Central Nervous System Disorders
Juliana G. Szakacs
Edward I. Ginns
INTRODUCTIONIn the 11th edition, this chapter has been updated to include recent advances in genetic and molecular studies and diagnostic criteria. Evaluation of the nervous system requires a multidisciplinary approach to the patient, and, where appropriate, pertinent clinical findings, radiologic procedures, and laboratory tests have been included to aid in the diagnosis. Please see the e-book version for the figures referenced in this chapter.
DISORDERS OF COGNITIVE FUNCTIONDEVELOPMENTAL AND INTELLECTUAL DISABILITY
□ Definition
The term “developmental delay” (DD) or “global development delay” (GDD) is used when a child takes longer to reach certain development milestones than other children his or her age. This might include learning to walk or talk, movement skills, learning new things, and interacting with others socially and emotionally.
Developmental disability is a severe, long-term disability that can affect cognitive ability, physical functioning, or both. These disabilities appear before age 22 and are likely to be lifelong. The term “developmental disability” encompasses intellectual disability but also includes physical disabilities. Some developmental disabilities may be solely physical, such as blindness from birth. Others involve both physical and intellectual disabilities stemming from genetic or other causes, such as Down syndrome and fetal alcohol syndrome.
Intellectual disability refers to a group of disorders characterized by a limited mental capacity and difficulty with adaptive behaviors such as managing money, schedules and routines, or social interactions. Intellectual disability originates before the age of 18 and may result from physical causes, such as autism or cerebral palsy, or from nonphysical causes, such as lack of stimulation and adult responsiveness.
□ Clinical Presentation
The most common presenting signs are delayed language, age-inappropriate play, and behavioral skills. Developmental screening with standard screening tools should be performed at every well-child visit. A comprehensive history and physical should include measurements of height, weight, and head circumference, including growth velocity, dysmorphic features, neurologic and sensory development, and a detailed observation of behavior.
□ Etiology
Prenatal
Genetic causes are the most common forms of DD in the prenatal group. Current testing for fetal trisomies and a number of other known genetic disorders is routinely carried out as part of the prenatal screen. Amniotic fluid or chorionic villi sampling may be used for microarray or chromosomal analyses, and maternal blood may now be tested by cell-free DNA methods. The most common disorder resulting in DD is Down syndrome.
Additional syndromes involve deletions, microdeletions, and duplications. Single-gene disorders have also been implicated in autosomal dominant, autosomal recessive, or X-linked inheritance. (See Chapter 12, Hereditary and Genetic Diseases.)
Nongenetic prenatal causes include the following:
▼ Central nervous system (CNS) malformations
▼ Congenital infections (e.g., syphilis, rubella, toxoplasmosis, cytomegalovirus [CMV]) resulting in hydrocephalus (see eBook Figure 6-1)
▼ Maternal metabolic abnormalities (e.g., DM, eclampsia, placental dysfunction)
▼ Environmental toxins or teratogens (alcohol, lead, mercury, hydantoin, and valproate) and radiation exposure
▼ Fetal metabolic abnormalities (congenital hypothyroidism)
Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease, homocystinuria, cystathioninuria, hyperglycemia, argininosuccinicaciduria, citrullinemia, histidinemia, hyperprolinemia, oasthouse urine disease, Hartnup disease, Joseph syndrome, familial iminoglycinuria)
Lipid metabolism (e.g., Batten disease, Tay-Sachs disease, Niemann-Pick disease, abetalipoproteinemia, Refsum disease, metachromatic leukodystrophy) resulting in abnormal storage disorders (see eBook Figure 6-2)
Carbohydrate metabolism (e.g., galactosemia, mucopolysaccharidoses)
Purine metabolism (e.g., Lesch-Nyhan syndrome, hereditary orotic aciduria)
Mineral metabolism (e.g., idiopathic hypercalcemia, pseudopseudohypoparathyroidism, and pseudohypoparathyroidism)
Other syndromes (e.g., tuberous sclerosis, Louis-Bar syndrome)
Perinatal
Kernicterus
Prematurity (see eBook Figure 6-3)
Anoxia, hypoxia
Trauma (CNS hemorrhage) (see eBook Figure 6-4)
Postnatal
Poisoning (e.g., lead, arsenic, carbon monoxide)
Infections (e.g., meningitis, encephalitis)
Metabolic abnormalities (e.g., hypoglycemia, malnutrition)
Postvaccinal encephalitis
Cerebrovascular accident, stroke
Trauma (CNS hemorrhage)
Hypoxia
Psychosocial deprivation
□ Laboratory Findings
Genetic Studies
Children with GDD have a 4% incidence of abnormal cytogenetic studies. A karyotype should be routinely performed on all affected patients even if dysmorphic features are not present. Additional factors that should prompt genetic testing include family history of multiple miscarriages, unexplained infant death, parental consanguinity, or developmental regression or loss of milestones.
Chromosomal microarray analysis (CMA) identifies subtelomeric chromosomal rearrangements, which may be seen in an additional 5% of children with DD. FISH may be used if microarray diagnosis is not available or if a specific telomeric disorder such as cri du chat syndrome is suspected.
Whole-exome sequencing (WES) may be of use if CMA does not identify the cause. The diagnostic yield of WES in moderate to severe DD may reach 30-45% and includes findings of de novo point mutations.
Down syndrome (trisomy 21) is the most common form of inherited DD followed by fragile X syndrome, caused by an abnormal expansion mutation of a CGG triplet repeat in the fragile X mental retardation 1 (FRM1) gene. Testing for fragile X mutations should be considered in male and female patients, especially in those with a family history of DD. Because Down syndrome often presents with nonspecific GDD in young children, there should be a low threshold for this investigation.
Metabolic studies: DD is a clinical feature of some inborn errors of metabolism; these may be identified by newborn screening.
Thyroid screening: Congenital hypothyroidism may result in DD; thyroid testing is not indicated unless clinical features suggest dysfunction.
