DISORDERS OF COGNITION AND DEMENTIA
Intellectual disability (ID) is defined by the DSM-IV1 as significant subaverage intellectual function, significant limitations in adaptive functioning, and onset before 18 years. It is an unchanging encephalopathy that may be due to a number of disorders that affect brain development and function.
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.
Genetic causes are the most common forms of ID 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. Chromosomal disorders resulting in ID include Down syndrome; trisomy 18; fragile X; autosomal recessive genes PRSS12, CRBN, CC2D1A, TUSC3, GRIK2, and SYNGAP1; autosomal dominant genes STXBP1, SYBGAP1, and SCN2A; cri-du-chat syndrome; and Klinefelter syndrome2–4 (See Chapter 10 Hereditary and Genetic Diseases).
Nongenetic prenatal causes include the following:
Congenital infections (e.g., syphilis, rubella, toxoplasmosis, CMV) resulting in hydrocephalus (see eBook Figure 4-1)
Metabolic abnormalities (e.g., DM, eclampsia, placental dysfunction)
Environmental toxins or teratogens (alcohol, lead, mercury, hydantoin, and valproate) and radiation exposure
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 4-2)
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)
Infections (e.g., syphilis, rubella, toxoplasmosis, CMV, HIV, HSV)
Prematurity (see eBook Figure 4-3)
Trauma (CNS hemorrhage) (see eBook Figure 4-4)
Poisoning (e.g., lead, arsenic, carbon monoxide)
Infections (e.g., meningitis, encephalitis)
Metabolic abnormalities (e.g., hypoglycemia, malnutrition)
Trauma (CNS hemorrhage)
Children with global developmental delay 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.5–7
Chromosomal microarray analysis identifies subtelomeric chromosomal rearrangements, which may be seen in an additional 5% of children with ID. FISH may be used if microarray diagnosis is not available or if a specific telomeric disorder such as cri-du-chat syndrome is suspected.2
Down syndrome (trisomy 21) is the most common form of inherited ID 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 ID.8 Because Down syndrome often presents with nonspecific global developmental delay in young children, there should be a low threshold for this investigation.5
Metabolic studies: ID is a clinical feature of some inborn errors of metabolism; these may be identified by newborn screening.
Thyroid screening: Congenital hypothyroidism may result in ID; 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 1950.9
1. American Psychiatric Association. Diagnostic and Statistical Manual, 4th ed. Washington, DC: APA Press; 1994.
2. Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord. 2010;2:182.
3. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developments disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749.
4. de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921.
5. Moeschler JB, Shevell M. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics. 2006;117:2304.
6. Ropers HH. Genetics of intellectual disability. Curr Opin Genet Dev. 2008;18:241–250.
7. Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology. 2003;60:367.
8. Hagerman PJ. The fragile X prevalence paradox. J Med Genet. 2008;45:498.
9. American Academy of Pediatrics Committee on Environmental Health. Screening for elevated blood lead levels. Pediatrics. 1998;101:1072.
According to the DSM-IV,1 dementia is defined by impairment of memory and at least one other cognitive domain such as aphasia, agnosia, apraxia, or executive function. It must also represent a decline in the patient’s prior ability and interfere with daily life.
The most common form of dementia is Alzheimer disease followed by vascular dementia, frontotemporal dementia, Lewy body disease, Parkinson disease, and progressive supranuclear palsy. These must be differentiated from depression, delirium, and drug or alcohol effects. Disorders that present with no other neurologic symptoms include Alzheimer disease, depression, delirium, and drug effect. Disorders that present with other neurologic symptoms in addition to dementia include neurosyphilis, Huntington disease, hepatic encephalopathy, Creutzfeldt-Jakob disease, Parkinson disease, progressive supranuclear palsy, toxic and alcoholic disorders, endocrine abnormalities, and malignancies.
1. American Psychiatric Association. Diagnostic and Statistical Manual, 4th ed. Washington, DC: APA Press; 1994.
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.
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 10%, frontotemporal dementia 10%, and Parkinson disease with dementia 5%.1 Recent studies now suggest that patients with some types of cancer may have a decreased risk of AD.2 Laboratory testing should be performed to rule out treatable causes of dementia; definitive diagnosis of AD is not currently possible, although newer biomarkers are becoming more useful in suggesting the diagnosis.
Initial screening for patients with dementia should include B12 and thyroid studies to rule out deficiencies. Routine screening labs such as CBC, electrolytes, glucose, renal, and liver functions have not been shown to be helpful in the general population. 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. In patients with rapidly progressing disease or who are under the age of 60, the American Academy of Neurology recommends the following tests: serology, CSF, and EEG.3 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 4-5).
Early-onset (<60 years) AD has been associated with three genes seen in approximately 60% of these cases and is transmitted as an autosomal dominant. APP (amyloid precursor protein) on chromosome 1q (also seen in Down syndrome) and PSEN1 (presenilin 1) on chromosome 14q are the more common genes affected, and PSEN2 (presenilin 2) on chromosome 1q is rare. Commercial testing for these genes is not available, and in order to fully rule out abnormalities, full gene sequencing would be needed as numerous mutations have been found. 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.4
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.5 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.6 Testing for the APOE ε4 allele is available through commercial laboratories. An increased number of APOE ε4 alleles is associated with a greater risk of disease; risk is also dependent on age, gender, and race.
