the brain
  • Hemorrhagic necrosis and hemorrhagic leukoencephalopathy
  • Bilateral necrosis of the putamen with cystic changes
  • Loss of retinal ganglion cells, gliosis and axon loss of optic nerves

Central Pontine Myelinolysis

• General considerations:
  • Most commonly seen with Wernicke Korsakoff syndrome
  • 4–12% incidence with Wernicke Korsakoff syndrome
  • Also noted in patients with:
    • Post orthotropic liver transplantation
    • Severe burns
    • Hyponatremia
    • Anorexia
    • Immune suppressed states
• Clinical features:
  • Young or middle aged adults
  • Flaccid tetraplegia
  • Facial, glottal and pharyngeal paralysis
  • Often occurs during an acute illness
  • Frequently patients are locked in
  • May have a striking recovery
• Pathology:
  • Lesions often in the center of the basis pontis at the level of the Vth nerve:
    • Extends from below the midbrain through the upper 2/3 of the pons
    • Tegmentum of pons is spared
    • Extrapontine lesions occur in 10% of patients:
      • Striatum
      • Thalamus
      • Cerebellum
      • Centrum semiovale
      • Cerebral white matter

Manganese

• General considerations:
  • Exposure due to manufacture:
    • Steel
    • Dry cell batteries
    • Gasoline additive
    • Fungicide
    • Welding
    • Water purification
  • Mn binds to transferrin; transported across the BBB by transferrin receptor mediated endocytosis
  • Preferential accumulation of Mn in the:
    • Globus pallidus
    • Substantia nigra pars reticularis
• Clinical features:
  • Extrapyramidal syndrome:
    • Depression (early)
    • Loss of postural reflexes
    • Rigidity akinesia
    • Minimal or no tremor
  • Initial stage:
    • Depression
    • Fatigue
    • Insomnia
    • Poor memory
  • Intermediate stage:
    • Psychomotor excitement
    • Dysphonia
    • Agraphia
    • Flexed posture
    • Gait abnormalities
  • Late stage:
    • Akinetic rigid state
    • Dystonic posture
• Pathology:
  • Degeneration of medial GP; and SNPr
  • Some involvement of caudate and putamen
• MRI evaluation
  • Increased signal on T2 weighted images of
    • Striatum
    • Globus pallidus
    • Substantia nigra

Mercury

• General considerations:
  • Exposure:
    • Dental amalgam
    • Manufacture of scientific instruments
    • Metallic mercury poorly absorbed from GI tract
    • Mercury vapor is actively absorbed
• Clinical features:
  • Psychological disturbances with bursts of anger
  • Intention tremor

Organic Mercury

• General considerations:
  • Mercury vapor and alkyl mercury compounds are the most neurotoxic
  • Inorganic mercury is changed to methyl mercury by microorganisms in estuaries which is then concentrated in fish
  • Methyl mercury is used as a fungicide
• Clinical features:
  • Visual field constriction (tunnel vision)
  • Sensory deficits
  • Ataxia
  • Bradykinesia
  • Cognitive deficits
• Pathology:
  • Spongiosis of the cerebral cortex
  • Involvement of the calcarine cortex, precentral frontal lobe and cerebellar cortex
  • In Minamata Bay disease (poisoning in Japan) involvement of:
    • Basal ganglia
    • Cortex
    • Posterior fossa structure
    • Peripheral nerves

Trimethyl Tin

• General considerations:
  • Industrial exposure:
    • Biocides
    • Surface disinfectants
    • Polymer stabilizers
    • Antioxidants in rubber products
• Clinical features:
  • Mental confusion
  • Seizures
  • Memory dysfunction
  • Increased aggression
  • Insomnia
• Neuropathology
  • Neuronal degeneration in:
    • Temporal cortex
    • Basal ganglia
    • Amygdala
    • Pontine nuclei

Solvent Abuse Dementia

• General considerations:
  • Mixed exposure most common
  • Most often a mixture of:
    • Toluene
    • Styrene
    • Trichloroethylene
    • Xylene
• Clinical features:
  • The dementia and personality changes in industrial solvent exposure:
    • Psycho organic syndrome
    • Deteriorating intellect
    • Emotional changes
  • Long term toluene abuse symptoms and signs:
    • Cognitive impairment
    • Short term memory loss
    • Emotional lability
    • Ataxia
    • Nystagmus
    • Tremor
    • Hearing loss occurs with:
      • Toluene
      • Styrene
      • Trichloroethylene (often there is concomitant Vth nerve involvement)
• Pathology:
  • Cerebral atrophy
  • Ventricular enlargement
  • Cerebellar and brainstem atrophy:
    • More cerebellar atrophy with toluene than other solvents
  • Dementia may precede other signs
• MRI evaluation:
  • Diffuse cerebral and cerebellar atrophy
  • Ventricular enlargement
• Neuropathology:
  • Patchy demyelination of cerebral and cerebellar white matter
  • Trilaminar inclusions within PAS positive macrophages
  • Increased VLCF acids in white matter
  • Cerebral and cerebellar atrophy
  • Irregular μ fiber involvement

Drugs and Toxins that Impair Cognitive Function

• Arsenic is associated with prominent memory deterioration
• Barbiturates cause psychomotor slowing
• Lead encephalopathy causes intellectual deterioration in adults as well as children
• MPTP generalized intellectual decline with parkinsonism
• Methotrexate:
  • Inhibits dihydrofolic acid reductase
  • Intrathecal use combined with craniospinal X-RT causes:
    • Necrotizing leukoencephalopathy
    • Confusion
    • Seizures
    • Ataxia
    • Spasticity
    • Cognitive decline
  • Pathology:
    • Periventricular and centrum semiovale white matter affected