JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

March 2023

N-T05

 

Signalment (#80-A164-33): 4-month-old female calf

 

HISTORY: This calf presented with blindness, staggering gait and pyrexia (105° F).  The animal died in convulsions. Lead levels in the liver and rumen were 32 ppm and 8200 ppm, respectively.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum: Multifocally and preferentially at the tips of the gyri, within the middle to deep cortical gray matter are focally extensive areas of laminar cortical necrosis characterized by spongiosis and loss of neuropil (liquefactive necrosis) with replacement by high numbers of gitter cells, reactive astrocytes (gemistocytes), and microglial cells (gliosis). Neurons in the superficial cortex of the gyral tips are often shrunken, hypereosinophilic, and angulated with pyknotic or karyolytic nuclei (necrotic). Multifocally, the Virchow-Robin space is mildly expanded by macrophages, fewer lymphocytes and plasma cells, and edema. Multifocally, there is occasional capillary endothelial hypertrophy.   

 

MORPHOLOGIC DIAGNOSIS: Cerebrum, cortex, middle to deep laminae: Necrosis, laminar, focally extensive, with neuronal necrosis, spongiosis and gliosis, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Toxic encephalopathy 

 

CAUSE: Lead poisoning

 

CONDITION: Plumbism

 

GENERAL DISCUSSION:  

• Consistently important poison in farm animals; common and fatal in cattle; less common but fatal in sheep; occasional in horses, dogs, and cats; rare in swine; increasingly recognized in wildlife
• Young animals are more susceptible than adults; there is species variation in susceptibility
• Disease in cattle is almost always acute, disease in horses is almost always chronic (differences in lead exposure)
• Many lead-containing products have been implicated, but the usual sources for cattle are paint and metallic lead in storage batteries 

 

PATHOGENESIS:  

• Lead is usually obtained via ingestion, although there is limited absorption (1-2%)
• Lead is slowly excreted in bile, milk (source for neonates), and urine and is deposited in tissues, especially liver and kidney (acute poisoning) and bone (chronic poisoning); the turnover in tissue is slow, with a half-life in blood of months to years
• Lead is transported in association with erythrocyte membranes and albumin, small amounts are unbound
• The relative neurotropism of lead is not well explained; it crosses the blood-brain barrier rapidly using a cationic transporter but does not tend to accumulate in nervous tissue; the observed laminar cortical necrosis is best explained by ischemia-anoxia rather than toxic effect of lead
• Lead is toxic through multiple mechanisms:
  • Competes with calcium, interfering with nerve transmission and brain development; alters the function of dopaminergic, cholinergic, and glutaminergic neurotransmitter systems
  • Binds to calcium- and zinc-binding proteins and causes calcium accumulation in cells, inducing calcium release by mitochondria leading to apoptosis
  • Hydrolyzes nucleic acids
  • Induces RNA catalysis through activation of ribosomal 5S RNA, a natural leadzyme
  • Inhibits gamma-aminolevulinic acid dehydratase and ferrochelatase, resulting in blocking of iron from the heme molecule (inhibition of heme synthesis) with resultant microcytic hypochromic anemia
  • Inhibits 5’-nucleotidase activity and sodium-potassium ion pumps leading to hemolysis, renal damage, and hypertension
  • Impairs production of 1,25-dihydroxyvitamin D (active metabolite of vitamin D) 
  • Interferes with osteoclastic function and leads to osteosclerosis

 

TYPICAL CLINICAL FINDINGS:  

• Acute neurologic signs including convulsions, head pressing, and apparent blindness followed by death in 12-24 hours; rarely cattle may live 4-5 days
• A hemogram with mild microcytic hypochromic anemia, basophilic stippling of erythrocytes, and increased rubricytes, metarubricytes, with nucleated red blood cells (greater than 5/100 WBC) is suggestive of lead intoxication
• The diagnosis of lead poisoning is chemical, although lead levels in the gastrointestinal tract, kidney, CNS, blood, urine and hair vary from species to species; tissue levels do not correlate with clinical course or extent of neuropathologic changes
• In chronic cases, the characteristic lesion is a band of sclerotic bone, or “lead line”, which is visible radiographically at the metaphysis of developing bone

 

TYPICAL GROSS FINDINGS:  

• Usually absent
• Chronic forms: 
  • CNS lesions: Foci of cerebrocortical malacia, cavitation, and laminar cortical necrosis followed by cerebral cortical atrophy with widened sulci and narrowed gyri; resembles polioencephalomalacia (N-T02B, thiamine deficiency)
  • Bone lesion: “Lead line” is a band of grossly appreciable sclerotic bone at the metaphysis of developing bone
• Peracute/acute cases: Upper gastrointestinal tract contents may include lead-containing items (e.g. fragments of battery plates or flakes of paint)
• Subacute form (4-5 days in cattle): Foul gastrointestinal contents due to GI immotility