Blood and CSF Testing
Biomarkers including increased levels of tau protein and decreased levels of Aβ40 and 42 in the CSF and plasma may either predict development of or suggest a diagnosis of AD.7–9
1. 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.
2. 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.
3. Knopman Ds, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56:1143.
4. Campion D, Dumanchin C, Hannequin D, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664.
5. Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon 4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137:149.
6. Myers RH, Schaefer EJ, Wilson PW, et al. APOE ε4 association with dementia in a populationbased study: the Framingham study. Neurology. 1996;46:763.
7. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer’s disease. Neurology. 1997;48:632.
8. Kahle PJ, Jakowec M, Teipel SJ, et al. Combined assessment of tau and neuronal thread protein in Alzheimer’s disease CSF. Neurology. 2000;54:1498.
9. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003;289:2094.
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 infarcts, lacunar infarct, and chronic subcortical ischemia.1 Vascular dementia is the second most common form of dementia in the United States and Europe.
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.2
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.1
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 is commercially available (see eBook Figure 4-6).
1. Kalaria RN. Cerebrovascular disease and mechanisms of cognitive impairment: evidence from clinicopathological studies in humans. Stroke. 2012;43:2526.
2. 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.
Frontotemporal dementia (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.
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.1,2 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.
Recent genetic abnormalities have been identified that are associated with FTD. These include mutations in the MAPT gene on chromosome 17 that encodes the tau protein (tau protein repeats are found in the deposition of Pick bodies) and an abnormal form of TARDBP called pathologic TDP43, which is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein–negative frontotemporal dementia.3
The diagnosis is primarily made by clinical assessment, neuropsychologic testing, and neuroimaging with MRI. Laboratory tests to rule out treatable forms of dementia (B12, thyroid, syphilis, electrolytes) should be considered. There is no definitive test for diagnosis of FTD, but 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.4
1. Snowden JS, Neary D, Mann DM. Frontotemporal dementia. Br J Psychiatry. 2002;180: 140–143.
2. Rosen HJ, Hartikainen KM, Jagust W, et al. Utility of clinical criteria in differentiating frontotemporal lobar degeneration from Alzheimer disease. Neurology. 2002;58:1608.
3. Hardy J, Parastoo M, Bryan JT. Frontal temporal dementia: dissecting the aetiology and pathogenesis. Brain. 2006;26(4):830–831.
4. Goldman JS, Rademakers R, Huey ED, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology. 2011;76:475.
DEMENTIA WITH LEWY BODIES
Dementia with Lewy bodies (DLB) is a degenerative dementia that also presents with at least two of the following three clinical features: cognitive fluctuations, visual hallucinations, or parkinsonism.1
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 4-7). DLB is not thought to be a familial disorder; however, recent association with the PARK11 gene has been described.2
Diagnosis of DLB is made by clinical assessment, neuropsychologic testing, neuroimaging (MRI), and screening laboratory studies to rule out treatable forms of dementia (B12, thyroid, syphilis, electrolytes). No specific test for definitive diagnosis of DLB is available. EEG may be helpful to rule out seizure or Creutzfeldt-Jakob disease. Genetic testing is not currently recommended.
1. 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.
2. Bogaerts V, Engelborghs S, Kumar-Singh S, et al. A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder. Brain. 2007;130(9):2277.
PARKINSON DISEASE DEMENTIA
Parkinson disease (PD) when severe may present with dementia as a symptom surpassing the functional effects of the motor features (see also Disorders of Movement) and is then classified as Parkinson disease dementia.
The differential diagnosis from Alzheimer disease 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 41%, and therefore, differentiation from other dementias should be undertaken for proper treatment.1 In addition, Parkinson disease may coexist with Alzheimer disease or vascular dementia as all three are fairly common. Research continues to determine if Parkinson disease dementia and dementia with Lewy bodies may represent different presentations of the same disease.2
The risks for dementia in PD include an older age of onset, longer duration, and severity of parkinsonism. Genetic risk factors have been described; these include mutations on chromosome 1P in the ATPase gene, which is associated with juvenile parkinsonism with dementia3; multiplication-type mutations of the alpha-synuclein gene; APOE ε4 and APOE ε24; and the microtubule-associated protein tau (MAPT) H1/H1 gene, which has been implicated in more rapid onset of dementia.5
The diagnosis of PD dementia is primarily made by clinical assessment and history. Dementia usually occurs in the setting of well-established parkinsonism, while in DLB, dementia may occur at the same time as the development of motor signs, and in AD, motor symptoms only develop very late in the course of disease6. Neuropsychiatric testing may assist in the diagnosis, but no published clinical criteria for PD dementia exist. Neuroimaging with MRI may reveal more atrophy with dementia than in PD without dementia but is not diagnostic7. Lab tests should be performed to exclude other treatable causes of dementia (CBC, electrolytes, glucose, thyroid studies, and renal and liver functions). The diagnosis of PD dementia is suggested when dementia occurs at least 1 year after the development of established parkinsonism.
1. Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol. 1992;49:492.
2. Lippa CF, Duda JE, Grossman M, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68:812.
3. de Lau LM, Schipper CM, Hofman A, et al. Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study. Arch Neurol. 2005;62:1265.
4. Huang X, Chen P, Kaufer DI, et al. Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol. 2006;63:189.
5. Burton EJ, McKeith IG, Burn DJ, et al. Brain atrophy rates in Parkinson’s disease with and without dementia using serial magnetic resonance imaging. Mov Disord. 2005;20:1571.
6. Portet F, Scarmeas N, Cosentino S, et al. Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study. Arch Neurol. 2009;66:1120.
7. Melzer TR, Watts R, MacAskill MR, et al. Grey matter atrophy in cognitively impaired Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2012;83:188.
Huntington disease (HD) is a neurodegenerative disease presenting with choreiform movements, psychiatric disorder, and dementia (see HD in the section on Disorders of Movement).
DISORDERS OF ALTERED MENTAL STATE
COMA AND STUPOR
Coma is defined as unconsciousness lasting for more than 6 hours. There is 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.
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.1,2
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)
Brain contusion, hemorrhage, infarction, seizure, or aneurysm
Brain mass (e.g., tumor, hematoma, abscess, parasites)
Subdural or epidural hematoma
Venous sinus occlusion
Decreased blood O2 content and tension (e.g., lung disease, high altitude) (see eBook Figure 4-8)
Decreased blood O2 content with normal tension (e.g., anemia, carbon monoxide poisoning, methemoglobinemia)
Infection (e.g., meningitis, encephalitis)
Vascular abnormalities (e.g., subarachnoid hemorrhage, hypertensive encephalopathy [see eBook Figure 4-9], shock, acute myocardial infarction, aortic stenosis, Adams-Stokes disease, tachycardias)
Metabolic abnormalities, such as hyponatremia with central pontine myelinolysis (see eBook Figure 4-10)
Acid–base imbalance (acidosis, alkalosis)
Electrolyte imbalance (increased or decreased sodium, potassium, calcium, magnesium)
Other disorders (e.g., leukodystrophies, lipid storage diseases, Bassen-Kornzweig syndrome)
Nutritional deficiencies (e.g., vitamin B12, thiamine, niacin, pyridoxine)
Pancreas (diabetic coma, hypoglycemia)
Thyroid (myxedema, thyrotoxicosis)
Adrenal (Addison disease, Cushing syndrome, pheochromocytoma)
Parathyroid (hypofunction or hyperfunction)
Psychogenic Conditions That May Mimic Coma
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.
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.3 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 OCB.
Blood tests to exclude treatable causes of coma and stupor include the following:
Serum electrolytes, calcium, magnesium, phosphate, glucose, BUN, and creatinine
Liver and renal function tests
Ketones, lactose, and osmolarity to rule out diabetic coma
PT and PTT
Drug screen to include ethanol, acetaminophen, salicylates, opiates, benzodiazepines, barbiturates, cocaine, amphetamines, ethylene glycol, and methanol
If the initial screening is unrevealing, additional testing should include the following:
Thyroid and adrenal function tests
Blood smear: to screen for thrombotic thrombocytopenic purpura and hemolysis
LDH, D-dimer, and fibrinogen to rule out DIC
Antiphospholipids if a coagulation problem is suspected
Carboxyhemoglobin if carbon monoxide poisoning is suggested
1. Goldman L, et al. Cecil Medicine. Coma and Other Disorders of Consciousness, 24th ed. Philadelphia, PA: Saunders Elsevier; 2012.
2. Plum F, Posner JB. The Diagnosis of Stupor and Coma, 4th ed. Philadelphia, PA: FA Davis; 1995.
3. Hasbun R, Abrahams J, Jekel J, et al. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001;345:1727.
REYE SYNDROME (ACUTE TOXIC–METABOLIC ENCEPHALOPATHY)
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.
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. 1 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.
The diagnostic criteria for Reye syndrome include a markedly increased CSF pressure with no other abnormalities.
Screening tests to eliminate other etiologies include CBC, glucose, electrolytes, BUN, creatinine, calcium, magnesium, and phosphate.
Serum AST, ALT, or ammonia may be three times greater than the upper limit of normal.
On biopsy of the liver, noninflammatory, panlobular fatty changes are seen.
1. Belay ED, Bresee JS, Holman RC, et al. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340:1377.
Seizures represent a sudden change in behavior as a result of brain dysfunction.
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, 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 fetus–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. Electroencephalography (EEG) may be diagnostic in epileptic seizures. It may also determine whether a patient has generalized or partial seizures. Neuroimaging (MRI) should be performed to rule out structural abnormalities in the brain.1
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, renal function tests, liver function tests, and toxicology screens. 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.2
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 count, LDH, CO2, and ammonia. CPK may be elevated following generalized seizures but not usually after a partial seizure.2
1. 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.
2. 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.