Lead screening: Lead is the most common environmental neurotoxin. At concentrations >10 µg/dL (0.48 µmol/L), it has been associated with cognitive deficits. Children should be screened at 1-2 years of age. Risk factors for increased levels of lead include living in a community where >12% of children have blood lead levels of >10 µg/dL and living in a house built before 1950.
Suggested Readings
American Academy of Pediatrics Committee on Environmental Health. Screening for elevated blood lead levels. Pediatrics. 1998;101:1072.
Hagerman PJ. The fragile X prevalence paradox. J Med Genet. 2008;45:498.
Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord. 2010;2:182.
Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674.
Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev. 2008;18:241-250.
DEMENTIA (MAJOR NEUROCOGNITIVE DISORDER)
□ Definition
According to the DSM-V, dementia is defined by significant cognitive impairment in one of the six domains: learning and memory, language, executive function, complex attention, perceptual-motor function, and social cognition. It must also represent a decline in the patient’s prior ability and interfere with daily life.
□ Clinical Presentation
Cognitive impairment is insidious and usually brought to the clinician’s attention by a spouse or family member. The most common form of dementia is Alzheimer disease (AD) followed by vascular dementia, frontotemporal dementia (FTD), Lewy body disease, Parkinson disease, and progressive supranuclear palsy (PSP). These must be differentiated from depression, delirium, and drug or alcohol effects.
Disorders that present with no other neurologic symptoms include AD, depression, delirium, and drug effect. Disorders that present with other neurologic symptoms in addition to dementia include neurosyphilis, Huntington disease (HD), hepatic encephalopathy, Creutzfeldt-Jakob disease, Parkinson disease, PSP, toxic and alcoholic disorders, endocrine abnormalities, and malignancies.
In patients <65 years with early-onset dementia additional causes should be entertained: HIV and other infectious causes, MS, paraneoplastic disorders and autoimmune diseases, leukodystrophies, mitochondrial disease, chronic traumatic encephalopathy, alcohol and drug abuse, and normal-pressure hydrocephalus.
□ Laboratory Findings
Screening for hypothyroidism and B12 and folate deficiency in the initial workup of dementia is recommended to rule out treatable causes.
Screening for neurosyphilis should be undertaken if there is increased suspicion, and testing for RBC folate in alcoholics may be of help in the differentiation of these disorders. In patients with multiple myeloma or breast or prostate cancer, ionized calcium may also be helpful.
Suggested Reading
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
ALZHEIMER DISEASE
□ Definition
Alzheimer disease (AD) is the insidious onset of dementia due to cortical atrophy with accumulation of plaques containing abnormal proteins and fibrillary tangles in the neurons. The dominant abnormal protein is Aβ-peptide, a form of amyloid.
□ Clinical Presentation
AD is the most common cause of dementia in the elderly. It begins insidiously and progresses over 5-10 years to severe cortical dysfunction. The incidence of AD doubles every 5 years, starting at 1% in the 60- to 64-year-old age group and rising as high as 40% in the 85- to 89-year-old age group.
In patients older than 60 with dementia, the usual causes are AD 60-80%, vascular dementia 10-20%, dementia with Lewy Bodies (DLB) 10%, FTD 10%, and Parkinson disease with dementia 5%. Recent studies now suggest that patients with some types of cancer may have a decreased risk of AD.
Definitive diagnosis of AD by genetic testing is controversial with false-positive and false-negative results.
□ Laboratory Findings
The gold standard for the diagnosis of AD is the histologic finding of plaques and fibrillary tangles in the brain on biopsy or at autopsy (see eBook Figure 6-5).
Genetic Testing
Early-onset (<60 years) AD is transmitted as an autosomal dominant in up to 70% of cases. Mutations in APP (amyloid precursor protein) on chromosome 1q (also seen in Down syndrome), PSEN1 (presenilin 1) on chromosome 14q, and PSEN2 (presenilin 2) on chromosome 1q are associated with a high risk for disease, and tests are commercially available. APP mutations increase the production of amyloidogenic Aβ or alter the ratio of Aβ42 to Aβ40. PSEN1 mutations in AD most likely are involved in the γ-secretase cleavage of APP. PSEN2 is similar to PSEN1, affecting cleavage of APP, and also enhances apoptotic activity, leading to neurodegeneration.
The APOE ε4 gene allele has been associated with both late-onset AD and vascular dementia. The APOE lipoprotein is involved in cholesterol homeostasis and neuronal protection in the brain. It may also participate in Aβ-deposition. APOE ε4 may be measured in the serum, and increased levels have been associated with late-onset AD and atherosclerotic vascular disease. Genetic testing for late-onset AD is controversial due to the significant number of both false positives and false negatives; in addition, APOE ε4 is a susceptibility gene, and 40% of patients with AD do
not carry the APOE ε4 gene. An increased number of APOE ε4 alleles are associated with a greater risk of disease. Genome-wide association studies have shown up to 700 candidate genes that may also play a role in late-onset AD. Risk is also dependent on age, gender, and race.
Blood and CSF Testing
Biomarkers including increased levels of tau protein and phosphor-tau and decreased levels of Aβ42 or Aβ42:Aβ40 ratio in the CSF, and plasma may either predict development of or suggest a diagnosis of AD.
Suggested Readings
Bertram L, McQueen MB, Mullin K, et al. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17.
Hebert LE, Scherr PA, Bienas JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263.
Musicco M, Adorni F, DiSanto S, et al. Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology. 2013;81(4):322-328.
VASCULAR DEMENTIA
□ Definition
First described by Binswanger and Alzheimer, vascular dementia or vascular cognitive impairment is a heterogeneous group of cerebrovascular disorders resulting in dementia. Three pathologic entities contribute to this disorder: cortical infarct, lacunar infarct, and chronic subcortical ischemia. Vascular dementia is the second most common form of dementia in the United States and Europe.