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Peracute cases: microscopic lesions are absent
• Brain – typically very mild, progressing with duration of disease; lesions most commonly at the tips of the gyri
  • Cerebral edema
  • Capillary and venule congestion, especially in the grey matter, more notable in the cerebellum (often accompanied by astrogliosis and microgliosis)
  • Astrocytic swelling
  • Capillary endothelial cell hypertrophy
  • Ischemic neuronal necrosis characteristically confined to the gyral tips
  • Chronic lesions may progress to laminar cortical necrosis 
  • Bilateral symmetrical demyelination and axonal degeneration
  • Vascular necrosis and thrombosis (canine)
• Kidney (U-T02)
  • Proximal tubules may contain eosinophilic acid-fast intranuclear inclusions
  • Tubular degeneration and necrosis +/- interstitial fibrosis (chronic)
• Liver
  • Degeneration and necrosis (predominately centrilobular)
  • Eosinophilic acid-fast intranuclear inclusions within hepatocytes
• Peripheral nervous system
  • Segmental demyelination and axonal degeneration of motor nerves
• Bone
  • Persistence of mineralized cartilage trabeculae in the metaphysis 
  • Many osteoclasts are present, but they may be separated from the bone trabeculae and may contain acid fast intranuclear inclusions

 

ULTRASTRUCTURAL FINDINGS:  

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Acid-fast intranuclear inclusions in kidney and liver are virtually diagnostic; they must be distinguished from eosinophilic brick-shaped intranuclear inclusions in the kidney and liver of some normal older dogs (U-M22)
• Chemical analysis:
  • Blood lead levels (antemortem)
  • Tissue levels: Liver and kidney are best; body cavity fluids have been shown to correlate well; liver lead  concentrations  in   the  range  of  2 to 10 μg/g are considered consistent with lead intoxication depending on the species exposed
  • Aminolevulinic acid dehydrogenase (ALAD):  Very sensitive
  • Urinary d-aminolevulinic acid
  • Elevated levels of free erythrocyte protoporphyrin (FEP) due to iron being displaced from hemoglobin

 

DIFFERENTIAL DIAGNOSIS:  

• Laminar cortical necrosis:
  • Polioencephalomalacia (N-T02B, thiamine deficiency) 
  • Sulfur toxicosis
  • Salt poisoning (N-T08): Mild edema and cerebral malacia
  • Mercury (N-T07): Striking necrosis of the cerebellar granular cell neurons and loss of Purkinje cells
• Peripheral nucleated erythrocytes
  • Erythroid hyperplasia
  • Hemangiosarcoma
  • Extramedullary hematopoiesis
  • Myelophthisis
  • Bone marrow trauma
• Basophilic stippling of erythrocytes
  • Anemia, especially in cattle, sheep, and cats
  • Exposure to some drugs
  • Severe burns
  • Septicemia
• Intranuclear inclusion bodies in kidney and liver
  • Acidophilic, brick-shaped intranuclear inclusions are normal in old dogs (U-M22)
  • Herpesvirus, adenovirus, or morbillivirus inclusions
• Metaphyseal sclerosis
  • Bovine viral diarrheal virus in-utero infection
  • In dogs, canine distemper viral infection can interfere with osteoclast function or number

 

COMPARATIVE PATHOLOGY:  

• Horses: Chronic disease, known as chronic plumbs, results in cranial nerve paresis (especially laryngeal and pharyngeal paralysis), with associated histologic segmental degeneration of axons and myelin in distal motor neurons; acute disease (less common) results in severe depression, general paralysis, and sometimes clonic convulsions and abdominal pain
• Dogs: Neurologic syndrome manifests as anorexia, emaciation, mental irritability, muscular tremors, ataxia, and intermittent convulsions; histologic lesions include edema of the white matter of the brain and spinal cord; degenerative changes in myelin sheaths; and spongy degeneration of the subthalamus, head of the caudate nucleus, and deep cortical laminae with neuronal loss in these areas; vascular lesions can progress to mural hyalinization, necrosis, and thrombosis; mild degenerative changes of the liver and kidneys
• Sheep: Subacute syndrome similar to cattle
• Pigs: Uncommon
• NHPs: Most commonly due to ingestion of lead based paints, lead encephalopathy (epilepsy), anemia, lead lines in bone 
• Water fowl and shorebirds: Mainly due to ingestion (ie. fishing tackle and ammunition); clinical signs include weakness, anorexia, loss of muscle mass, and diarrhea; gross lesions can include hydropericardium and esophageal distention; histologic lesions may include rare eosinophilic acid-fast intranuclear inclusions in renal tubular epithelial cells and hepatocytes and Wallerian degeneration of peripheral nerves
• Wildlife, particularly birds of prey: Due to ingestion of carcasses or offal containing lead based ammunition 
  • Lead toxicity in bald eagles is characterized by fibrinoid necrosis of small to medium caliber arteries of the heart, brain and eyes; lesions, both gross and histologic, are consistent with ischemia due primary vascular injury (Manning, Vet Pathol. 2019)

 

References:  

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3. Buckles EL. Phoenicopteriformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:690. 
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