According to the DSM-IV, delirium is defined as having four key features: disturbance of consciousness, change in cognition, development over a short period of time, and an etiology due to medical illness, substance abuse, or intoxication or medication effect. Additional features that may accompany delirium include psychomotor disturbances and emotional disturbances.1
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 sun downing, nonconvulsive status epilepticus, dementia, primary psychiatric illness, and focal syndromes such as Wernicke aphasia, Anton syndrome, and brain tumor particularly in the frontal lobe.
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 even 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.2
1. American Psychiatric Association. Diagnostic and Statistical Manual, 4th ed. Washington, DC: APA Press; 1994.
2. Plaschke K, von Haken R, Scholz M, et al. Comparison of the confusion assessment method for the intensive care unit (CAM-ICU) with the Intensive Care Delirium Screening Checklist (ICDSC) for delirium in critical care patients gives high agreement rate(s). Intensive Care Med. 2008;34:431.
DISORDERS WITH FOCAL NEUROLOGIC DEFICITS (NEUROPATHIES)
Disorders 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 central nervous system disorders and peripheral nerve or muscle diseases can be made on clinical assessment with help from various diagnostic modalities including EEG, 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)
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.
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 central nervous system 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.
Initial diagnosis includes obtaining a history of the disease and its progression, physical examination with neurologic testing, and electromyography 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.1
Screening for predominantly axonal disorders:
Serum protein electrophoresis and immunofixation
Urine/blood for heavy metals
Urine/blood for porphyrins
Sjögren syndrome testing (anti-Ro, anti-La antibodies)
Methylmalonic acid and homocysteine levels (in patients with borderline low serum B12 levels)
Hepatitis screen (for types B and C)
Screening for predominantly demyelinating disorders:
Serum protein electrophoresis and IEP
Urine protein electrophoresis
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)
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:
Diphtheria: CSF protein is 50–200 mg/dL
EBV (mononucleosis associated: CSF shows increased protein and up to several hundred mononuclear cells)
Additional laboratory information that may be contributive:
Serum and urine for toxicity to drugs and chemicals (lead, arsenic, etc.)
Blood tests for vitamin deficiencies, pregnancy, and porphyria
Nerve biopsy may be useful in diagnosing the underlying cause of the neuropathy especially in cases that are difficult to differentiate between axonal and demyelinating etiologies. Nerve biopsy may also help to diagnose amyloidosis, leprosy, vasculitis, and sarcoidosis.2 Skin biopsy may be helpful in disorders that affect small unmyelinated nerve fibers, such as in pain, numbness, and paresthesias.3
1. 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.
2. England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363:2151.
3. McCarthy BG, Hsieh ST, Stocks A, et al. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology. 1995;45:1848.
Diabetic polyneuropathy is primarily a symmetrical neuropathy affecting the distal lower extremities. There is loss of vibratory sensation and impairment of pain, light touch, and temperature sensation.1
Patients with diabetes may present with a number of different neuropathies including symmetric polyneuropathy, autonomic neuropathy, radiculopathies, mononeuropathies, and mononeuropathy multiplex.
The differential diagnosis includes 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 findings and physical examination using one of a number of testing tools.2,3 When the presentation is atypical electrodiagnostic, testing may be helpful. Laboratory testing should include screening to rule out vitamin B12 deficiency, hypothyroidism, and uremia.
1. Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:89.
2. Dyck PJ, Kratz KM, Lehman KA, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology. 1991;41:799.
3. 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, Jun 21. doi: 10.1002/dmrr.1226. [Epub ahead of print]
CRANIAL NERVE NEUROPATHY, MULTIPLE
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 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 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.
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
Infections (e.g., HIV, diphtheria, herpes zoster, leprosy)
Tumor (leukemia, lymphoma, carcinomas)
Drugs, toxic substances
Chronic renal failure
The diagnosis of a mononeuropathy is based on history, neurologic examinations over time evaluation of progression, electrodiagnostic studies, somatosensory potentials, and neuroimaging (MRI).
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
Lumbar puncture: Evaluation of CSF is warranted in patients with unusual presentations. CSF should be examined for evidence of inflammation, elevated CSF protein, and serologic testing for Lyme disease, syphilis, and CMV. Cytologic evaluation for tumor cells may be warranted.
FACIAL PALSY (BELL PALSY)
Bell palsy is the loss of function of cranial nerve VII resulting in facial paralysis.
Patients with Bell palsy typically present with the sudden onset (usually over hours) of unilateral facial paralysis and comprise approximately 50% of patients with facial nerve palsy.1 Current research suggests that herpes simplex virus is the etiologic agent causing neural inflammation, demyelination, and palsy.2 Other infectious agents associated with facial palsy include herpes zoster, CMV, Epstein-Barr virus, adenovirus, rubella virus, mumps, influenza B, HIV, and coxsackie virus.3
Lyme disease may produce bilateral palsy. Early negative blood serology does not exclude the diagnosis. A lymphocyte pleocytosis in the CSF is suggestive, and the finding of specific oligoclonal IgG in the CSF is a sensitive indicator.4 Rickettsial and Ehrlichia infection have also been found in patients with facial palsy.5,6
Bacterial infections such syphilis, leprosy, diphtheria, catscratch disease, M. pneumoniae, and nonspecific local inflammation including otitis media have also been known to cause facial palsy as have some 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 4-11], tumors invading the temporal bone), cholesteatoma, and Paget disease of 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 Guillain-Barré syndrome may cause bilateral facial palsy.
