AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2017

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, disruption and loss of neuropil with replacement by high numbers of gitter cells, reactive astrocytes, 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:  Necrosis, laminar, focally extensive, with neuronal necrosis, spongiosis and gliosis, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS:  Toxic encephalopathy

 

CAUSE:  Lead poisoning

 

CONDITION:  Plumbism

 

GENERAL DISCUSSION: 

·       Perhaps the most consistently important poison in farm animals; common and fatal in cattle; less common but fatal in sheep; occasionally 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

·       Due to differences in exposure types, cattle disease is almost always acute while horse disease is almost always chronic

·       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, with small amounts unbound

·       The relative neurotropism of lead is not well explained, although it crosses the blood-brain barrier rapidly using a cationic transporter; however, lead 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:

o   Competes with calcium, interfering with nerve transmission and brain development; alters the function of dopaminergic, cholinergic, and glutaminergic neurotransmitter sytems

o   Binds to calcium- and zinc-binding proteins and causes calcium accumulation in cells, inducing calcium release by mitochondria leading to apoptosis

o   Hydrolyzes random nucleic acids:  Induces RNA catalysis through activation of ribosomal 5S RNA, a natural leadzyme

o   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

o   Inhibits 5’-nucleotidase activity and sodium-potassium ion pumps leading to hemolysis, renal damage, and hypertension

o   Impairs production of 1,25-dihydroxyvitamin D (active metabolite of vitamin D)

o   Interferes with osteoclastic function and leads to osteosclerosis

 

TYPICAL CLINICAL FINDINGS: 

·       Acute neurologic signs including convulsions 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

·       Resembles polioencephalomalacia:  Meningeal and laminar cerebrovascular congestion, brain swelling with flattening of gyri, petechial hemorrhage

·       Chronic forms: Foci of cerebrocortical malacia, cavitation, and laminar cortical necrosis followed by cerebral cortical atrophy with widened sulci and narrowed gyri

·       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

·       Chronic form, bone lesion:  “Lead line” is a band of grossly appreciable sclerotic bone at the metaphysis of developing bone

 

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

o   Cerebral edema

o   Capillary and venule congestion, especially in the grey matter, more notable in the cerebellum where it is often accompanied by astrogliosis and microgliosis

o   Astrocytic swelling

o   Capillary endothelial cell hypertrophy

o   Ischemic neuronal necrosis characteristically confined to the gyral tips

o   Chronic lesions may progress to laminar cortical necrosis

o   Bilateral symmetrical demyelination and axonal degeneration

o   Vascular necrosis and thrombosis (canine)

·       Kidney

o   Proximal tubules may contain eosinophilic acid-fast intranuclear inclusions

o   Tubular degeneration and necrosis

o   Chronic toxicity may lead to interstitial fibrosis

·       Liver

o   Degeneration and necrosis (predominately centrilobular)

o   Eosinophilic acid-fast intranuclear inclusionswithin hepatocytes

·       Peripheral nervous system

o   Segmental demyelination and axonal degeneration of motor nerves

·       Bone

o   Persistence of mineralized cartilage trabeculae in the metaphysis

o   Many osteoclasts are present, but they may be separated from the bone trabeculae and may contain acid fast intranuclear inclusions

 

ULTRASTRUCTURAL FINDINGS: 

·       Intranuclear lead-protein complex inclusionsare found within hepatocytes, proximal tubule epithelial cells, and the cytoplasm of osteoclasts

 

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

·       Chemical analysis:

o   Blood lead levels (antemortem)

o   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

o   Aminolevulinic acid dehydrogenase (ALAD):  Very sensitive

o   Urinary d-aminolevulinic acid

o   Elevated levels of free erythrocyte protoporphyrin (FEP) due to iron being displaced from hemoglobin

 

DIFFERENTIAL DIAGNOSIS: 

·       Laminar cortical necrosis:

o   Polioencephalomalacia (thiamine deficiency)

o   Sulfur toxicosis

o   Salt poisoning:  Mild edema and cerebral malacia

o   Mercury:  Striking necrosis of the cerebellar granular cell neurons and loss of Purkinje cells

·       Peripheral nucleated erythrocytes

o   Erythroid hyperplasia

o   Hemangiosarcoma

o   Extramedullary hematopoiesis

o   Myelophthisis

o   Bone marrow trauma

·       Basophilic stippling

o   Anemia, especially in cattle, sheep, and cats

o   Exposure to some drugs

o   Severe burns

o   Septicemia

·       Intranuclear inclusion bodies in kidney and liver

o   Acidophilic, brick-shaped intranuclear inclusions are normal in old dogs

o   Herpesvirus, adenovirus or morbillivirus inclusions

·       Metaphyseal sclerosis

o   Bovine viral diarrheal virus in-utero infection

o   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

·       Water fowl:  Weakness, anorexia, loss of muscle mass, and diarrhea

·       Wildlife, particularly wild birds:  Due to ingestion rather than embedded lead (e.g. nonfatal gunshot) due to lack of tissue acidity for lead dissolution

 

References: 

1.      Cantile C., Youssef S. Nervous system. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol I. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:316-317

2.      Constable PD, Hinchcliff KW, Done SH, Grunberg W.  Veterinary Medicine:  A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats, Vol 2.  11th ed.  St. Louis, MO: Elsevier; 2017: 1202-1208.

3.      Craig LE, Dittmer KE, Thompson KG.  Bones and joints. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol I. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:86-87.

4.      LaDouceur EEB, Kagan R, Scanlan M, Viner T.  Chronically embedded lead projectiles in wildlife: a case series investigating the potential for lead toxicosis.  J Zoo Wildl Med 2015;46(2):438-442.

5.      Miller AD and Zachary JF: Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby, Inc.; 2016:854-855.

6.      Port CD, Baxter DW, Richter WR.  The Mongolian gerbil as a model for lead toxicity.  Am J Pathol. 1974;76(1)79-94.

7.      Summers BA, Cummings JF, de Lahunta A. Degenerative diseases of the central nervous system. In: Summer BA, Cumming JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book; 1995:250-252.

8.      Summers BA, Cummings JF, de Lahunta A. Diseases of the peripheral nervous system. In: Summer BA, Cumming JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book; 1995:421, 465-466.

9.      US Geological Survey Biological Resources Division.  Lead.  In: Field manual of wildlife diseases: general field procedures and disease of birds. Washington, DC: US Geological Survey, 1999;317–334.

10.   Vandevelde M, Higgins RJ, Oevermann, A.  Veterinary neuropathology: essentials of theory and practice, 1st ed.  Ames, IA: Wiley-Blackwell; 2012:50, 110.


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