Chapter 11

Disorders of the Immature Brain


1. Major brain developmental periods and associated anomalies

a. neural groove and neural tube formation

1. gestational days (GD) 18-20; neural groove forms; failure produces frontal or occipital encephalocele

2. GD 22; neural tube begins to close; failure produces anencephaly (aprosencephaly)

3. GD 26-28; neural tube continues to close; failure produces myelomeningocele although an abnormality in mesoderm and bone development may contribute

b. paired telencephalon forms from cleavage of the single midline prosencephalon; GD 33; failure to cleave produces holoprosencephaly; often associated with bilateral cleft palate and micro-ophthalmia

c. commissures form and neuroblast migration has begun; GD 74 (11-12 weeks, end of embryonic period); failure toform commissures produces corpus callosum agenesis

d. neuronal migration from the subventricular (germinal matrix) zone centrifugally into cerebral cortex; migration continues from gestational weeks 7-8 topost-natal life but is maximal from weeks 12-24 (secondtrimester of pregnancy); abnormal migration produceslissencephaly (argyria/pachygyria) i.e., a smooth brain with few or no sulci and incompletely migrated heterotopic grey matter along the ventricles.

e. Arnold-Chiari (or Chiari Type II) malformation is a complex combination of neural tube defects (generally lumbar meningomyelocele), brainstem and cerebellar deformities (elongation of caudal brainstem and infero-medial cerebellum down through the foramen magnum into the cervical canal), distortion and occlusion of cerebral aqueduct with secondary hydrocephalus. The condition is unfortunately common but its pathogenesis is complex and probably involves anomalies of both neuroectoderm and mesoderm.

f. Hydromyelia and syringomyelia In both conditions, fluid-filled cysts lie within the spinal cord. The central canal within the cord is dilated and remains directly connected with the fourth ventricle. Hydromyelia is a congenital asymptomatic passive dilatation of the central canal that may complicate Arnold-Chiari malformation. In syringomyelia the cyst lies in the cervical cord, is surrounded by marked gliosis or even a glioma, and in young adults compresses adjacent spinal cord structures, especially the pain and temperature fibers that cross the cord near the central canal. The initial symptoms, therefore, are loss of pain and temperature perception in upper extremities followed by hand atrophy due to erosion of anterior horns and lower extremity spasticity due to compression of corticospinal tracts. The pathogenesis of syringomyelia is unknown.

g. Minor cerebral malformations, commonly associated withmild mental retardation, include simplified gyral pattern, anomalous cortical neuronal laminations, decreased synaptogenesis. Prototype is Down's syndrome which is also associated with early onset of Alzheimer's disease.

2. Mixed developmental anomalies and repair reactions (gliosis, necrosis)

a. injuries prior to mid-gestation (16-20 weeks) produce CNS malformations.

b. injuries (e.g., in utero cytomegalovirus infections) that begin prior to mid-gestation and continue beyond 20 gestational weeks, produce a combination of malformation and tissue destruction with repair (necrosis, gliosis, calcification, major brain tissue defects).

c. examples of mixed malformation and destruction: micropolygyria due to gliosis and abnormal neuronal migration and/or porencephaly, defects that replace much of one or both cerebral hemispheres.

3. Perinatal brain injuries

a. During the last trimester of gestation and first few postnatal days, injury to the brain (usually from anoxia) produces necrosis and/or hemorrhage and the same repair reactions seen in the adult brain (neuronal loss, ingestion of debris by macrophages, cyst formation, gliosis).

b. Subcortical structures (basal ganglia, germinal matrix vessel walls, and cerebral white matter) are more susceptible to anoxia than cerebral cortex. Reverse of pattern in adult.

c. Periventricular/intraventricular hemorrhage is a common cause of death in the hypoxic premature newborn with hyaline membrane disease and defects in clotting. Sequelae include communicating hydrocephalus and cystic brain necrosis.

4. Causes, associations and clinical syndromes

a. Very few proven environmental causes of human brain malformations: radiation, lead, mercury, hyperthermia, alcohol, prenatal viral infection, tumor chemotherapeutic agents including folate antagonists.

b. Maternal folic acid dietary supplements appear to decrease the incidence of neural tube defects but the mechanism probably involves multiple factors.

c. Almost any chemical applied at the critical period of gestation can produce almost any anomaly in the rat brain but no one is quite certain how to use this information in the search for causes of similar human anomalies.

d. Many brain anomalies are associated with chromosomal abnormalities; e.g., Trisomy 13 with holoprosencephaly, Trisomy 21 with mild brain simplification, "the unfinished brain", of Down's syndrome.

e. Clinical syndromes are lumped into "mental retardation" if cognition and other mental functions are the major symptoms or "cerebral palsy" if motor dysfunction is the chief presentation. Both terms are inexact and should be avoided.