Melkersson-Rosenthal syndrome, a granulomatous disorder of unknown etiology, may display recurrent facial palsy.7
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.
1. Peitersen E. The natural history of Bell’s palsy. Am J Otol. 1982;4:107.
2. Peitersen E. Bell’s palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl. 2002;(549):4–30.
3. Morgan M, Nathwani D. Facial palsy and infection: the unfolding story. Clin Infect Dis. 1992;14:263.
4. Markby DP. Lyme disease facial palsy: differentiation from Bell’s palsy. BMJ. 1989;299:605.
5. Bitsori M, Galanakis E, Papadakis CE, et al. Facial nerve palsy associated with Rickettsia conorii infection. Arch Dis Child. 2001;85:54.
6. Lee FS, Chu FK, Tackley M, et al. Human granulocytic ehrlichiosis presenting as facial diplegia in a 42-year-old woman. Clin Infect Dis. 2000;31:1288.
7. Levenson MJ, Ingerman M, Grimes C, et al. Melkersson-Rosenthal syndrome. Arch Otolaryngol. 1984;110:540.
Bitemporal hemianopsia is the loss of vision in the temporal fields due to a mass lesion causing compression of the optic chiasm.
Patients present with decreased vision in the temporal fields. The most common cause is pituitary adenoma (see eBook Figure 4-12), but any mass lesion may be causative, including metastatic tumor, sarcoidosis, Hand-Schüller-Christian disease, meningioma of sella (see eBook Figure 4-13), craniopharyngioma (see eBook Figure 4-14), and aneurysm of the circle of Willis.
Diagnosis is predominantly made by neuroimaging. Biopsy may help identify tumor type.
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.
Patients may present with a number of causative disorders including MS (approximately 30% of cases and most common in younger patients, also tends to be bilateral), 1,2 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.2 The differential diagnosis includes oculomotor nerve palsy.
Testing is directed at identifying the causative disease. Tests to rule out DM, vasculopathies, multiple sclerosis, myasthenia gravis, hyperthyroidism, infection, and drug toxicities will be of help.3
1. Frohman EM, Zhang H, Kramer PD, et al. MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis. Neurology. 2001;57:762.
2. Frohman EM, Frohman TC, O’Suilleabhain P, et al. Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score. J Neurol Neurosurg Psychiatry. 2002;73:51.
3. Keane JR. Internuclear ophthalmoplegia: unusual causes in 114 of 410 patients. Arch Neurol. 2005;62:714.
OCULOMOTOR NERVE PALSY
Oculomotor nerve palsy may result from lesions of the third cranial nerve (oculomotor nerve) anywhere along its path.
The diagnosis varies by patient age, type of diplopia, and lid involvement. The most common causes include intracranial aneurysm, ischemia, trauma, and migraine. Ischemic diabetic third nerve palsies are the most common etiology in adults. Traumatic third nerve palsy arises only from severe blows to the head. Ophthalmoplegic “migraine” has been reclassified as a cranial neuralgia by the International Headache Society in 2004.1
The differential diagnosis includes MS (may mimic pupil-sparing ophthalmoplegia) and orbital inflammation or fracture. The diagnosis rests on complete history, and neurologic exam and neuroimaging with MRI, MRA, or CTA to rule out aneurysm.2
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.
1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders. Cephalalgia. 2004;24:1.
2. Jacobson DM, Trobe JD. The emerging role of magnetic resonance angiography in the management of patients with third cranial nerve palsy. Am J Ophthalmol. 1999;128:94.
TRIGEMINAL NEURALGIA (TIC DOULOUREUX)
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.
Eighty to ninety percent of cases are caused by compression of the trigeminal nerve root, by an artery or vein, leading to demyelination.1 Compression may also be caused by vestibular schwannoma (acoustic neuroma), meningioma, epidermoid, or other cyst. Saccular aneurysm or arteriovenous malformations are rare causes of compression. MS may cause demyelination of one or more of the trigeminal nerve nuclei resulting in pain.
Diagnosis is performed predominantly by neuroimaging (CT or MRI) and electrophysiologic testing. Laboratory findings may assist in identifying MS or herpes zoster. Tissue biopsy may be needed in the diagnosis of schwannoma (see eBook Figure 4-11), meningioma (see eBook Figures 4-13 and 4-15), and cysts.
1. Love S, Coakham HB. Trigeminal neuralgia: pathology and pathogenesis. Brain. 2001;124:2347.
RETROBULBAR NEUROPATHY (OPTIC NEURITIS)
Retrobulbar neuropathy is a disorder of the optic nerve resulting in pain behind the affected eye, impaired vision, and rarely blindness.