□ Clinical Presentation
The clinical presentation varies depending on the location of the underlying lesion. Patterns of dementia may be divided into cortical or subcortical ischemic injury with the most severe being those in which there is damage to the region of the thalamus.
Conditions related to vascular dementia include cerebral amyloid angiopathy, which is caused by the deposition of amyloid in the cerebral vessels resulting in hemorrhage or infarct; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by a mutation in the NOTCH3 gene resulting in leukoencephalopathy, subcortical infarcts, migraines, and psychiatric symptoms; and mixed dementia of cerebrovascular disease and AD, which is seen in 35-50% of patients with AD.
□ Laboratory Findings
Diagnosis is made by neuroimaging (MRI is significantly more sensitive than CT). When evidence of CNS infarction is found, additional testing to determine the stroke subtype or etiology should be undertaken, including carotid artery Doppler, echocardiogram, and Holter monitor.
Patients should be screened for hypertension, diabetes, and hyperlipidemia. If a patient has a history suggestive of CADASIL, genetic testing for the NOTCH3 gene mutations is available; alternatively, skin biopsy for electron microscopy to identify extracellular deposits in the vascular smooth muscle may be diagnostic (see eBook Figure 6-6).
Suggested Readings
Benitsy S, Gouw AA, Porcher R, et al. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry. 2009;80:478.
Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathologic studies in humans. Stroke. 2012;43:2526.
FRONTOTEMPORAL DEMENTIA
□ Definition
FTD results from degeneration of the frontal or temporal lobes resulting in personality, language, and behavior abnormalities. It is a group of disorders with onset in the 45-65 age range that may progress to global dementia.
This entity was once called Pick disease, but this diagnosis is now reserved for a subset of patients who exhibit Pick bodies (abnormal protein deposition within cells) on autopsy or biopsy.
□ Clinical Presentation
FTD appears to be associated with genetic abnormalities more frequently than AD, the symptoms progress more rapidly, and FTD patients are less likely to demonstrate memory loss on initial examination.
Three variants of FTD are based on the functional aspects of the frontal lobe. These include a behavioral variant, several progressive aphasia variants, and semantic dementia. A smaller group of patients will also have motor impairment.
□ Laboratory Findings
The diagnosis is primarily made by clinical assessment, neuropsychological testing, and neuroimaging with MRI. Laboratory tests to rule out treatable forms of dementia (B12, thyroid, syphilis, electrolytes) should be considered.
Genetic testing for some known mutations is now available. Caution should be taken in interpretation of negative tests since not all mutations underlying FTD have been identified.
Suggested Readings
Goldman JS, Farmer JM, Wood EM, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology. 2005;65:1817.
Goldman JS, Rademakers R, Huey ED, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology. 2011;76:475.
Rosen HJ, Hartikainen KM, Jagust W, et al. Utility of clinical criteria in differentiating frontotemporal lobar degeneration from Alzheimer disease. Neurology. 2002;58:1608.
DEMENTIA WITH LEWY BODIES
□ Definition
DLB is a degenerative dementia that also presents with at least two of the following three clinical features: cognitive fluctuations, visual hallucinations, or parkinsonism. Most commonly, it is sporadic but may also be familial.
□ Clinical Presentation
In contrast to AD, DLB presents early on with alterations in attention, visual, and executive functions and only later with memory deficits. It is characterized by cortical atrophy with less hippocampal atrophy than that seen in AD and by the presence of Lewy bodies, clumps of alpha-synuclein and ubiquitin protein in neurons of the cortex, on autopsy (see eBook Figure 6-7).
□ Laboratory Findings
Diagnosis of DLB is predominantly made by clinical assessment, neuropsychological testing, neuroimaging (MRI), and screening laboratory studies to rule out treatable forms of dementia (B12, thyroid, syphilis, electrolytes).
PET and SPECT are potentially useful revealing decreased perfusion and metabolism, respectively. A potential biomarker is alpha-synuclein, which may be identified in nerve fibers on skin biopsy.
Genetic testing is not currently recommended as a large number of genetic alterations are noted. In familial cases, the alpha-synuclein gene may show duplication. Symptoms overlap with Parkinson disease dementia.
Suggested Readings
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863.
Meeus B, Theuns J, Van Broeckhoven C. The genetics of dementia with Lewy bodies: what are we missing? Arch Neurol. 2012;69:1113.
PARKINSON DISEASE DEMENTIA
Parkinson disease when severe may present with dementia as a symptom surpassing the functional effects of the motor features and is then classified as Parkinson disease dementia (see Disorders of Movement for full discussion of Parkinson Disease).
□ Clinical Presentation
The differential diagnosis from AD and other degenerative dementias is made by a history of motor dysfunction predating the dementia in PD.
Dementia in PD may be as high as 31%, and therefore, differentiation from other dementias should be undertaken for proper treatment.
In addition, Parkinson disease may coexist with AD or vascular dementia as all three are fairly common. Research continues to determine if PDD and DLB may represent different presentations of the same disease. The risks for dementia in PD include an older age of onset, longer duration, and severity of Parkinsonism.
Suggested Readings
Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord. 2005;20:1255.
Gomperts SN. Lewy body dementias: dementia with Lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):435-463.
HUNTINGTON DISEASE
Huntington disease (HD) is a neurodegenerative disease presenting with choreiform movements, psychiatric disorder, and dementia (see HD in the section on Disorders of Movement).
PSEUDOTUMOR CEREBRI
□ Definition
Pseudotumor cerebri is idiopathic intracranial hypertension.
□ Clinical Presentation
Patients present with headache and visual disturbance. On examination, there is papilledema. The CSF is normal except for increased opening pressure. The primary means of diagnosis is one of exclusion and consists of neuroimaging to rule out a mass lesion or ventricular obstruction and funduscopic exam and visual field testing to determine the severity of optic nerve involvement.
