11

Infections of the

Nervous System

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Bacteria

1.Bacterial meningitis

a.General symptoms: Only subtle behavioral changes may be apparent early in the disease course, but progression of the disease typically involves

i.fever, headache, meningismus, photophobia, somnolence

ii.focal neurological dysfunction (15%), particularly hearing loss

iii.seizures (20%)

b.general diagnostic testing

i.blood cultures identify causative pathogens in 50% of cases

ii.cerebrospinal fluid analysis

(1)increased intracranial pressure, protein, and lactate

(2)decreased glucose

(3)pleocytosis is typically 100 cells/ L, and 60% neutrophils; may be lower early in disease course

(4)Gram stain is positive in 60% (Box 11.1)

(5)cultures identify causative pathogen in 75%

iii.neuroimaging: usually is normal, but it may demonstrate hydrocephalus, parenchymal edema, and/or meningeal enhancement; in complicated cases, venous thrombosis or collections of pus between the dura and arachnoid layers of the meninges {empyema} may develop

c.pathophysiology (Table 11–1)

d.general treatment

i.antibiotics, as in Table 11–1; adjust as the causative bacteria are identified

(1)always use bactericidal agents, not bacteriostatic agents

(2)meningeal inflammation makes the brain permeable to essentially all antibiotics

ii.dexamethasone: reduces morbidity and mortality by 40% when used in children or adults with meningitis; give first dose prior to initiation of antibiotic therapy

iii.surgical drainage of any empyema, otitis media, or sinusitis

iv.prophylaxis with the Haemophilus influenza vaccine routinely in children, and with the Neisseria meningitidis vaccine in persons at high-risk for exposure

e.prognosis: 20% mortality; 40% of survivors will develop seizures

2.Brain abscess

a.pathophysiology: causes include

i.contiguous spread: the most common route for brain abscess formation; always results in a single abscess (Box 11.2)

Bacteria

Box 11.1

Yield of CSF Gram stain in bacterial meningitis is reduced only with 2 hour of antibiotic administration.

Box 11.2

Metastic tumors more commonly spread to the brain by a hematogenous route

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250

Table 11–1 Common Causes of Bacterial Meningitis

Note: Local flora and sensitivity patterns require consultation with an infectious diseases expert.

(1)the initial infection is located in a parameningeal site, such as

(a)purulent sinusitis, which produces frontal lobe abscesses

(b)otitis media or mastoiditis, which produce temporal lobe or cerebellar abscesses

ii.hematogenous spread: abscesses preferentially target areas of old brain injury (e.g., infarction), and are multiple in 15% of cases (Box 11.3)

(1)in adults, hematogenous spread of bacteria is usually from a pulmonary infection or (less commonly) endocarditis

(2)in children, hematogenous spread of bacteria is usually from some type of cyanotic congenital heart disease that provides a hypoxic environment and a right–left shunt thereby bypassing normal lung filtration

iii.head injury: closed head trauma is a rare cause of abscesses except in cases that involve unrepaired cerebrospinal fluid leaks

iv.neurosurgery, usually in cases where an air sinus has been opened

v.idiopathic (20%)

b.common pathogens: abscesses include multiple organisms in 90%, usually

Streptococcus species (50%), Bacteroides, and Enterobacteriaceae and other anaerobic bacteria

i.abscesses from trauma also include multiple Staphylococcal species

ii.abscesses in infants often include Gram-negative bacteria

c.symptoms: headache, nausea, and somnolence caused by increased intracranial pressure focal neurological injury

i.increased intracranial pressure may enlarge the head circumference in infants

ii.fever occurs in only 50% because the infection is isolated

d.diagnostic testing: ultimately requires tissue therapy

Box 11.3

Osler-Weber-Rendu syndrome/hereditary hemorrhagic telangiectasia—pulmonary arteriovenous fistulas bypass normal lung filtration; 5% of cases develop cerebral abscesses

i.neuroimaging staging

(1)early cerebritis (stage I): exhibits poorly demarcated ring enhancement that does not wash out and parenchymal edema

(2)late cerebritis (stage II): exhibits a developing necrotic center

(3)early encapsulation (stage III): exhibits a vascularized, necrotic center

(4)late encapsulation (stage IV): exhibits a thin collagen capsule that enhances but then washes out; gliosis develops around capsule

ii.diagnosis requires tissue biopsy

iii.blood cultures are rarely helpful; avoid lumbar puncture due to herniation risk

e.treatment

i.medical treatment: most effective in neuroimaging stages I–II, before the development of an abscess capsule

(1)empiric therapy: vancomycin third-generation cephalosporin metronidazole or chloramphenicol

(2)glucocorticoids prevent fibrous encapsulation but also reduce penetration of antibiotics, therefore use only in patients who are clinically deteriorating

ii.surgical drainage in cases with mass effect, elevated intracranial pressure, poor neurological condition, or proximity of the abscess to a ventricle (i.e., to prevent ventriculitis)

3.Bacterial encephalitis: an uncommon form of bacterial infection in the brain

a.Bartonella henselae/cat scratch disease

i.pathophysiology: a Gram-negative bacillus transmitted by scratches from a colonized cat and possibly by cat fleas

ii.symptoms: fever; lymphadenopathy proximal to the scratch; encephalitis with seizures develops in only 1% of infected patients

(1)may also cause myelitis and/or radiculitis in conjunction with angiomatous skin lesions that are similar to Kaposi’s sarcoma in the immunosuppressed

iii.diagnostic testing: B. henselae enzyme linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR); cerebrospinal fluid is normal in 70% and otherwise shows only a mild lymphocytosis; cultures are unrevealing

iv.treatment: gentamicin or trimethoprim-sulfamethoxazole (TMP-SMX)

v.prognosis: complete recovery in the immunocompetent

4.Bacterial vasculitis (see p. 77)

II. Mycobacteria

1.Mycobacterium tuberculosis/tuberculosis

a.pathophysiology: transmitted from person to person by infected respiratory droplets; infection of the central nervous system may develop during the initial infection (usually pulmonary) or after reactivation of a dormant infection (as in the newly immunosuppressed)

i.Mycobacterium usually spread from a peripheral site of infection to the brain by a hematogenous route or rarely by rupture of a mass of infected granulation tissue {tubercles} into the cerebrospinal fluid; may form abscesses {tuberculomas} directly in brain parenchyma as well

ii.target organs

(1)pulmonary, lymphatic, genitourinary

(2)bones and joints, including the vertebral bodies and intervertebral disks causing spondylosis {Pott’s disease}

(3)meninges brain parenchyma

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251

b.epidemiology: neurological complications are most common in children5 years of age and in the immunosuppressed HIV infection, glucocorticoid use, diabetics

c.symptoms (neurological): neurological symptom from

Box 11.4

The Foix-Alajouanine syndrome is more commonly seen with spinal arteriovenous malformation (AVM) growth.

b.symptoms: exhibits tuberculoid, intermediate, and lepromatous forms, that can occur in the same patient at different times depending upon the level of cellular immunity

i.tuberculous leprosy (in patients with strong cell-mediated immunity): a few skin nodules develop that are associated regions of sensory loss; palpable nerve hypertrophy

ii.indeterminate leprosy: a single hypopigmented patch that has sensory loss

(1)progresses to either tuberculous or lepromatous forms depending upon the effectiveness of the patient’s cell-mediated immunity

iii.lepromatous leprosy (in patients with poor cell-mediated immunity): multiple skin nodules with cartilage erosion in the nose and ears {leonine face deformity}; distal small-fiber sensory loss in the extremities, nose, and ears with palpable nerve hypertrophy