Patients with retrobulbar neuropathy may present with a number of causative disorders including MS (demyelinating optic neuritis), ischemia (arteritic or nonarteritic ischemic optic neuropathy), infectious (West Nile virus, catscratch disease, toxoplasma, Tuberculosis, and Cryptococcus), tumors, and medications (chloramphenicol, ethambutol, isoniazid, penicillamine, phenothiazines, phenylbutazone, quinine, and streptomycin).1,2 Postviral infectious optic neuritis may also occur. Less common causes include sarcoidosis and autoimmune diseases such as lupus, Sjögren syndrome, and Wegener granulomatosis.3 Retrobulbar neuropathy is associated with MS, which ultimately develops in 30–50% of patients with optic neuritis. Ischemic optic neuropathy is the most common etiology in older patients.4 There are two hereditary forms of optic neuropathy: Leber hereditary optic neuropathy and Kjer disease.5,6
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 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 multiple sclerosis. CSF may be normal or reveal increased protein and ≤200/μL lymphocytes. Oligoclonal bands 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.
1. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354:1273.
2. Lee AG, Brazis PW. Systemic infections of neuro-ophthalmic significance. Ophthalmol Clin North Am. 2004;17:397.
3. Rabadi MH, Kundi S, Brett D, et al. Neurological pictures. Primary Sjögren syndrome presenting as neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2010;81:213.
4. Hayreh SS. Posterior ischaemic optic neuropathy: clinical features, pathogenesis, and management. Eye (Lond). 2004;18:1188.
5. Lamirel C, Cassereau J, Cochereau I, et al. Papilloedema and MRI enhancement of the prechiasmal optic nerve at the acute stage of Leber hereditary optic neuropathy. J Neurol Neurosurg Psychiatry. 2010;81:578.
6. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26:211.
Autonomic neuropathy is a group of diseases or syndromes affecting the parasympathetic and/or the sympathetic nerves. It can be hereditary or acquired.
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 DM1 (see also Polyneuropathy and the section on Autoimmune Disorders of the CNS).
Disorders that may cause autonomic dysfunction include amyloidosis, Guillain-Barré syndrome, hereditary neuropathies, infections (e.g., Chagas disease, HIV, botulism, diphtheria, and leprosy), toxicities including drugs (vincristine, cis-platinum, 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).2
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, response to the Valsalva maneuver, and evaluation for orthostatic hypertension.
1. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956.
2. Freeman R. Autonomic dysfunction. In: Samuels M, Fesky S, eds. The Office Practice of Neurology, 2nd ed. Philadelphia, PA: Churchill Livingstone; 2003;14:141–145.
Pseudotumor cerebri is idiopathic intracranial hypertension.
Patients present with headache and 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, funduscopic exam to rule out papilledema, and visual field testing to determine the severity of optic nerve involvement.1
Laboratory findings may help in the diagnosis of “secondary pseudotumor cerebri,” which is due to an underlying condition. 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. Obesity has been associated with increased CSF opening pressures.2
Testing 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 SLE, polyarteritis nodosa, and serum sickness. Other conditions that may be tested for as the symptoms warrant include sarcoidosis, Guillain-Barré syndrome, head trauma, various anemias, and chronic renal failure.
1. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology. 2002;59:1492.
2. Corbett JJ, Mehta MP. Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology. 1983;33:1386.
DISORDERS OF MOVEMENT
Parkinson disease (PD) is a progressive neurodegenerative disorder resulting from the loss of dopaminergic cells in the substantia nigra.
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, dementia with Lewy bodies, cortical basal degeneration, progressive supranuclear palsy, and multiple system atrophy. It must also be distinguished from secondary parkinsonism due to drugs, toxins, head trauma, infections, cerebrovascular disease, and metabolic disorders.1
The diagnosis is based on clinical evaluation, there are no specific physiologic or blood tests to confirm the diagnosis. Neuroimaging is usually not helpful in distinguishing PD from other syndromes with motor disorders. MRI may be performed to exclude structural abnormalities of the brain. Olfactory dysfunction is seen early in PD, and testing may help to establish the diagnosis.2 At autopsy, gross sectioning of the brain stem through the substantia nigra reveals the loss of pigmentation. Microscopy demonstrates loss of neurons and Lewy Bodies (see eBook Figures 4-7 and 4-16).
1. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol. 2006;5:75.
2. Katzenschlager R, Zijlmans J, Evans A, et al. Olfactory function distinguishes vascular parkinsonism from Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:1749.
PROGRESSIVE SUPRANUCLEAR PALSY
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting in the loss of neurons and glia in the basal ganglia, brain stem, cerebral cortex, dentate nucleus, and upper spinal cord.
Patients present with symptoms similar to Parkinson disease. Symptoms more specific to PSP include vertical supranuclear gaze palsy and unexplained falls due to postural instability. A genetic susceptibility has been suggested, but no genetic abnormality has been found to be causative. The diagnosis of PSP is made on clinical examination.