□ Laboratory Findings
Lumbar puncture should be performed only after neuroimaging to measure the opening pressure and to evaluate for cell count, differential, and glucose and protein levels. Culture and cytology may be indicated based on the clinical situation.
Blood tests may be helpful to rule out Addison disease, infection, and metabolic disorders including acute hypocalcemia and other electrolyte disturbances, empty sella syndrome, and pregnancy. Testing for drugs that may be implicated in secondary pseudotumor cerebri includes psychotherapeutic drugs, sex hormones, and oral contraceptives and a reduction in dosage of corticosteroids. Immune diseases may be implicated, including systemic lupus erythematosus (SLE), polyarteritis nodosa, and serum sickness.
Other conditions that may be tested for as the symptoms warrant include sarcoidosis, Guillain-Barré syndrome (GBS), head trauma, various anemias, and chronic renal failure.
DISORDERS OF ALTERED MENTAL STATECOMA AND STUPOR
□ Definition
Coma is defined as unconsciousness lasting for more than 6 hours with no response to external stimuli, including pain and no voluntary movements. Stupor is defined as a decreased level of consciousness in which there is only response to pain.
□ Clinical Presentation
Patients with coma or stupor are poorly or nonresponsive to external stimuli. The causes are many and can be divided into several etiologic categories (see “Causes” below). The goal of diagnostic testing is to identify treatable conditions including infection, metabolic abnormalities, seizures, intoxications/overdose, and surgical lesions as rapidly as possible. Diagnosis is made on physical and neurologic examination, history, neuroimaging, and laboratory testing.
□ Etiology
Poisons, Drugs, or Toxins
Sedatives (especially alcohol, barbiturates)
Enzyme inhibitors (especially salicylates, heavy metals, organic phosphates, cyanide)
Other (e.g., paraldehyde, methyl alcohol, ethylene glycol)
Cerebral Disorders
Brain contusion, hemorrhage, infarction, seizure, or aneurysm
Brain mass (e.g., tumor, hematoma, abscess, parasites)
Subdural or epidural hematoma
Venous sinus occlusion
Hydrocephalus
Hypoxia
Decreased blood O2 content and tension (e.g., lung disease, high altitude) (see eBook Figure 6-8)
Decreased blood O2 content with normal tension (e.g., anemia, carbon monoxide poisoning, methemoglobinemia)
Infection (e.g., meningitis, encephalitis)
Postictal.
Vascular abnormalities (e.g., subarachnoid hemorrhage, hypertensive encephalopathy [see eBook Figure 6-9], shock, acute myocardial infarction, aortic stenosis, Adams-Stokes disease, tachycardias)
Metabolic abnormalities, such as hyponatremia with central pontine myelinolysis (see eBook Figure 6-10)
Acid-base imbalance (acidosis, alkalosis)
Electrolyte imbalance (increased or decreased sodium, potassium, calcium, magnesium)
Porphyrias
Aminoacidurias
Uremia
Hepatic encephalopathy
Other disorders (e.g., leukodystrophies, lipid storage diseases, Bassen-Kornzweig syndrome)
Nutritional deficiencies (e.g., vitamin B12, thiamine, niacin, pyridoxine)
Endocrine Disorders
Pancreas (diabetic coma, hypoglycemia)
Thyroid (myxedema, thyrotoxicosis)
Adrenal (Addison disease, Cushing syndrome, pheochromocytoma)
Panhypopituitarism
Parathyroid (hypofunction or hyperfunction)
Psychogenic Conditions That May Mimic Coma
Psychogenic conditions that may mimic coma are
▼ Depression, catatonia
▼ Malingering
▼ Hysteria, conversion disorder
Initial workup must be based on the clinical presentation. Rapid evaluation of treatable lesions, especially surgical, may improve survival. Conditions that may be mistaken for coma or stupor include the locked-in syndrome, akinetic mutism, and psychogenic unresponsiveness. In children, also consider complete paralysis with lesions of the brain stem, botulism, and Guillain-Barré syndrome.
□ Laboratory Findings
Diagnosis is made on clinical examination, history, and urgent CT scan to rule out possible structural abnormalities such as papilledema, focal neurologic changes, acute stroke, expanding mass lesion, or herniation syndrome.
In patients with fever, a lumbar puncture should be performed to rule out bacterial meningitis or viral encephalitis. Neuroimaging prior to lumbar puncture in a comatose patient is recommended to avoid precipitating transtentorial herniation. CSF may exclude subarachnoid hemorrhage (absence of xanthochromia) when CT is normal and may help in the diagnosis of demyelinating, inflammatory, and neoplastic disease with evaluation of glucose, cytology, and oligoclonal bands (OCB).
Blood tests to exclude treatable causes of coma and stupor include the following:
▼ CBC
▼ Serum electrolytes, calcium, magnesium, phosphate, glucose, BUN, and creatinine
▼ Liver and renal function tests
▼ Ketones, lactose, and osmolarity to rule out diabetic coma
▼ ABG
▼ PT and PTT
▼ Drug screen to include opioids, fentanyl, benzodiazepines, barbiturates, ethanol, acetaminophen, salicylates, cocaine, amphetamines, ethylene glycol, and methanol
If the initial screening is unrevealing, additional testing should include the following:
▼ Blood cultures
▼ Thyroid and adrenal function tests
▼ Blood smear: to screen for hemolysis
▼ LDH, D-dimer, and fibrinogen to rule out DIC
▼ Antiphospholipids
▼ Carboxyhemoglobin
Suggested Reading
Edlow JA, Rabinstein A, Traub SJ, et al. Diagnosis of reversible causes of coma. Lancet. 2014;384: 2064.
REYE SYNDROME (ACUTE TOXIC-METABOLIC ENCEPHALOPATHY)
□ Definition
Reye syndrome is an acute toxic noninflammatory encephalopathy with fatty changes of the liver and kidney. Rarely, fatty changes are also seen in the heart and pancreas.