(1)skin nodules are not initially associated with sensory loss, as they are in the tuberculous form of leprosy

(2)weakness and arthropathy develop late in the disease course

c.diagnostic testing

i.identifying bacterial particles in macrophages in skin biopsies, nasal mucosa, or nerve biopsies

ii.lepromin skin test is useful for distinguishing between lepromatous and tuberculous forms of the disease, but is not useful in diagnosis because it is commonly negative in the lepromatous form

d.treatment: dapsone clofazimine rifampin; treat for 1 year in patients with indeterminate or tuberculous forms, or for 2 years in patients with lepromatous form

i.treatment often induces an erythema nodosum-like reaction upon initiation

III. Spirochetes

1.Lyme disease

a.pathophysiology: caused by Borrelia burgdorferi in North American; ticks of Ixodes (Box 11.5) genus serve as the vectors and deer serve as the reservoir

i.the host reaction is largely directed against Borrelia outer-surface proteins (Osp), which are membrane lipoproteins encoded by 21 plasmids that have high antigenic variability, which may account for the organism’s prolonged infectious course

ii.Borrelia preferentially invades meninges, nerve roots, and peripheral nerves, but only rarely brain parenchyma

b.epidemiology: common in New England, Minnesota–Wisconsin, and the Pacific Northwest

c.symptoms: 50% of infections are asymptomatic

i.stage 1 (acute infection): localized erythema migrans

ii.stage 2 (within weeks): nonspecific flu-like symptoms or meningitis; heart block and myocarditis; arthritis

iii.stage 3 (within months): mild sensory polyneuropathy; subtle cognitive disturbances occur in 5% of cases {Lyme encephalitis}

(1)radiculoneuritis is prominent only with B. afzelii or B. garinii infection, which cause Lyme disease in Europe

iv.“chronic” Lyme disease: similar to chronic fatigue syndrome and fi- bromyalgia, however, there is no clear evidence for its existence as a distinct disease entity

d.diagnostic testing: cerebrospinal fluid B. burgdorferi ELISA and Western blotting, or else positive blood serology in the presence of a consistent clinical syndrome

i.serum or cerebrospinal fluid Borrelia PCR is not sufficiently reliable

Spirochetes

Box 11.5

Some Ixodes ticks also produce holocyclotoxin, causing tick paralysis.

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11 Infections of the Nervous System

e.treatment

i.prior to development of neurological symptoms: doxycycline for 14–21 days

ii.with neurological symptoms: third-generation cephalosporin IV for 2–4 weeks

iii.prophylaxis with the Lyme disease vaccine, an OspA adjuvant

(1)single-dose doxycycline may prevent infection it administered within 72 hours of a tick bite

2.Syphilis: Caused by Treponema pallidum

a.primary syphilis: the only symptom is a painless chancre that is acquired by contact with an actively infected site on another person (i.e., another chancre, mucous membrane or skin rash, condyloma lata)

i.may exhibit asymptomatic central nervous system infection as documented by pleocytosis of the presence of spirochetes on dark field microscopy

b.secondary syphilis (Fig. 11–1)

i.symptoms

(1)flu-like syndrome

(2)rash with hyperkeratosis involving the palms and soles

(4)meningitis in only 2% of cases, although 30% of secondary syphilis patients have an asymptomatic central nervous system infection

ii.diagnostic testing: cerebrospinal fluid evaluation by a Venereal Disease Research Laboratory (VDRL) test is specific but not sensitive, and cerebrospinal fluid fluorescent treponemal antibody (FTA) testing is sensitive but not specific; therefore, evaluate with a VDRL, but treat even if these tests are negative so long as there is pleocytosis or the presence of oligoclonal bands in a patient with a compatible clinical syndrome

(1)baseline cerebrospinal fluid cell count, protein level, and VDRL titer should be obtained to compare with follow-up tests to assess the adequacy of treatment

iii.treatment: penicillin G 4 106 U IV q.4.h. for 14 days

(1)to determine the adequacy of treatment, reexamine cerebrospinal fluid every 6 months for 3 years whereas successful treatment is defined as

(a)reduction in the lymphocyte pleocytosis and protein level, which are the most sensitive and rapidly changing indicators of treatment efficacy

(b)fourfold reduction in VDRL titer, which may take 1 year to achieve

(2)repeated treatment is indicated if the cerebrospinal fluid studies fail to normalize or if symptoms persist

(3)in penicillin-allergic patients, attempt penicillin desensitization or else use doxycycline for 4 weeks

c.latent syphilis: an asymptomatic central nervous system infection that can be demonstrated in 40% of cases

i.diagnostic testing: as above; obtain baseline cerebrospinal fluid studies to assess adequacy of treatment, as per secondary syphilis

ii.treatment: penicillin G as described above

ii.meningovascular neurosyphilis, involving arteries of all sizes and causing strokes typically in the MCA distribution (see p. 77)

(1)diagnosis and treatment as per secondary syphilis

iii.parenchymatous neurosyphilis: develop years to decades after primary syphilis

(1)tabes dorsalis: inflammatory destruction of the lumbosacral dorsal root ganglia with subsequent loss of spinal sensory pathways

(a)symptoms: begin after a period of meningitis

(i)episodic pain in the lower extremities, or in the abdomen and thorax {visceral crises}

(ii)vision loss from optic atrophy

(iii)ataxia, areflexia, Charcot joints, and trophic ulcers from large-fiber sensory loss

(iv)insensitivity to pain, overflow incontinence, constipation, and sexual dysfunction from small-fiber sensory loss

(v)small, irregular pupils that accommodate but do not react to light {Argyll-Robertson pupil}; involves an unknown injury in the light reflex circuit

(b)diagnosis and treatment as per secondary syphilis

(2)general paresis: an encephalitic infection

(a)symptoms

(i)personality changes

(ii)affect abnormalities

(iii)reflex abnormalities (generally hyperreflexic)

(iv)eye: Argyll-Robertson pupils

(v)sensorium: illusions, delusions, hallucinations

(vi)intellectual dysfunction progressive dementia

(vii)speech dysarthria

(b)diagnosis and treatment as per secondary syphilis

IV. Rickettsia

1.Rocky Mountain spotted fever

a.pathophysiology: caused by Rickettsia rickettsii; Dermacentor (Box 11.6) ticks serve as the vector, and rodents and dogs serve as the reservoir

i.epidemiology: predominant in the north and east United States, Canada, and Mexico

b.symptoms: rash beginning on the ankles (Box 11.7); meningitis with focal neurological signs (15%) and seizures (5%)

c.diagnostic testing: immunofluorescence or immunoperoxidase staining of skin biopsy from the rash site; R. rickettsii serology

i.cerebrospinal fluid analysis is nondiagnostic

d.treatment: tetracycline or doxycycline continued until 2 days after the fever ends

e.prognosis: 20% mortality if treatment is delayed

2.Typhus

a.pathophysiology: caused by Rickettsia prowazekii, which is transmitted from human to human by lice; epidemic typhus occurs in overcrowded and unsanitary conditions during cold weather

b.symptoms: rash beginning in the axilla; meningitis focal neurological injury

c.diagnostic testing: R. prowazekii ELISA, PCR, or agglutination tests

d.treatment: tetracycline or doxycycline; vaccination for persons at exposure risk

Rickettsia

Box 11.6

Dermacentor also carries Colorado tick fever virus.