1. Analysis techniques

a. Peripheral nerve biopsy - usually sural nerve (sensory) at ankle

b. Embed a portion in plastic for high resolution lightmicroscopy and electron microscopy

2. Microscopic changes

a. Wallerian degeneration - if axon is severed (e.g., trauma), both distal myelin sheath and axon degenerate and are phagocytosed; later axon sprouts attempt regeneration.

b. Axonal degeneration ("dying back") - due to disease of neuron cell body - axons develop dense bodies and masses of neurofilaments, then break apart; concomitant myelin breakdown; distal parts of nerve degenerate first and most severely.

c. Segmental demyelination: myelin breaks down initiallyin isolated segments between nodes of Ranvier. Axon remains intact and remyelination begins by newly proliferated Schwann cells.

d. Onion bulb development: follows repeated demyelination-remyelination sequences; concentric proliferation of Schwann cells and collagen; associated with palpable enlargement of nerve.

e. Interstitial abnormalities: amyloid accumulation,non-specific fibrosis accompanying axonal loss.

f. Inflammation: usually chronic inflammatory cells between nerve fibers and bundles

g. Vascular inflammation and/or occlusion of large orsmall arteries with necrosis of nerve fascicles

3. Clinical correlates

a. Patterns:

1. mononeuropathy (ischemia, entrapment)

2. mononeuropathy multiplex (ischemia, especially polyarteritis)

3. distal (diffuse) polyneuropathy (toxic, metabolic, immune-mediated)

b. Tempo:

1. acute (ischemic, Guillain-Barré)

2. subacute evolving (toxic, metabolic)

3. chronic relapsing or recurrent (hypertrophic neuropathy, relapsing demyelinative neuropathy)

4. chronic progressive (many cases of toxic or metabolic)

c. Neurologic deficit (weakness, atrophy, reflex loss, altered sensation)

1. motor: ischemia, lead, demyelinative

2. sensory (or mixed): toxic, metabolic, genetic (often hypertrophic). One sensory modality may be more severely involved than others (e.g., loss of pain and temperature perception in certain hereditary neuropathies)

d. Diseases of Skeletal Muscle

1. Histopathology of skeletal muscles

a. Changes in muscle fiber diameter

1. Atrophy - focal

a. group atrophy: portions or entire fascicles are atrophic amid other fascicles that have normal sized fibers; seen only in denervation. Occurs by successive cycles of denervation and reinnervation.

b. perifascicular atrophy: the atrophy of fibers on the periphery of a large fascicle; seen in dermatomyositis, especially the juvenile form; due to ischemia of the peripheral fibers from associated vasculitis.

2. Atrophy and/or hypertrophy - random

a. isolated small fibers and isolated hypertrophic fibers of over 100 micrometers are common in primary myopathies, in particular dystrophic myopathy

b. angular atrophy and clumps of pyknotic sarcolemmal nuclei are common, in neurogenic atrophy.

b. Changes in muscle fiber structure

1. Necrosis: homogeneous or floccular sarcoplasm; often associated with phagocytosis. Suggests myopathy (dystrophic or inflammatory).

2. Regeneration: basophilic, faintly striated fibers with rows of large vesicular nuclei and prominent nucleoli. Myopathy (dystrophic or inflammatory).

3. Storage material: PAS-positive glycogen, oil red O-positive lipid.

4. Other vacuoles: fluid in potassium-related myopathies; rimmed vacuoles in severe polymyositis.

5. Mitochondrial masses ("ragged red fibers") in mitochondrial myopathies.

c. Changes in cellular content

1. Cell types: usually round cells (lymphocytes, small macrophages) lying outside muscle fibers. Less often plasma cells, neutrophilic or eosinophilic polymorphs.

2. Phagocytosis of necrotic fibers by macrophages that enter the fiber.

3. These changes usually indicate an inflammatory myopathy (polymyositis) but may be seen in rapidly progressive dystrophy.

4. Inflammatory cells in and around walls of vessels with little or no extension into muscle fibers suggest a primary vasculitis such as polyarteritis nodosa; in some cases of polymyositis, both muscles and vessels may be inflamed.

5. Lymphorrhages = clusters of tightly packed lymphocytes without evidence of fiber necrosis seen in myasthenia gravis.

d. Changes at the motor end plates: immune complex deposition, loss of acetylcholine, axon sprouting, degeneration of terminals; seen in myasthenia gravis, botulism.

e. Changes in supporting structures (majority not diagnostic)

1. Collagen: increased in endomysium and perimysium: found in all types of neuromuscular disease of moderate to marked severity and long duration. Severe endomysial collagen increase occurs early in dystrophy.