□ Clinical Presentation
The syndrome occurs typically in children recovering from influenza, varicella, or nonspecific viral illness and is associated with the use of aspirin.
Reye syndrome presents with nausea, vomiting, headache, and delirium with frequent progression to coma. Since aspirin was identified as a major precipitating factor for the development of Reye syndrome, this complication has virtually disappeared.
The differential diagnosis includes sepsis, meningitis, brain tumor, and intracranial hemorrhage and in small children shaken baby syndrome. Imaging studies should be undertaken to rule out intracranial hemorrhage or mass and sinus thrombosis.
Some inborn errors of metabolism (i.e., medium-chain acyl-coenzyme A dehydrogenase deficiency) may predispose a child to Reye syndrome.
□ Laboratory Findings
Suggested Reading
Pugliese A, BePugliese A, Beltramo T, et al. Reye’s and Reye’s-like syndromes. Cell Biochem Funct. 2008;26:741.
SEIZURE DISORDERS
□ Definition
Seizures represent a sudden change in behavior as a result of brain dysfunction.
□ Clinical Presentation
Patients present in one of three major groups: epileptic (resulting from electrical hypersynchronization of neuronal networks in the cerebral cortex), provoked (resulting from metabolic abnormality, drug or alcohol withdrawal, and acute illness or neurologic disorders such as stroke), and nonepileptic events (imitators of epilepsy such as syncope, psychological disorders, migraine, and transient ischemic attack).
Conditions associated with seizure activity include the following:
▼ Brain tumors, abscess, and space-occupying lesions
▼ Circulatory disorders such as thrombosis, hemorrhage, embolism, hypertensive encephalopathy, vascular malformations, and angiitis
▼ Hematologic disorders such as sickle cell anemia, leukemia, and TTP
▼ Metabolic abnormalities such as DM and hyperthyroidism
▼ Porphyria, eclampsia, and renal failure
▼ Drugs that may induce seizures such as crack cocaine, amphetamines, ephedrine, and other sympathomimetics
▼ Allergic disorders including drug reactions and postvaccinal reactions
▼ Disorders in amino acid metabolism such as phenylketonuria and maple syrup urine disease
▼ Disorders in lipid metabolism such as the leukodystrophies and lipidoses
▼ Glycogen storage diseases
▼ Infections, meningitis, encephalitis, and postinfectious encephalitis (measles, mumps)
▼ In the fetal-maternal infection with rubella, measles, and mumps
▼ Degenerative brain diseases
The diagnosis of seizure requires an excellent history and evaluation of the events leading up to the seizure and the behavior during the seizure and after the seizure. The primary goal is to determine whether the event was a seizure and if so whether it was epileptic or due to a treatable or preventable cause. EEG may be diagnostic in epileptic seizures. It may also determine whether a patient has generalized or focal seizures. Neuroimaging (MRI) should be performed to rule out structural abnormalities in the brain.
□ Laboratory Findings
Laboratory diagnosis is directed at determining an underlying cause of a provoked or nonepileptic seizure. Most important are blood tests for electrolytes, glucose, calcium, magnesium, hematology studies, toxicology
screen, and renal and liver function tests. Testing for underlying conditions should be performed as indicated by the history and physical examination. A lumbar puncture is helpful if there is an acute infectious process involving the CNS or the patient has a history of cancer. In other circumstances, the test may be misleading, since a prolonged seizure can cause CSF pleocytosis.
Carbohydrate metabolism abnormalities may result in seizures with hypoglycemia (glucose <40 mg/dL) or hyperglycemia (glucose >400 mg/dL). Electrolyte imbalance results in neurologic change when sodium is <120 or >145 mEq/L, calcium is <7 mg/dL, or magnesium is low. Hyperosmolality (serum osmolality >300 mOsm/L) may also result in seizure activity.
Laboratory tests that may help to differentiate between seizures and syncope or psychogenic abnormalities include creatinine phosphokinase (CPK), cortisol, white blood cell (WBC) count, LDH, CO2, and ammonia. CPK may be elevated following generalized seizures but not usually after a focal seizure. Neurogenetic tests for inherited epilepsy are also available.
Suggested Readings
Krumholz A, Wiebe S, Gronseth, G, et al. Practice Parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69:1996.
Petramfar P, Yaghoobi E, Nemati R, et al. Serum creatine phosphokinase is helpful in distinguishing generalized tonic-clonic seizures from psychogenic nonepileptic seizures and vasovagal syncope. Epilepsy Behav. 2009;15:330.
DELIRIUM
□ Definition
According to the DSM-V, delirium is defined as having five key features: disturbance of attention and awareness, change in cognition, development over a short period of time, not explained by another neurocognitive disorder, and an etiology due to medical illness, substance abuse, or intoxication or medication effect. Additional features may include psychomotor disturbances and emotional disturbances.
□ Clinical Presentation
In elderly patients and in patients with medical illness, delirium and confusional states are not uncommon. The diagnosis of delirium requires that the practitioner recognize that delirium is present, a thorough history and physical examination, neurologic examination, and testing to determine the underlying etiology.
The differential diagnosis includes sundowning, nonconvulsive status epilepticus, dementia, primary psychiatric illness, and focal syndromes such as Wernicke aphasia, Anton syndrome, and brain tumor particularly in the frontal lobe.
□ Laboratory Findings
Targeted testing is recommended based on the history and physical. General screening tests should include electrolytes, creatinine, glucose, calcium, CBC, and urinalysis.
Appropriate drug levels should be ordered. Delirium may occur with therapeutic drug levels of digoxin, lithium, or quinidine. Blood and urine toxicology screens should be considered. Blood gas analysis to rule out hypoxia, respiratory alkalosis (which may be seen in sepsis, hepatic failure, or cardiopulmonary disease), and metabolic acidosis is helpful.