Box 11.7

Other types of meningitis with petechial rash: N. meningitidis, S. pneumoniae, S. aureus

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256

V. Viruses

1. Herpes viruses

a.herpes simplex (HSV) type I and II

i.pathophysiology: causes hemorrhagic necrosis of the temporal lobes that is histologically characterized by large, solitary nuclear inclusions surrounded by a halo in neurons, astrocytes, and oligodendroglia {Cowdry type A

inclusions} (Fig. 11–2) and by Alzheimer’s disease-like neurofibrillary tangles

(2)Ramsay-Hunt syndrome/otic zoster: viral reactivation in the geniculate ganglion of CN VII causes facial paresis and rash on the tympanic membrane and external auditory canal

(a)associated with a large-vessel vasculitis

(b)flaccid weakness develops in 5%, likely because the infection has involved the ventral root and spinal cord

(c)zoster sine herpete: radicular pain without rash; requires demonstration of varicella in the cerebrospinal fluid by PCR analysis or an increased ratio of cerebrospinal fluid-to-serum varicellazoster virus (VZV) titres

(2)treatment: acyclovir, famciclovir, valacyclovir for 7 days, started within 3 days of symptom onset; glucocorticoids for 3 weeks

iii.varicella encephalitis: dissemination to the brain occurs in 2% of immunocompetent patients and 50% of immunosuppressed patients who develop shingles; treat with acyclovir (Box 11.9)

c.cytomegalovirus (CMV)

i.histology: Cowdry type A inclusions are found in ependymal cells neurons, glia

ii.types of infection

(1)in utero infection: symptoms include retinitis and encephalitis, leading to vision loss, deafness, and mental retardation; cerebral calcifications, microcephaly, and migrational defects (lissencephaly/ pachygyria, polymicrogyria, cerebellar agenesis) can occur even without signs of systemic infection

(2)infection in the immunosuppressed (e.g., HIV, following bone marrow transplantation): usually spreads to the brain by a hematogenous route (causing encephalitis) or by direct spread through the cerebrospinal fluid (causing ventriculoencephalitis); often occurs with CMV retinitis, esophagitis, or colitis, and CMV viremia is invariably present

(a)symptoms: confusional state developing over weeks (encephalitis) or days (ventriculoencephalitis); cranial nerve palsies, nystagmus, hydrocephalus

(b)prognosis: usually fatal within a few months

iii.diagnostic testing: demonstration of CMV by PCR in the cerebrospinal fluid

iv.treatment: ganciclovir, foscarnet, cidofovir

2.Rabies virus

a.pathophysiology: viral inoculation occurs after a bite from an infected animal (dog, cat, fox, raccoon, bat); retrograde and transsynaptic transport carries the virus up the peripheral nerves and into the central nervous system (i.e., to the brain producing an encephalitic disease, or to the spinal cord producing a paralytic disease)

i.histology: characterized by microglial nodules {Babes nodes}, perivascular inflammation, and viral inclusions in the cytoplasm of Purkinje cells and hippocampal pyramidal cells {negri bodies} that appear as bullet-shaped particles on electron microscopy (Fig. 11–3)

b.symptoms: begins several days to weeks after the inoculating bite as a flulike syndrome that progresses to either

i.an encephalitic form, involving behavioral changes (agitation, hyperactivity), severe dysphagia producing frothing, and eventually seizures and psychosis before death

(1)hydrophobia is likely due to the inability to swallow

ii.a paralytic form, which develops over a period of days leading to death

Box 11.9

Reye’s Syndrome

A pediatric encephalopathy from cerebral edema and elevated ammonia levels caused by rapid liver failure with fatty infiltration of the liver

Induced by aspirin use during several types of viral infections, including varicella and influenza

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11 Infections of the Nervous System

4.Polio viruses and polio-related syndromes

a.polio: commonly caused by one major (i.e., poliovirus) and several minor enteroviruses that directly infect the anterior horn lower motoneurons, causing their death; polio has been largely eradicated by vaccination

i.symptoms: developed 2–5 days after viral gastroenteritis with asymmetric and focal myalgias, fasciculations, and weakness in the lower extremity upper extremity bulbar muscles

ii.epidemiology: risk increased with age into young adulthood

iii.diagnostic testing: stool cultures for poliovirus

iv.treatment: prophylaxis with inactivated polio vaccine, which is routine in children

v.prognosis: significant improvement occurred in 80% after the acute illness

b.polio-related syndromes

i.postvaccination polio: caused by oral polio vaccine use, which was a live-attenuated virus that is no longer in use in the US; occurred in 0.04 per 100,000 vaccinations

ii.postpolio syndrome: progressive weakness beginning at least 10 years after polio that occurs in the previously affected musculature; a dubious disease entity that may reflect normal age-related loss of lower motoneurons

5.JC virus/progressive multifocal leukoencephalopathy (PML)

a.pathophysiology: a polyoma virus infection of oligodendroglia and astrocytes that causes cell death and demyelination; usually occurs in immunosuppressed patients after reactivation of a latent infection

b.histology: “ground glass” intranuclear inclusions in oligodendroglia; spheres and elongated rods (“spaghetti and meatballs”) on electron microscopy

c.symptoms: focal neurological injury with dementia progressing over months

d.diagnostic testing: identification of JC virus in cerebrospinal fluid by PCR

i.neuroimaging demonstrates multiple nonenhancing areas of decreased T1 and increased T2 signal without mass effect or edema; begin as small lesions that eventually form large confluent lesions

e.treatment: none specific against the JC virus, but reversing an immunosuppressed state (e.g., highly active antiretroviral therapy (HAART) therapy in HIV patients) may improve the symptoms

f.prognosis: 4-month survival, but 10% exhibit spontaneous remission

6.Measles virus

a.general pathophysiology: histologically characterized by Cowdry type A inclusion bodies in neurons and glia, and multinucleated giant cells

b.types of infection

i.acute self-limited encephalitis, associated with the rash

ii.measles inclusion body encephalitis: occurs in immunosuppressed patients several months after measles infection

(1)symptoms: rapidly-progressive dementia, seizures, and myoclonus progressing to coma

(2)treatment: reverse immunosuppressed state, if possible

iii.subacute sclerosing panencephalitis: a post-infection complication caused by abnormal assembly of the measles virus particles in the infected cells, leading to viral particle accumulation and transmission only at sites of cell–cell contact; develops in children several years after the viral rash

Viruses

11 Infections of the Nervous System

260

(a)subcortical dementia: impaired concentration, memory loss, apathy

(b)psychosis (10%)

(c)bradykinesia; hyperreflexia and spasticity

(3)diagnostic testing

(a)neuroimaging: MRI demonstrates diffuse high white matter signal on T2; late in the disease diffuse atrophy becomes apparent

(b)cerebrospinal fluid demonstrates increased protein, lymphocytosis, and elevated markers of lymphocyte and macrophage activation (e.g., 2 microglobulin, quinolinic acid)

(4)treatment: high-dose zidovudine, which can be a component of HAART

ii.vacuolar myelopathy: symptoms include spastic weakness, loss of large-fiber sensation (particularly proprioception), and incontinence developing over a period of months, caused by degeneration of posterior and lateral spinal cord columns

(1)unlikely caused directly by HIV infection, instead may be related to impairment of vitamin B12 utilization

iii.distal sensory polyneuropathy: symmetric sensory motor, rarely painful (Box 11.11)

(1)epidemiology: develops in 30% of AIDS patients

iv.HIV myopathy: can develop at any CD4 count; histologically is a poorly defined condition because of coincident myopathy from antiretroviral medications (particularly zidovudine) and from cachexia

(1)symptoms: proximal distal weakness, muscle soreness

(2)diagnostic testing: normal or increased baseline CK that is greatly increased by exercise

v.stroke: may be caused by HIV vasculitis, induced protein C and S deficiency, antithrombin III deficiency, or antiphospholipid antibody syndrome