As in PD, laboratory and imaging studies are not definitive and should be performed to rule out treatable forms of disease (encephalitis, dopaminergic drug use, tumors, and Whipple disease). Blood, urine, and CSF are normal in PSP. Recent studies suggest that there may be biomarkers for PSP including a low homovanillic acid level in the CSF and decreased levels of tau protein.1,2 Pathologic evaluation of the brain at autopsy will identify globose neurofibrillary tangles within neurons and glia predominantly in the basal ganglia typical for PSP3 and midbrain and cerebral cortical atrophy with hypopigmentation of the substantia nigra and locus ceruleus.4 The abnormal filaments are composed of 4R tau.5,6
1. Mendell JR, Engel WK, Chase TN. Modification by L-dopa of a case of progressive supranuclear palsy. With evidence of defective cerebral dopamine metabolism. Lancet. 1970;1:593.
2. Urakami K, Wada K, Arai H, et al. Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J Neurol Sci. 2001;183:95.
3. Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009;8:270.
4. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for Steele- Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;44:2015.
5. Kumar V, Abbas AK, Fausto N, et al. Robbins and Code Trend Pathologic Basis of Disease, 8th ed. Philadelphia, PA: Saunders Elsevier; 2004:1318.
6. Takahashi M, Weidenheim KM, Dickson DW, et al. Morphological and biochemical correlations of abnormal tau filaments in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2002;61:33.
Huntington disease (HD) is a neurodegenerative disease inherited as autosomal dominant and is caused by a repeat expansion in the huntingtin gene on chromosome 4p. The disease exhibits variable penetration rates in affected families but is fully penetrant when the repeat size is >38.1
Patients present with choreiform movements, psychiatric disorder, and dementia. The differentiation from other neurodegenerative dementias is made based on the preexistence of choreiform movements and/or psychiatric illness and from other movement disorders by the manner of abnormal movements.
The diagnosis of HD is based on a familial history, clinical assessment, and genetic testing. Genetic screening is also available for family members who wish to know their risk of disease. Testing for the CAG repeat length is now commercially available with good sensitivity and 100% specificity based on a cutoff of >38 repeats for HD.2 Neuroimaging is no longer recommended.
1. Richards RI. Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum Mol Genet. 2001;10:2187.
2. Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994; 330:1401.
Definition Dystonia is a movement disorder with sustained muscle contractions. It may be hereditary or acquired.
Patients present with twisting repetitive movements and abnormal posture. Classification is by age of onset, anatomic distribution, and etiology. In primary dystonia, there are no neurologic symptoms in addition to the dystonic findings while in secondary dystonia, additional findings such as spasticity, ataxia, muscle weakness, ocular or cognitive impairment, or seizures may be present.1,2
A genetic etiology has been determined for dystonia with the two most common mutations the TOR1A gene in DYT1 dystonia and the THAP1 gene in DYT6 dystonia representing early-onset and late-onset dystonia, respectively.3,4 Doparesponsive dystonia presents in early childhood with focal dystonia and is frequently due to an autosomal dominant DYT5 dystonia caused by mutation in the GTP cyclohydrolase-1 gene.5 Segawa syndrome, an autosomal recessive form, is due to a mutation in the tyrosine hydroxylase gene.6
The diagnosis of dystonia is predominantly made on clinical examination with special attention to evaluation of the movement disorders.
Genetic testing for the DYT1 dystonia gene is available for early-onset dystonia, and in some areas, DYT5 dystonia genetic testing may be obtained. Other tests may help to exclude secondary dystonia these include neuroimaging with MRI or CT to evaluate the basal ganglia, CBC, electrolytes, renal and liver function tests, ANA, ceruloplasmin, serum copper and 24-hour urinary copper to rule out Wilson disease, and sedimentation rate.
1. Geyer HL, Bressman SB. The diagnosis of dystonia. Lancet Neurol. 2006;5:780.
2. Phukan J, Albanese A, Gasser T, et al. Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis. Lancet Neurol. 2011;10:1074.
3. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology. 2000;54:1746.
4. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet. 2009;41:286.
5. Trender-Gerhard I, Sweeney MG, Schwingenschuh P, et al. Autosomal-dominant GTPCH1- deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry. 2009;80:839.
6. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol. 2003;54 (Suppl 6):S32.
Tourette syndrome (TS) is an inherited neuropsychiatric disorder of unknown etiology resulting in motor and phonic tics with an onset in childhood.
Patients present with sudden, repetitive movements and sounds. The disorder may be chronic or transient. It has a genetic component that is complex and has been associated with a mutation in the gene SLITRK1 on chromosome 13.1 This gene appears to be involved in dendritic growth. Patients with TS also frequently have comorbid conditions including attention deficit disorder, obsessive–compulsive disorder, obsessive–compulsive behavior, learning disorders, and oppositional defiant disorder.2
The diagnosis of TS is predominantly made on the clinical examination and history. Neuroimaging is not helpful. No laboratory tests are available for the positive diagnosis of TS; however, drug testing to rule out secondary tics should be performed especially for cocaine and dopamine receptor blocking agents. Review of a blood smear may rule out neuroacanthocytosis, which has been associated with tics.
1. Abelson JF, Kwan KY, O’Roak BJ, et al. Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science. 2005;310:317.
2. Freeman RD, Fast DK, Burd L, et al. An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol. 2000;42:436.
Cerebral palsy is a nonprogressive dysfunction of the cerebral motor regions resulting from perinatal jaundice or asphyxia.1
Patients present in childhood with chorea and muscle tone abnormalities, abnormal reflexes, and coordination. The diagnosis is made primarily based on history and physical findings.