Liver function tests may be contributory in patients with a history of alcoholism or liver disease. Thyroid function and vitamin B12 may be helpful in patients with a history of cognitive decline over several months.
Suggested Reading
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
CNS AND PERIPHERAL NEUROPATHIESDisorders of the peripheral nerve system include polyneuropathies, mononeuropathies, and mononeuropathy multiplex (multiple mononeuropathies). The etiology of each of these is varied and includes systemic illnesses, toxins, or genetic abnormalities. The distinction between CNS disorders and peripheral nerve or muscle diseases can be made on clinical assessment with help from various diagnostic modalities including EEG, electromyography (EMG), blood tests, genetic testing, and muscle or nerve biopsy. The involvement of a single limb, especially if with pain, suggests a peripheral neuropathy. This section reviews the major categories and several of the more common individual disorders.
POLYNEUROPATHY (NEURITIS/NEUROPATHY, MULTIPLE)
□ Definition
Polyneuropathy is a generalized, homogeneous process affecting multiple peripheral nerves. Polyneuropathy must be distinguished from mononeuropathy, mononeuropathy multiplex (multifocal neuropathy), and disorders of the CNS.
□ Clinical Presentation
Patients may present with symmetric distal sensory loss, burning, or weakness. Etiologies vary and include medication side effects or manifestations of systemic disease (DM, alcoholism, and HIV). The rate of progression of the polyneuropathy and type (axonal or demyelinating) can help identify its etiology. Polyneuropathy may also be difficult to distinguish from CNS disorders such as brain tumor, stroke, or spinal cord lesion.
The etiology of polyneuropathy varies and includes infections, metabolic and immune disorders, neoplasms, postvaccinal effect, and rare genetic disorders such as Charcot-Marie-Tooth.
□ Laboratory Findings
Initial diagnosis includes obtaining a history of the disease and its progression, physical examination with neurologic testing, and EMG and nerve conduction studies. Based on EMG studies, a decision can be made as to whether the disorder is axonal or demyelinating. Laboratory tests are recommended by the American Academy of Neurology for each of these categories.
Screening for predominantly axonal disorders:
▼ Serum glucose and A1c
▼ Serum protein electrophoresis and immunofixation
▼ B12 level and methylmalonic acid
▼ Anti-nuclear antibodies
▼ Sedimentation rate
▼ Rapid plasma reagin
▼ Urine/blood for heavy metals
▼ Urine/blood for porphyrins
▼ Rheumatoid factor (RF)
▼ Sjögren syndrome testing (anti-Ro, anti-La antibodies)
▼ Lyme testing
▼ HIV
▼ Anti-Hu
▼ Hepatitis screen (for types B and C)
Screening for predominantly demyelinating disorders:
▼ Serum and urine protein electrophoresis and immuno-electrophoresis
▼ Lumbar puncture
▼ Hepatitis screen (for types B and C)
▼ Anti-myelin-associated glycoprotein (MAG) testing (in patients with predominantly sensory symptoms)
▼ Anti-GM1 test (in patients with predominantly motor symptoms)
▼ HIV
▼ Genetic testing for Charcot-Marie-Tooth disease
Findings of the CSF:
▼ The CSF is usually normal; however, in approximately 70% of patients with diabetic neuropathy, the CSF protein is increased to >200 mg/dL.
▼ In inflammatory demyelinating polyneuropathies, increase in CSF protein with minimal elevation in CSF white cells (albuminocytologic dissociation).
▼ In some cases of chronic uremia, the CSF protein is 50-200 mg/dL.
▼ In collagen vascular disease (polyarteritis nodosa has nerve involvement in 10% of patients), the CSF is usually normal.
▼ In neoplasms (leukemia, multiple myeloma, carcinoma), the CSF protein is often increased and may be associated with an occult primary neoplastic lesion outside the CNS.
▼ In alcoholism, the CSF is usually normal.
Additional laboratory tests to rule out infectious disorders:
▼ Leprosy
▼ Diphtheria: CSF protein is 50-200 mg/dL.
Additional laboratory information that may be contributive:
▼ Serum and urine toxicology (lead, arsenic, etc.)
▼ Blood tests for vitamin deficiencies, pregnancy, and porphyria
Biopsy:
▼ Nerve biopsy may be useful in determining the underlying cause of the neuropathy in cases that are difficult to differentiate between axonal and demyelinating etiologies. Nerve biopsy may also help to diagnose amyloidosis, leprosy, vasculitis, and sarcoidosis. Skin biopsy may be helpful in disorders that affect small unmyelinated nerve fibers, such as in pain, numbness, and paresthesias.
Suggested Readings
England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72:185.
McCarthy BG, Hsieh ST, Stocks A, et al. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology. 1995;45:1848.
DIABETIC POLYNEUROPATHY
□ Definition
Diabetic polyneuropathy is primarily a symmetrical, ascending neuropathy affecting the distal lower extremities and the hands.
□ Clinical Presentation
There is loss of vibratory sensation; impairment of pain, light touch, and temperature sensation; and decreased ankle reflexes. Patients with diabetes may present with a number of different neuropathies including symmetric polyneuropathy, autonomic neuropathy, radiculopathies, mononeuropathies, and mononeuropathy multiplex.
□ Laboratory Findings
Testing focuses on exclusion of other etiologies including metabolic disorders such as uremia, folic acid deficiency, hypothyroidism, and acute intermittent porphyria. Other entities in the differential should include alcohol, heavy metal toxicity, and exposure to hydrocarbons. Collagen vascular diseases such as periarteritis nodosa and lupus may also cause symmetric polyneuropathy. Also in the differential is infection with leprosy or inflammatory disorders such as sarcoidosis. Rare disorders including paraneoplastic syndromes, hematologic malignancy, amyloidosis, and hereditary neuropathies may also be considered.
In a patient with known diabetes, the diagnosis is based on clinical examination using one of a number of testing tools. When the presentation is atypical electrodiagnostic, testing may be helpful. Laboratory testing should include screening to rule out vitamin B12 deficiency, hypothyroidism, and uremia.