(1)vasculitis can also be caused by cytomegalovirus, varicella, tuberculosis, or syphilis coinfection

e. opportunistic diseases with focal findings (Box 11.12)

i.toxoplasmosis: caused by Toxoplasma carinii (see p. 264)

(1)epidemiology: develops in 10% of AIDS patients

(2)symptoms: focal symptoms and encephalopathy fever headache developing over days to weeks

(3)diagnostic testing

(a)neuroimaging: usually exhibits multiple ring-enhancing lesions with mass effect, most commonly at the gray–white junction or basal ganglia

(i)70% of cases have multiple lesions

(ii)negative Toxoplasma IgG titers suggests the lesions are lymphoma

(iii)repeat neuroimaging after antibiotic treatment for 10 days to determine if the lesions have been reduced in size; avoid glucocorticoids unless the mass is inducing herniation as they will reduce both infectious and cancerous lesions

(4)treatment

(a)acute: pyrimethamine sulfadiazine or clindamycin folate

(b)prophylactic: TMP-SMX or dapsone

(5)prognosis: 90% of patients respond to treatment

Box 11.11

Neuropathy from antiretroviral treatments is painful unlike that directly from HIV infection.

Box 11.12

Brain Lesion Management in AIDS

1.Acute empiric treatment for toxoplasmosis except in cases of negative serologic studies

Evaluate for radiographic shrinkage within 10 days

Continue toxoplasmosis treatment indefinitely if the lesions are shrinking

2.Lesions with negative toxoplasmosis serology are an indication for brain biopsy

3.SPECT or PET suggests primary CNS lymphoma, which still requires brain biopsy confirmation

4.Immediately brain biopsy in children with AIDS and lesions

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Fungus

11 Infections of the Nervous System

264

Prion Diseases

Box 11.13

Kuru

Pathophysiology: Transmissible only by cannibalism, occurs only in New Guinea

Histology: Kuru-type plaques in cerebellum

Symptoms: limb and truncal ataxia; dementia

Idiopathic Infection-Like Conditions

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11 Infections of the Nervous System

ii.cerebrospinal fluid demonstrates a lymphocyte pleocytosis and increased protein

d.treatment: glucocorticoids

2.Mollaret’s meningitis

a.pathophysiology: possibly related to recurrent bouts of limited herpes virus reactivation, but generally no pathogen can be identified

b.symptoms: several days of meningitis-like symptoms that spontaneously resolve

c.diagnostic testing: cerebrospinal fluid contains various types of leukocytes and large endothelium-like cells {Mollaret’s cells}; Mollaret’s cells usually are observable only at the very beginning of an attack

d.treatment: none specific

3.Vogt-Koyanagi-Harada syndrome

a.pathophysiology: possibly an autoimmune reaction against retinal photoreceptor antigens; associated with (HLA)-DR

b.symptoms: a self-limited episode of meningitis and iritis followed weeks later by hair loss, focal loss of hair pigmentation {poliosis}, and vitiligo; meningitis episode can involve focal neurological injury, and vision loss can occur from iritis

c.diagnostic testing: cerebrospinal fluid has melanin-containing macrophages

d.treatment: glucocorticoids

12

Developmental and Metabolic

Diseases of the Nervous System

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Disorders of Embryogenesis

A. Malformations

1. Cortical malformations—general symptoms include medication-refractory

Disorders of Embryogenesis

269

ii.subtypes

(1)alobar holoprosencephaly: no divisions develop between the hemispheres or lobes; associated with a single underlying ventricle, agenesis of the septum and corpus callosum, and olfactory and optic nerve hypoplasia

(2)semilobar prosencephaly: failure of the anterior interhemispheric division allows for fusion of the anterior cortices with significant hypoplasia of the corpus callosum and olfactory nerves; a posterior interhemispheric division exists and the basic lobar structure is otherwise preserved

(a)septo-optic dysplasia—a variant of semilobar prosencephaly; specific features include hypothalamic hamartomas causing panhypopituitarism, agenesis of the cerebellar vermis and fusion of the dentate nuclei causing ataxia (Fig. 12–3).

(3)lobar prosencephaly: interhemispheric connections occurring between frontal poles and the cingulate cortices through an oversized indusium griseum (a vestigial gray matter band normally located on top of the corpus callosum); limited hypoplasia of the corpus callosum

g.hydranencephaly—reduction of the cerebral cortex to a flat, thin layer, often sparing the basal cortex and hippocampus but severely disrupting the thalamus and basal ganglia; caused by destructive processes (which produce microcephaly at birth) or by hydrocephalus

i.generally fatal within a few days due to hypothalamic dysfunction

2.Subcortical malformations

a.agenesis of the corpus callosum—caused by complete or partial failure of the extension of the developing corpus callosum posteriorly from the lamina terminalis; fibers that cannot cross in the corpus callosum run ipsilaterally in a rostrocaudal direction {bundle of Probst} (Box 12.3)

i.other commissures are enlarged

ii.occurs in isolation in 2% of population

iii.symptoms: generally asymptomatic without other malformations, but may exhibit

(1)learning disabilities or mental retardation

(2)abnormally wide-spaced eyes {hypertelorism}

(3)exotropia with inability to converge

3.Abnormalities of cerebrospinal fluid and the ventricular system

a.symptoms of hydrocephalus include irritability, bulging fontanelles, prominent scalp veins, false-localizing CN VI palsies, Parinaud’s syndrome, hyperreflexivity, and irregular respiration

b.diagnosis requires a head circumference 2 standard deviations for gestational age or an increase in head circumference 2 standard deviations during first year of life; diagnosis does not require elevated intracranial pressure, which only occurs after fusion of the cranial sutures

c.pathophysiology: acquired pediatric hydrocephalus conditions

i.noncommunicating: aqueduct stenosis caused by intrauterine infection, hemorrhage, trauma, or tumor

ii.communicating: following subarachnoid hemorrhage or meningitis

d.pathophysiology: syndromal hydrocephalus conditions

i.trisomy 9, 13, 18

ii.VACTERL syndrome with hydrocephalus (Box 12.4)

iii.Hunter’s and Hurler’s syndromes

iv.Walker-Warburg syndrome (also has congenital muscular dystrophy, lissencephaly, Dandy-Walker malformation, and eye malformations)

v.craniosynostosis syndromes: all involve premature closure of skull sutures leading to skull deformation, and have autosomal dominant and sporadic forms

(1)simple craniosynostosis: early closure of one or a few sutures that does not cause hydrocephalus or other symptoms

(2)complex craniosynostosis

(a)Crouzon’s syndrome—other symptoms include multiple cranial nerve palsies caused by jugular foramen narrowing; no mental retardation

(b)Apert’s syndrome—other symptoms include facial deformity, syndactyly, short upper extremities, and mental retardation

vi.X-linked hydrocephalus syndromes: both are caused by mutations in L1CAM, a cell adhesion molecule (Box 12.5)

(1)mental retardation, aphasia, shuffling gait, adducted thumbs (MASA) disorder

(2)X-linked aqueduct stenosis—also exhibits adducted thumbs, agenesis of the corpus callosum, brainstem malformations, and hypoplastic corticospinal tracts

4.Cerebellar and brainstem malformations

a.Chiari malformations

Box 12.3

Aicardi’s syndrome

Pathophysiology—X-linked inherited agenesis of corpus callosum and anterior commissure, and polymicrogyria

Symptoms—Mental retardation; myoclonic epilepsy; chorioretinal abnormalities; vertebral abnormalities

Box 12.4

VACTERL syndrome

Vertebral anomalies; anal atresia; cardiac defects; tracheoesophageal fistula; renal abnormalities; l imb abnormalities. Some cases can be caused by mutation in the sonic hedgehog gene, like holoprosencephaly.