2. Fat: similar to collagen in distribution and cause.

3. Biopsy may be useless if performed late in a disease or in a muscle so severely involved that only the non-specific fibrotic and fatty changes remain.

f. Muscle enzyme histochemistry

1. Purpose

a. first to divide muscle fibers into Type 1 (slow) and Type 2 (fast) fibers using their enzyme content. Type 1 is high in oxidative enzymes (SDH, NAD diaphorase). Type 2 is high in alkaline adenosine triphosphatase (ATPase).

b. then to identify abnormal distributions of fiber types, changes in fiber size related to fiber type, or abnormal enzyme distribution within a fiber.

2. Normal pattern (in adult vastus lateralis)

a. 1/3 of fibers are Type 1 and are slightly smaller than Type 2: 1/3 are Type 2A and 1/3 Type 2B.

b. the three fiber types randomly mingle

c. enzyme is evenly distributed throughout the fibers or in narrow bands that stain myofilaments or mark rows of mitochondria between myofilament bundles.

3. Abnormalities

a. fiber-type grouping: groups of fibers of one type cluster together -- this indicates neurogenic atrophy. Due to reinnervation by collateral sprouting of remaining axons. The reinnervated fibers assume the type of the new axon.

b. fiber-type atrophy: all fibers of a given type are atrophic - Type 1 fiber atrophy is found in certain myopathies (e.g., myotonic dystrophy); Type 2 fiber atrophy is relatively non-specific and is found in chronic diseases of many types as well as upper motor neuron lesions, prolonged corticosteroid administration and myasthenia gravis. In myasthenia gravis Type 2 atrophy is relatively specific as long as the clinical picture is typical.

g. Major types of skeletal muscle disease Neurogenic muscular atrophy

1. causes

a. diseases of the anterior horn cell (amyotrophic lateral sclerosis and infantile spinal muscular atrophy)

b. peripheral neuropathy

2. typical histologic changes: angular atrophy and fiber type grouping (early), group atrophy (late)

3. clinical correlates: distal weakness, muscle atrophy, fasciculations; hyporeflexia and sensory loss in neuropathy. In ALS bulbar weakness and hyperreflexia.

b. Muscular dystrophy

1. subtypes divided according to sex and age of onset; most common is sex-linked, early onset Duchenne's muscular dystrophy.

2. typical histologic changes: fiber hypertrophy, fiber splitting, increased endomysial collagen, fiber necrosis and regeneration with limited inflammatory response.

3. immunohistochemical and biochemical analyses show decreased amounts or complete absence of the sarcolemmal membrane protein dystrophin in sex-linked childhood forms of dystrophy.

4. clinical correlates: progressive proximal weakness, calf hypertrophy, lordotic waddling gait, CPK elevation (up to 10,000).

c. Myasthenia gravis

1. The lesion is at the motor end plate and stops electrical transmission beyond that point.

2. Histologic changes: none in routine sections except rare lymphorrhages; antibody deposits at the motor end plate demonstrated by immunohistochemistry; type 2 fiber atrophy is seen often, but is confirmatory, not diagnostic.

3. clinical correlates: weakness and atigue that increases with exertion; often includes eye muscles; symptoms respond to anticholinesterase drugs.

d. Inflammatory myopathy (polymyositis and dermatomyositis)

1. Causes: probably an immune response similar to that seen in other collagen-vascular diseases; rarely may be associated with malignancy in adults.

2. Typical histologic changes: chronic inflammatory cells (lymphocytes, plasma cells and mononuclear macrophages) associated with fiber necrosis and regeneration; perifascicular atrophy in dermatomyositis.

3. clinical correlates: muscle pain and tenderness, proximal weakness, CPK 20,000+, systemic signs of fever, joint pain, skin eruption or other connective tissue disorders.

e. Metabolic myopathies (multiple types)

1. multiple types (examples)

a. glycogenoses (especially Type V McArdle's syndrome with myophosphorylase deficiency)

b. lipid storage: carnitine-related disorders

c. mitochondrial myopathies - many subtypes; usually involve respiratory chain enzymes.

2. Typical histologic changes: storage of deficient enzyme sulstrates (neutral lipid, glycogen); absence of stainable enzymes (myophosphylase, cytochrome oxidase); excessive or abnormally formed mitochondria.

3. clinical correlates: weakness, of limb or ocular muscles, exertional pain and exercise intolerance, rhabdomyolysis, high CPK after exertion.

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