Suggested Reading
Dyck PJ, Albers JW, Andersen H, et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27:620.
CRANIAL NERVE NEUROPATHY, MULTIPLE
□ Definition
Neuropathies of the cranial nerves are most commonly due to local compression of the nerve by trauma, infection, or tumor, vascular and collagen vascular disorders, and some metabolic diseases.
□ Laboratory Findings
Laboratory findings may be helpful to determine the underlying etiology:
Peripheral blood for glucose, HgbA1c, BUN, creatinine, AST, and ALT may reveal a metabolic disorder (DM, renal failure, chronic liver disease, myxedema, and porphyria).
Serology and/or culture may be helpful in identification of infection (herpes zoster, benign polyneuritis associated with cervical lymph node TB, or Lyme disease).
Tissue biopsy of the nerve or adjacent soft tissues may diagnose sarcoidosis and tumors (meningioma, neurofibroma, carcinoma, cholesteatoma, chordoma).
Imaging studies are most useful for the detection of trauma and aneurysms.
MONONEUROPATHY
□ Definition
Mononeuropathy is defined as the focal dysfunction of a single nerve and may be due to trauma or compression such as carpal tunnel syndrome. Mononeuropathy multiplex is the involvement of several noncontiguous nerves.
□ Clinical Presentation
Patients present with various symptoms such as pain, paresthesias, or weakness relating to the nerve that is involved. Mononeuropathy may be due to a systemic vasculitic process that affects the vasa vasorum resulting in multiple infarcts. Other causes of mononeuropathy include
DM
Infections (e.g., HIV, diphtheria, herpes zoster, leprosy)
Sarcoidosis
Polyarteritis nodosa
Tumor (leukemia, lymphoma, carcinomas)
Trauma
Serum sickness
Bell palsy
Idiopathic
Drugs, toxic substances
Chronic renal failure
Thyroid disorders
The diagnosis of a mononeuropathy is based on history, neurologic examinations over time evaluation of progression, electrodiagnostic studies, somatosensory potentials, and neuroimaging (MRI).
□ Laboratory Findings
Blood tests:
▼ Fasting glucose and glycohemoglobin in patients with possible diabetic amyotrophy, idiopathic radiculopathy, or polyneuropathy
▼ Lyme titers in patients with polyradiculopathy, especially in endemic areas
▼ Genetic tests for hereditary neuropathy with predisposition to pressure palsy for patients with multiple mononeuropathies (usually affecting at least two to three extremities) and Chédiak-Higashi syndrome
FACIAL PALSY (BELL PALSY)
□ Definition
Facial palsy is the sudden loss of function of cranial nerve VII resulting in facial paralysis and may be due to a number of etiologies, the most common being herpes simplex viral infection. Bell palsy is facial nerve paralysis of unknown etiology, but may be due to reactivation of herpes simplex.
□ Clinical Presentation
Patients with Bell palsy typically present with the sudden onset (usually over hours to days) of unilateral facial paralysis and constitute approximately 50% of patients with facial nerve palsy. Facial palsy may be due to viruses in addition to HSV: herpes zoster, CMV, EBV, adenovirus, rubella virus, mumps, influenza B, HIV, and coxsackie virus; bacteria including Lyme, syphilis, leprosy, diphtheria, catscratch disease, Mycoplasma pneumoniae, and nonspecific local inflammation including otitis media; and parasitic infections such as malaria. Granulomatous disease such as sarcoidosis should be considered, especially in patients with bilateral facial palsy.
Trauma, tumor (acoustic neuromas [see eBook Figure 6-11], tumors invading the temporal bone), cholesteatoma, and Paget disease of the bone should be suspected if the onset of facial palsy is gradual. These can be diagnosed on imaging.
Drug reaction, particularly to dental injections, may cause local facial neuropathy, diagnosed on history. Postvaccinal effect and GBS may cause bilateral facial palsy.
□ Laboratory Findings
Testing should be designed to rule out causes of underlying diseases, serology for herpes simplex, HIV, and other viruses, Borrelia, Ehrlichia, and other agents
as appropriate by history. If collagen vascular disease is suspected, an ANA test may be of help. Bell palsy may occasionally present with a slight increase in cells in the CSF.
as appropriate by history. If collagen vascular disease is suspected, an ANA test may be of help. Bell palsy may occasionally present with a slight increase in cells in the CSF.
HEMIANOPSIA, BITEMPORAL
□ Definition
Bitemporal hemianopsia is the loss of vision in the temporal fields due to a mass lesion causing compression of the optic chiasm.
□ Clinical Presentation
Patients present with decreased vision in the temporal fields. The most common cause is pituitary adenoma (see eBook Figure 6-12), but any mass lesion may be causative, including metastatic tumor, sarcoidosis, Hand-Schüller-Christian disease, meningioma of sella (see eBook Figure 6-13), craniopharyngioma (see eBook Figure 6-14), and aneurysm of the circle of Willis.
Diagnosis is predominantly made by neuroimaging. Biopsy may help identify tumor type.
OPHTHALMOPLEGIA
□ Definition
Internuclear ophthalmoplegia is an impairment of horizontal eye movement. There is weak adduction of the affected eye and abduction nystagmus of the contralateral eye. It is the result of a lesion in the medial longitudinal fasciculus.
□ Clinical Presentation
Patients may present with a number of causative disorders including MS (most common in younger patients, also tends to be bilateral), cerebrovascular disorders (infarction is most common in older patients), infection, trauma, and tumor.
Diagnosis is based on physical findings and neuroimaging with MRI and specialized neural ophthalmologic techniques such as oculographic recording. The differential diagnosis includes oculomotor nerve palsy (see below).