Box 12.5

L1CAM is also mutated in X-linked hereditary spastic paraparesis.

Disorders of Embryogenesis

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Disorders of Embryogenesis

273

274

Neurocutaneous Syndromes/Phakomatoses

275

3.Diagnostic testing: neuroimaging with MRI; genetic testing

4.Treatment: none specific

C. Tuberous Sclerosis

1.Pathophysiology

a.caused by autosomal dominant mutations in the

i.TSC-1 gene (chromosome 9): encodes the hamartin protein, which functions in linking the cell membrane to the cytoskeleton

ii.TSC-2 gene (chromosome 16): encodes the tuberin protein, which is similar to GTPase-activating proteins and interacts with hamartin

b.TCS1 mutations may be more likely to cause familial disease and have a milder course, but otherwise there is no obvious phenotype difference between the two genetic subtypes

2.Histology

a.nervous system: cortical hamartomas {tubers}; focal cortical hypoplasia; subependymal heterotopias that are generally calcified; subependymal giant cell astrocytomas

b.eye: hamartomas, retinal depigmentation

c.cardiac, pulmonary, and renal hamartomas

d.vasculature: degeneration of the tunica media promotes aneurysm formation

3.Symptoms

a.neurological symptoms

i.mental retardation ( 50%)

ii.seizures (90%): may occur in the absence of mental retardation (Box 12.11)

iii.autism and behavioral disorders (psychosis, attention deficit– hyperactivity disorder)

b.skin

i.ash-leaf patches (Fig. 12–9): nonspecific for the phakomatoses

Figure 12–8 Unidentified bright objects (arrow) of neurofibromatosis type 1. (From Raininko R et al. Non-neoplastic brain abnormalities on MRI in children and adolescents with neurofibromatosis type 1. Neuropediatrics, 2001, 32: 226, Fig. 1b. Reprinted by permission.)

Box 12.11

Tuberous sclerosis is the most common cause of infantile spasms with a known etiology.

A

Figure 12–9 An ash-leaf patch (A). In a fair-skinned child (B), ash-leaf patches may be difficult to observe directly (left) and may require a Wood’s lamp (right). (Panel A, from Panteliadis CP, Darras BT. Encyclopaedia of Paediatric Neurology: Theory and Practice, 2nd ed. Stuttgart,

B

Germany: Georg Thieme; 1999:497, Fig. 25–4. Reprinted by permission. Panel B, from Kurlemann G, Schuierer G. Ash-leaf spots in tuberous sclerosis. New Eng J Med, 1998, 338:1887. Copyright 1998 Massachusetts Medical Society. All rights reserved.)

Neurocutaneous Syndromes/Phakomatoses

277

III. Aminoacidopathies (Box 12.12)

1.Maple syrup urine disease

a.pathophysiology: caused by autosomal recessive mutations of the branchedchain ketoacid dehydrogenase (BCKD) complex, which also decarboxylates branched chain amino acids (isoleucine, valine, leucine); BCKD requires thiamine cofactor, which accounts for a thiamine-responsive variant of the disease

i.histology: immature central nervous system myelination {dysmyelination}, heterotopias, diffuse spongy degeneration, and failure to develop all cortical layers

278 b. symptoms

Box 12.12

Diseases with Hyperammonemia

Aminoacidopathies—Glycine encephalopathy

Disorders of urea metabolism—Argininosuc- cinate lyase deficiency; argininosuccinate synthase deficiency; arginase deficiency

Disorders of organic acids—Isovaleric acidemia; propionic acidemia; methylmalonic acidemia

Toxicities—Valproate use (the most common cause)

i.neonatal onset (severe enzyme deficiency): normal at birth, but symptoms develop within days of starting a protein diet

(1)general symptoms: ketoacidosis and hypoglycemia

(2)neurological symptoms: hypotonia; lethargy; apnea, respiratory failure; seizures and coma, usually leading to death or mental retardation in the survivors

ii.infant onset (moderate enzyme deficiency): symptoms usually develop after a catabolic state (e.g., febrile illness)

(1)general symptoms: mild ketoacidosis

(2)neurological symptoms: ataxic gait; mental retardation

c.diagnostic testing

i.urine dinitrophenylhydrazine chromogenic test for amino acids

ii.elevated serum branched-chain amino acid levels

iii.neuroimaging: demonstrates areas of abnormal subcortical white matter signal at baseline, and cerebral edema that develops after a protein meal

d.treatment

i.thiamine

ii.low branched-chain amino acid diet; protein-free diet during acute exacerbations

iii.hemodialysis for severe ketoacidosis

2.Phenylketonuria

a.pathophysiology: autosomal recessive deficiency of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine; high levels of phenylalanine are directly toxic to glia more so than neurons

i.phenylalanine hydroxylase requires tetrahydrobiopterin cofactor (Box 12.13)

ii.histology: as per maple syrup urine disease

b.symptoms: develop 2–3 months after birth

i.general symptoms: musty body odor; dry, scaling hypopigmented skin; small stature; patients are always blonde and blue-eyed

ii.neurological symptoms: microcephaly with failure to acquire developmental milestones and mental retardation; hyperactivity, irritability; tremor; spasticity; infantile spasms progressing to generalized tonic-clonic seizures

c.diagnostic testing: screening blood test for blood phenylalanine taken 24 hours after protein the first feeding; if positive, phenylketonuria is confirmed by demonstrating normal urine tyrosine and tetrahydrobiopterin levels

d.treatment: phenylalanine-restricted diet beginning by 3 weeks of age

i.diet restrictions must be carefully monitored by a nutritionist and should be continued at least through adolescence; it is unclear if a normal diet can ever be safely instituted

e.prognosis: dietary management limits mental retardation

3.Hartnup’s disease

a.pathophysiology: abnormal function of the neutral amino acid transport protein impairs intestinal absorption and renal reabsorption of neutral amino acids, particularly tryptophan

b.symptoms: develop in childhood, and are unrelated to diet

i.general symptoms: photosensitive dermatitis

ii.neurological symptoms: headache; depression, psychosis; gait ataxia

c.diagnostic testing: increased urine excretion of tryptophan and other neutral amino acids, which is constant and does not correlate with symptom severity

d.treatment: nicotinamide and tryptophan supplementation

Aminoacidopathies

Box 12.13

Tetrahydrobioprotein Methylenetetrahydrofolate (used in conversion of homocysteine to methionine)

279

280

4.Glycine encephalopathy

a.pathophysiology: caused by an unknown defect in glycine metabolism that leads to glycine accumulation

b.symptoms: irritability, hiccupping, lethargy, and hypotonia developing within a few hours of birth; myoclonic seizures develop thereafter

i.no ketoacidosis, as in some disorders of organic acids (i.e., isovaleric acidemia, propionic acidemia)

c.diagnostic testing

i.EEG: shows a burst-suppression pattern progressing to hypsarrhythmia (see p. 92)

ii.increased serum and cerebrospinal fluid glycine level without hyperammonemia or organic acidemia (Box 12.14)

d.treatment

i.hemodialysis for severe encephalopathy

ii.diazepam benzoate for seizures; avoid valproate

e.prognosis: death within a few weeks of birth

5.Aromatic amino acid/DOPA decarboxylase deficiency

a.pathophysiology: mutations in aromatic amino acid/dihydroxyphenylalanine (DOPA) decarboxylase prevents L-DOPA conversion to dopamine (Box 12.15), and 5-hydroxytryptophan conversion to serotonin

b.symptoms: onset 2 years of age; symptoms become worse throughout the day and improve after sleep (Box 12.16)

i.axial hypotonia with limb hypertonia; dystonia; startle myoclonus

ii.autonomic dysfunction: diaphoresis, temperature instability, ptosis, miosis, episodic hypoglycemia

iii.mental retardation; failure to achieve motor milestones

iv.disturbed sleep–wake patterns

c.treatment: vitamin B6/pyridoxine (cofactor for the decarboxylase); monoamine oxidase (MAO) inhibitors; dopaminergic agonists (pergolide, bromocriptine); melatonin for disturbed sleep