□ Laboratory Findings
Testing is directed at identifying the causative disease. Tests to rule out DM, vasculopathies, multiple sclerosis (MS), myasthenia gravis, hyperthyroidism, infection, and drug toxicities will be of help.
OCULOMOTOR NERVE PALSY
□ Definition
Oculomotor nerve palsy may result from lesions of the third cranial nerve (oculomotor nerve) anywhere along its path.
□ Clinical Presentation
Patients present with a dilated pupil and loss of adduction, depression and elevation of the eye, and a droopy lid. The diagnosis varies by patient age,
type of diplopia, and lid involvement. The most common causes include intracranial aneurysm, ischemia, severe trauma, and migraine. Ischemic diabetic third nerve palsies are the most common etiology in adults.
The differential diagnosis includes MS (may mimic pupil-sparing ophthalmoplegia) and orbital inflammation or fracture. The diagnosis rests on complete history, neurologic exam, and neuroimaging with MRI, MRA, or CTA to rule out aneurysm.
□ Laboratory Findings
Laboratory testing can help in the diagnosis of diabetes and vasculopathies (glucose, hemoglobin A1c, sedimentation rate). Testing to exclude myasthenia gravis should be performed in younger patients.
TRIGEMINAL NEURALGIA (TIC DOULOUREUX)
□ Definition
Trigeminal neuralgia is a sudden, usually unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve.
□ Clinical Presentation
Compression of the trigeminal nerve root, by an artery or vein, or less likely by tumor or cyst leads to demyelination and sensation of pain following an innocuous stimulus.
□ Laboratory Findings
Diagnosis is performed predominantly by neuroimaging (CT or MRI) for mass and electrophysiologic testing.
Laboratory tests to rule out MS (CSF oligoclonal bands) or herpes zoster (serology).
Tissue biopsy may be needed in the diagnosis of schwannoma (see eBook Figure 6-11), meningioma (see eBook Figures 6-13 and 6-15), and cysts.
RETROBULBAR NEUROPATHY (OPTIC NEURITIS)
□ Definition
Retrobulbar neuropathy is a disorder of the optic nerve resulting in pain behind the affected eye, impaired vision, and rarely blindness.
□ Clinical Presentation
Patients may present with a number of causative disorders; however, the most common is MS (demyelinating optic neuritis [ON]). Other causes include ischemia (arteritic or nonarteritic ischemic optic neuropathy usually in elderly), infectious (West Nile virus, catscratch disease, toxoplasma, Tuberculosis, and Cryptococcus), tumors (paraneoplastic disease), and medications (chloramphenicol, ethambutol, isoniazid, penicillamine, phenothiazines, phenylbutazone, quinine, and streptomycin).
Postviral infectious ON may also occur.
Less common causes include sarcoidosis and autoimmune diseases such as lupus, Sjögren syndrome, and Wegener granulomatosis.
There are two hereditary forms of optic neuropathy: Leber hereditary optic neuropathy and Kjer disease.
The diagnosis is based on the elimination of underlying disorders by history and examination including funduscopic evaluation. Neuroimaging (MRI) may help confirm the presence of acute demyelinating disease and MS. Visual-evoked responses may be helpful in determining demyelination.
□ Laboratory Findings
Laboratory testing including sedimentation rate, ANA, angiotensin-converting enzyme levels, and serologic test for Lyme disease should be obtained.
Lumbar puncture is helpful to rule out MS. CSF may be normal or reveal increased protein and ≤200/µL lymphocytes. OCBs may be present.
Other testing should be performed to rule out possible infectious agents, toxins, and genetic disorders based on the history of the individual patient.
Suggested Reading
Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354:1273.
AUTONOMIC NEUROPATHY
□ Definition
Autonomic neuropathy is a group of diseases or syndromes affecting the parasympathetic and/or the sympathetic nerves. It can be hereditary or acquired.
□ Clinical Presentation
A wide range of symptoms affecting many different organ systems can occur, including the cardiovascular, GI, GU, pulmonary, and neuroendocrine systems. The most common cause of autonomic neuropathy is DM (see also Polyneuropathy and the section on Autoimmune Disorders of the CNS).
Disorders that may cause autonomic dysfunction include amyloidosis, GBS, hereditary neuropathies, infections (e.g., Chagas disease, HIV, botulism, diphtheria, and leprosy), toxicities including drugs (vincristine, cisplatinum, Taxol, thallium, and heavy metals), collagen vascular disease (e.g., Sjögren disease, systemic lupus, RA), porphyria, uremia, alcoholic neuropathy, hepatic disease, paraneoplastic syndromes, Lambert-Eaton syndrome, and medications (antihypertensives, tricyclics, MAO inhibitors, and dopamine agonists).
□ Laboratory Findings
Laboratory testing to determine the causative disease or toxin should be based on the presenting symptoms and history of the patient to rule out the preceding disorders. All patients with diabetes should be screened for autonomic neuropathy with a complete history and physical examination, including evaluation of
heart rate, respiratory rate, and response to the Valsalva maneuver and evaluation for orthostatic hypertension.
heart rate, respiratory rate, and response to the Valsalva maneuver and evaluation for orthostatic hypertension.
DISORDERS OF MOVEMENTPARKINSON DISEASE
□ Definition
Parkinson disease (PD) is a progressive neurodegenerative disorder resulting from the loss of dopaminergic cells in the substantia nigra.
□ Clinical Presentation
Patients present with rest tremor, rigidity, bradykinesia, and gait disturbance. In the late stages, PD may result in dementia (see Dementia). The differential diagnosis includes essential tremor (ET), DLB, cortical basal degeneration, PSP, and multiple system atrophy. It must also be distinguished from secondary parkinsonism due to drugs, toxins, head trauma, infections, cerebrovascular disease, and metabolic disorders.
The diagnosis is based on clinical evaluation with required specific diagnostic criteria (bradykinesia and rest tremor or rigidity), supportive criteria, and criteria that are signs of alternate pathology or absolute exclusion criteria.
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