6.Canavan’s disease/spongy degeneration of infancy: see p. 115

7.Homocysteinuria: see p. 72

IV. Disorders of Organic Acids

1.Isovaleric acidemia

a.pathophysiology: caused by autosomal recessive deficiency of isovalerylCoA dehydrogenase that leads to accumulation of isovaleric acid (a fatty acid); normally this enzyme is active in a multistep pathway converting leucine to acetoacetate

b.symptoms: lethargy and protracted vomiting developing within a few days of birth; exhibits ketoacidosis, unlike glycine encephalopathy

c.diagnostic testing: increased isovaleryl-lysine levels, which causes the urine to smell like sweaty feet and the patient to smell like stale sweat

d.treatment: dietary protein restriction, particularly leucine; L-carnitine and glycine supplementation

e.prognosis: 60% 3-week mortality

2.Propionic acidemia

a.pathophysiology: caused by autosomal recessive deficiency of propionylCoA carboxylase; enzymatic deficiency prevents the conversion of propionic acid to methylmalonyl-CoA (Fig. 12–16)

b.symptoms: lethargy, hypotonia, and dehydration developing within days to months of birth

c.diagnostic testing

Box 12.14

Increased glycine and ketoacidosis occurs in propionic academia and isovaleric acidemia.

Box 12.15

Dopamine is formed by tyrosine hydroxylase, which is mutated in Segawa’s syndrome.

Box 12.16

Worsening of symptoms during the day is similar to Segawa’s syndrome.

i.hyperammonemia; ketoacidosis (unlike glycine encephalopathy)

ii.increased serum glycine and propionate levels; increased urine glycine, methylcitrate, and -hydroxypropionate

iii.increased methylcitrate levels in the amniotic fluid for prenatal diagnosis

d.treatment

i.hemodialysis for severe encephalopathy

ii. dietary protein restriction

1.5 g/kg/d

iii.L-carnitine to reduce ketoge-

iv.biotin supplementation (an en-

zymatic cofactor for propionyl-CoA carboxylase)

3.Methylmalonic acidemia

a.pathophysiology: caused by autosomal recessive deficiency of methylmalonylCoA mutase, which leads to accumulation of propionyl-CoA, propionic acid, and methylmalonic acid

b.symptoms: lethargy, vomiting, dehydration, and hypotonia developing after the initiation of protein feeding

c.diagnostic testing: hyperammonemia; increased serum glycine and methylmalonic acid; increased urine methylmalonic acid

d.treatment

i.dietary protein restriction 1.5 g/kg/d

ii.vitamin B12 supplementation (a cofactor for methylmalonyl-CoA mutase)

iii.L-carnitine to reduce ketogenesis

e.prognosis: majority die within 2 months; survivors have episodic metabolic acidosis and mental retardation

V. Disorders of Urea Metabolism

1.Pathophysiology: all exhibit autosomal recessive inheritance except for ornithine transcarbamylase deficiency, which is X-linked (Fig. 12–17)

2.General symptoms: vomiting, lethargy, and hypotonia beginning within 24 hours of birth, due to ammonia toxicity; coma develops if ammonia 300 g/dL, and seizures if 500 g/dL

3.Specific symptoms

a.carbamyl phosphate synthetase deficiency—abnormal eye movements

b.ornithine transcarbamylase deficiency—respiratory alkalosis

c.argininosuccinate synthase deficiency/citrullinemia—hepatomegaly; ataxia

d.arginase deficiency—spastic diplegia

e.argininosuccinate lyase deficiency—brittle hair associated with small nodules along the hair shaft {trichorrhexis nodosa}

4.Diagnostic testing

a.hyperammonemia without organic aciduria that is greatly increased after a protein meal

b.elevated orotic acid levels, except in carbamyl phosphate synthetase deficiency

c.elevated serum levels of amino acids and orotic acid, and urine amino acids

Disorders of Urea Metabolism

281

Lysosomal Storage Disorders

Figure 12–18 The sphingolipid metabolic pathway.

C. Disorders of Sphingolipid Metabolism (Sphingolipidoses)

1.Pathophysiology: caused by mutations of enzymes in the sphingolipid metabolic pathway (Fig. 12–18)

2.General symptoms: onset before 2 years of age; developmental delays and/or mental retardation (Box 12.18)

3.Subtypes (Table 12–3)

4.Treatment: Bone marrow transplantation for metachromatic and globoid leukodystrophies with mild neurological involvement

Box 12.18

Diseases with Cherry-Red Spots—GM-1 & GM-2 gangliosidosis; metachromatic leukodystrophy; Niemann-Pick disease

Gaucher’s disease

GM1 gangliosidosis

GM2 gangliosidosis/ Tay-Sach’s disease

Glucocerebrosidase

(AR); rarely saposin C cofactor/ glucocerebrosides

-Galactosidase (AR); rarely saposin B/GM1 ganglioside

Hexosaminidase A or B (AR); rarely glycoprotein activator/GM2 gangliosides

Type I: visceral; IV enzyme responsive

Type II (infant): neurovisceral; therapy resistant

Type III (child): neurovisceral; IV enzyme responsive

Cherry-red macula spot similar to Hurler’s syndrome, a mucopolysaccharidosis

Tay-Sachs is infantile form

CNS: increased startle reflex, MR, motor regression; cherry-red spot on macula

D. Neuronal Ceroid Lipofuscinosis (NCL)

1.General histology: accumulation of autofluorescent lipid pigments (ceroid, lipofuscin) in brain, retina, and gastrointestinal tract that form inclusion bodies; degeneration of retinal photoreceptor and loss of specific layers of cortical neurons, depending upon subtype

a.epidemiology: most common in Scandinavians

2.General symptoms: progressive dementia; progressive vision loss from retinal and optic nerve degeneration; ataxia; myoclonus

3.Subtypes

a.early-infantile NCL: onset 1–2 years of age

i.pathophysiology: caused by mutation in the palmitoyl protein thioesterase (CLN1) gene, the protein of which removes fatty acids from lipoproteins

ii.specific symptoms: hyperactivity; hypotonia

b.late-infantile NCL: onset 2–3 years of age

i.pathophysiology: caused by mutations in the CLN2 gene, which encodes tripeptidyl peptidase that removes N-terminal tripeptides from polypeptides

ii.specific symptoms: seizures; dementia progressing to a vegetative state

c.juvenile NCL: onset 4–9 years of age

i.pathophysiology: caused by mutations in CLN3 gene, which encodes a lysosomal membrane protein of unknown function

ii.specific symptoms: Parkinsonism; tonic-clonic seizures

d.adult NCL: onset 40 years of age

i.pathophysiology: unknown

ii.specific symptoms: seizures; peripheral neuropathy

4.Diagnostic testing

a.reduced palmitoyl protein thioesterase and tripeptidyl peptidase levels (infantile NCLs)

b.neuroimaging: diffuse atrophy, usually cerebral cerebellar; increased T2 signal in the thalami and deep white matter

c.EEG, visual evoked potentials, and electroretinograms exhibit increased responsiveness to photostimulation

d.tissue biopsy of muscle, skin, conjunctiva, or rectum for inclusion bodies

5.Treatment: None specific

Disorders of DNA Repair and Nucleoside Metabolism

VII. Disorders of DNA Repair and Nucleoside Metabolism

1.Xeroderma pigmentosa

a.pathophysiology: caused by abnormalities of DNA repair throughout the genome (i.e., in actively transcribed and inactive regions); the majority of cases with neurological disease have autosomal recessive mutations in DNA helicase (Box 12.19)

i.histology: pronounced neuron loss in the cortex, basal ganglia, and cerebellum causes generalized atrophy; also exhibits anterior horn and dorsal root ganglia neuron loss, and cochlear hair cell atrophy

b.symptoms

i.general symptoms: sun sensitivity causing premature skin aging and an increased incidence of skin cancers

ii.neurological symptoms: microcephaly with progressive dementia; sensorineural hearing loss; spastic weakness that ultimately become areflexic due to a sensorimotor neuropathy; ataxia, dysarthria

c.treatment: avoid sun exposure

2.Cockayne’s syndrome

Box 12.19

Certain mutations in DNA helicase may cause a Cockayne-like syndrome.

285

VIII. Disorders of Oxidative Phosphorylation

Causing Lactic Acidosis

1.General pathophysiology: caused by enzymatic deficiencies in the Kreb’s cycle or mitochondrial electron transport chain that allow the accumulation of lactate, which is neurotoxic; failure of oxidative phosphorylation may also directly cause cellular death

a.neurons in the basal ganglia (particularly the putamen) are susceptible to lactate

b.histological changes are similar to thiamine deficiency (i.e., Wernicke’s encephalopathy), although the mamillary bodies are spared

2.Major subtypes

a.pyruvate dehydrogenase deficiency—the clinical course is variable and proportionate to the degree of enzyme deficiency

i.specific symptoms: often the lactic acidosis is fatal in the neonatal period; survivors exhibit mental retardation, hypotonia, choreoathetoid cerebral palsy, and a demyelinating polyneuropathy

b.Leigh’s disease (see p. 48), a subset of which is caused by pyruvate dehydrogenase deficiency

3.Diagnostic testing

a.elevated fasting lactate and reduced pyruvate in blood, which may require preceding ingestion of carbohydrates to detect

b.skin and muscle biopsy for identification of enlarged mitochondria

4.Treatment: Multivitamin, L-carnitine, and coenzyme Q10 supplementation; bicarbonate; dietary carbohydrate restriction; dichloroacetic acid for pyruvate dehydrogenase deficiency

IX. Developmental Delays and Regression

A.Normal Developmental Milestones (Table 12–4)

B.Abnormal Development

1.Language delay: causes include

a.hearing impairment: the most common cause of language delay; commonly occurs after intrauterine cytomegalovirus infection, neonatal meningitis, or kernicterus

i.even mild hearing loss can cause language delay if the loss is concentrated in the high-frequency tones

b.bilateral hippocampal sclerosis: usually presents with seizures; one normally functioning medial hippocampal gyrus is necessary for language development

Table 12–4 Normal Developmental Milestones

Developmental Delays and Regression

288

c.focal lesions in cortical language areas: produce language delay only in children 5 years of age; lesions in children 5 years of age displace language functions to the contralateral hemisphere

d.autism: see p. 290

2.Motor delay

a.cerebral palsy

i.pathophysiology: likely causes are in utero/pre-labor injuries (e.g., twining, in utero stroke, congenital malformations); not related to birth injury or obstetrical procedures

(1)the incidence of cerebral palsy has not changed except for the choreoathetotic subtype, which has been decreased by treatment of hyperbilirubinemia that prevents development of kernicterus

ii.general symptoms: usually identifiable only after 6 months of age; choreoathetotic subtype can be identified only by 12–18 months of age; 20% have coincidental mental retardation

iii.subtypes

(1)paraplegic cerebral palsy—associated with white matter damage high in centrum semiovale (i.e., a periventricular leukomalacia), specifically in the area above and lateral to the caudate nucleus; lesions damage the corticospinal tract fibers issuing from the lower extremity region of the motor cortex more so than upperextremity region

(2)hemiplegic cerebral palsy: likely caused by embolisms from the placenta; 70% involve the left hemisphere because the majority of flow of the fetal circulation through the patent ductus arteriosus goes straight into the left carotid artery

(a)may give the appearance of handedness in neonates (a pathological observation)

(3)quadriplegic cerebral palsy: usually caused by hypoxic-ischemic encephalopathy

(4)choreoathetotic cerebral palsy: caused by injuries to the basal ganglia; historically was due to erythroblastosis fetalis/Rh incompatibility causing kernicterus, but now is usually an idiopathic condition

(a)status marmoratus: a marble-like histological appearance of basal ganglia, due to oligodendrocytes that myelinate astrocytes in the absence of neurons

iv.diagnostic testing

(1)neuroimaging to assess for brain malformations or injury; metabolic and genetic testing should be considered if neuroimaging does not define a structural abnormality

(2)evaluation for a hypercoagulable state

b.hypotonic motor delays

i.general symptoms: all causes involve a loss of postural tone

(1)reduced spontaneous movements

(2)absence of neck and limb flexion when pulling the infant upright {traction response} (Box 12.20)

(3)hip dislocation and pectus excavatum due to regional muscle weakness

(4)joint contractures causing congenital limb deformities {arthrogryposis}

ii.upper motoneuron hypotonic disorders

(1)specific symptoms

(a)seizures

(b)decorticate and/or decerebrate posturing, often induced by passive head movements

Box 12.20

The Traction Response

Not present in premature infants; better than horizontal suspension for hypotonia

(c)persistence of fisting of the hand that encloses the thumb {cortical hand} (which is a normal finding only at 3 months of age); crossing of the thighs {scissoring}; hyperreflexia despite hypotonia

(2)subtypes: from cerebral palsy, leukoencephalopathies, or chromosomal disorders (e.g., Down’s syndrome/trisomy 21); also

(a)Prader-Willi syndrome

(i)pathophysiology: partial deletion of chromosome 15 (70%) or else disomy of the maternal chromosome 15; may involve the necdin gene, which encodes a growth suppressor protein that interacts with p53 cell cycle protein (Box 12.21)

(ii)symptoms: hypotonia, obesity and hyperphagia, mental retardation, hypogonadism and cryptorchidism

iii.lower motoneuron hypotonic disorders: perinatal asphyxia or trauma after breech presentation, or inherited (e.g., the spinal muscular atrophies)

iv.peripheral nerve hypotonic disorders: Charcot-Marie-Tooth neuropathies; Guillain-Barre syndrome; leukodystrophies

v.neuromuscular junction hypotonic disorders: botulism, myasthenia gravis

vi.myopathies and muscular dystrophies

c.ataxic motor delays: spinocerebellar degeneration, Friedreich’s ataxia, ataxia telangiectasia, abetalipoproteinemia, Refsum’s disease, aminoacidopathies

3.Global developmental delay

a.static encephalopathy: caused by

i.cerebral malformations from intrauterine infections, alcohol, lead, drug abuse

ii.genetic abnormalities

(1)chromosomal abnormalities: the most common cause of mental retardation

(a)risk factors: affected family members; parental consanguinity; organomegaly

(b)symptoms suggestive of chromosomal abnormalities

(i)head and neck abnormalities: microphthalmia, slanted eyes, small mandible, small/low-set ears, webbed neck

(ii)limb abnormalities: low-set thumb, polydactyly, radial hypoplasia, rocker-bottom feet

(iii)genitourinary abnormalities: ambiguous genitalia, polycystic kidney

(c)subtypes

(i)Down’s syndrome/trisomy 21—hypotonia, typical facies, Brushfield spots (Box 12.22), flat nape of neck

(ii)trisomy 18: pointed ears, micrognathia, occipital protuberance, narrow pelvis, rocker-bottom feet

(iii)5p monosomy: “cri du chat,” moonlike facies, hypertelorism, microcephaly

(2)focal genetic abnormalities: fragile X syndrome

(a)pathophysiology: caused by a trinucleotide repeat in the FMR1 gene, which encodes a protein that likely functions in translational regulation; exhibits X-linked inheritance, but 80% of males and 30% of females are affected

(b)specific symptoms: autistic-like behavior, long faces, enlarged ears, macroorchidism

iii.intrauterine infections: previously referred to as the “TORCH” infections, now considered the “STaRCH” infections

Box 12.21

Paternal chromosome disomy 15 produces Angelman’s syndrome, which has mental retardation, microcephaly, and myoclonus.

Box 12.22

Brushfield spots

Small white spots around the edges of the iris, caused by stromal hyperplasia centered in areas of hypoplasia

Developmental Delays and Regression

289

290

(1)syphilis (see p. 254)

(a)symptoms: sensorineural hearing loss, interstitial keratitis, peg-shaped upper incisors {Hutchinson’s triad}

(b)high coincidence with HIV infection

(2)toxoplasmosis (see p. 264)

(3)rubella: symptoms include . . .

(a)growth retardation, cataracts, congenital heart malformations

(b)chorioretinitis, hypotonia, seizures, somnolence from increased intracranial pressure, and sensorineural hearing loss

(4)cytomegalovirus/cytomegalic inclusion disease (see p. 257)

(5)HIV: neonatal infection can also occur via infected breast milk

(a)symptoms: onset between 2 months to 5 years of age

(i)encephalitis leading to failure to thrive with microcephaly

(ii)transverse myelitis

(iii)opportunistic infections, particularly with bacteria

(b)diagnostic testing: neonates of HIV-positive mothers will express HIV antibodies by passive transfer, therefore diagnose with HIV polymerase chain reaction (PCR) or culture

iv.subacute sclerosing panencephalitis (see p. 259)

v.other white matter diseases: adrenoleukodystrophy, Alexander’s disease

vi.other gray matter diseases: neuronal ceroid lipofuscinosis; xeroderma pigmentosum; mitochondrial disorders; spinomuscular atrophies

vii.other disorders: lead poisoning; hypothyroidism

b.autism (Box 12.23)

i.pathophysiology: possibly a first trimester disease process based on the high coincidence of minor physical malformations; not associated with childhood vaccinations

(1)anatomical abnormalities are rare, but can include

(a)ventriculomegaly

(b)decreased cerebellar Purkinje cell number; hypoplasia of cerebellar vermis is not a consistent finding

(c)decreased number of neurons and reduced dendritic arborizations in the subcortical limbic system (amygdala, hippocampus, septum) and the anterior cingulated cortex

(d)polymicrogyria

(e)increased volume of temporal, parietal, and occipital lobes

(2)immunologic abnormalities include a high coincidence of inflammatory bowel disease that suggests immunologic reaction to dietary factors; also associated with HLA-DRB1 allele

(3)genetic factors: multifactorial inheritance; monozygotic dizygotic concordance

(4)psychodynamic abnormalities: parents of autistic children exhibit poor language abilities, decreased social interaction, and a tendency toward routine, but this likely represents a mild, inherited autistic phenotype

ii.epidemiology: 3:1 male preference

iii.symptoms: generally begin 3 years of age; symptoms are more severe in females

(1)diagnostic symptoms

(a)abnormal social interactions: involves at least two of the following

(i)failure to use eye contact, facial expression, body posture, or gestures

Box 12.23

Diseases with autistic features: phenylketonuria; intrauterine infections (rubella, cytomegalovirus (CMV); neurofibromatosis, tuberous sclerosis; Rett’s syndrome; fragile X syndrome

(ii)failure to develop relationships with peers

(iii)abnormal social or emotional responses to other peoples’ emotions

(iv)lack of expression of personal interests

(b)abnormal communication skills: involves at least one of the following

(i)delayed or deficient speech without compensatory gesturing

(ii)failure to initiate or sustain conversation

(iii)stereotyped or repetitive use of words or phrases

(iv)lack of imitative play

(c)stereotyped or repetitive behaviors: involves at least one of the following

(i)preoccupation with specific, nonfunctional interests

(ii)preoccupation with nonfunctional elements of normal objects

(iii)compulsive performance of inappropriate routines

(iv)stereotyped or repetitive motor movements

(2)other symptoms (Box 12.24)

(a)mental retardation (70%)

(b)seizures (30%)

(c)echolalia, dysarthria

(d)decreased pain sensitivity

(e)bulbar affect; hyperactivity, aggressiveness, self-injury

(f)precocious abilities/splinter functions of the idiot savant (rare): photographic memory, mathematical ability, musical skill, early reading ability (may or may not have comprehension)

(g)GI symptoms: nausea, diarrhea, constipation

iv.treatment

(1)language development programs; encourage social behavior

(2)antipsychotics (haloperidol, risperidone) for hyperactivity, repetitive and self-injury behaviors, and irritability

(3)SSRIs for compulsive and repetitive behaviors

v.prognosis

(1)some symptomatic improvement occurs over time, particularly repetitive behaviors; rarely high-functioning autistic children outgrow the diagnosis

(2)majority of autistic patients will require an assisted-living environment

c.Rett’s syndrome

i.pathophysiology: almost all cases are associated with mutation of the MECP2 gene, which encodes a methylated DNA-binding protein that acts as a transcriptional repressor (Box 12.25)

(1)exhibits X-linked recessive inheritance, therefore the disease is most commonly observed in homozygous girls, although it can occur in heterozygous boys

(a)asymptomatic heterozygous females exhibit mosaicism caused by random X chromosome inactivation

(2)histology: reduced dendritic arborizations in the cortex and hippocampus

ii.symptoms: grossly normal development until 6 months of age, although subtle abnormalities of movement and posture are observable and fine motor skills fail to develop

Box 12.24

Asperger’s syndrome

Pathophysiology—Unknown, but occurs frequently in families with autism

Symptoms—As for autism, except that language ability is normal and there is no mental retardation or seizures; children with Asperger’s syndrome exert more effort in making social contacts than those with autism; language development may be delayed, but will ultimately obtain normal levels; thinking often appears illogical

Treatment—As per autism

Box 12.25

Other diseases associated with MECP2 mutations: autism; childhood-onset schizophrenia; an Angelman’s-like syndrome (but not real Angelman’s syndrome)

Developmental Delays and Regression

291

(1)diagnostic symptoms

(a)motor regression with loss of purposeful hand movements followed by development of repetitive and stereotypic movements

(b)failure to develop further language abilities

(c)gait apraxia, ultimately developing spasticity and muscle wasting

(d)loss of social interaction

(e)failure of normal head growth leading to microcephaly

(2)other symptoms

(a)seizures

(b)irregular breathing pattern when awake, often involving breath holding and apnea; breathing normalizes during sleep

iii.treatment: none specific

iv.prognosis: stabilization of the disease by 20 years of age, with decreasing seizure frequency and improved social and motor function

(1)1% death rate per year, typically from malnourishment or sudden cardiac death

(2)progressive muscle wasting will require use of a wheelchair