Testing that may help to rule out alternative causes such as abnormal development of the brain and infarcts includes MRI, cranial ultrasound, and CT scan. EEG may also be used to rule out seizure. Laboratory testing with PT, PTT, Protein C and S, and antithrombin may rule out coagulopathy as a basis for stroke that may mimic cerebral palsy.
1. Kuban KC, Leviton A. Cerebral palsy. N Engl J Med. 1994;330:188.
Sydenham chorea is a sequela of acute rheumatic fever.
Sydenham chorea is the most common acquired form of chorea in childhood. The onset is usually 1–8 months following the infection and may be insidious or abrupt.1 The diagnosis is made by clinical evaluation. No specific laboratory testing currently exists although initial testing for streptococcal infection and ASO titers may be helpful.
1. Eshel G, Lahat E, Azizi E, et al. Chorea as a manifestation of rheumatic fever—a 30-year survey (1960–1990). Eur J Pediatr. 1993;152:645.
Lesch-Nyhan syndrome is an inherited X-linked recessive trait resulting in hyperuricemia.
Patients present early on with mental retardation, delayed development, extrapyramidal motor symptoms, and self-mutilating behavior and also severe gout and renal disorders. A genetic mutation is found in the hypoxanthine–guanine phosphoribosyltransferase enzyme gene and results in deficient enzymatic activity. A large number of mutations of this gene have been reported.1
Molecular genetic testing with sequence analysis of the entire coding region is available for Lesch-Nyhan syndrome as both a carrier test and prenatal test.
1. Mak BS, Chi CS, Tsai CR, et al. New mutations of the HPRT gene in Lesch-Nyhan syndrome. Pediatr Neurol. 2000;23:332.
Essential tremor (ET) is defined as an isolated tremor with no other physiologic or psychological symptoms. It is common and may be seen in up to 5% of the population.1
Patients present with a tremor on exertion of the affected muscle group. Mental or physical stress may worsen the symptoms. Most common are tremors of the hands or arms, but the head, neck, jaw, and other body parts may be affected. There is a complex genetic inheritance of ET with a dominant form revealing linkage to genetic loci on chromosomes 2P, 3q13, and 6p23.2 In one study, neuropathologic changes noted in the brains of patients with ET at autopsy have revealed brain stem Lewy bodies and degenerative changes in the cerebellum.3 A separate study revealed loss of pigmented neurons in the locus ceruleus.4
Commercial genetic testing is not currently available for ET although this is a common form of motor disorder that should be distinguished from other progressive and treatable disorders such as Parkinson disease and metabolic disorders. Screening laboratory tests for thyroid disease (TSH and free T4), diabetes, and drug levels (sympathomimetic drugs and stimulants), caffeine, and alcohol may rule out causes for nonessential tremor.
1. Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord. 1998;13:5.
2. Shatunov A, Sambuughin N, Jankovic J, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain. 2006;129:2318.
3. Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain. 2007;130:3297.
4. Shill HA, Adler CH, Sabbagh MN, et al. Pathologic findings in prospectively ascertained essential tremor subjects. Neurology. 2008;70:1452.
RESTLESS LEG SYNDROME
Restless leg syndrome (RLS) is a motor disorder in which patients feel the need to move their legs to alleviate discomfort. It may be primary or secondary. The primary, idiopathic form of this disorder is associated with a familial component in patients with onset before age 40. RLS has been shown to be associated with genetic variants of BTBD9 and MEIS1, both of which influence expression of the disorder and are involved in iron homeostasis.1,2 RLS may also be associated with a number of medical disorders including iron deficiency, renal disease, diabetes, multiple sclerosis, Parkinson disease, pregnancy, rheumatic disease, and venous insufficiency.
Patients present with an irresistible urge to move, most commonly when at rest or trying to sleep, because of unpleasant sensations in the legs of other body parts. The diagnosis of RLS is primarily made on clinical evaluation and history. Genetic testing is currently not commercially available. Underlying medical disorders that may be causative should be ruled out with appropriate testing.
1. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000.
2. O’Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23:200.
AMYOTROPHIC LATERAL SCLEROSIS (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that may be familial resulting in muscle weakness and death.
Patients with ALS present with upper and lower motor neuron dysfunction beginning in the cranial/bulbar, cervical, thoracic, or lumbosacral regions. There is steady progression of the disease over years, spreading to the other regions, resulting in weight loss and muscle wasting. Familial ALS accounts for 5–10% of all ALS cases (see eBook Figure 4-17).
Diagnosis is made on clinical history and examination. Sensory and motor nerve conduction studies and electromyography may help support the diagnosis when features of acute and chronic denervation and reinnervation are present. Neuroimaging may exclude other possible diagnoses.
Creatine kinase may be elevated up to 1,000 U/L due to denervation.
Evaluation of the CSF may rule out Lyme disease, HIV infection, chronic inflammatory demyelinating polyneuropathy, malignancy, and paraneoplastic syndromes secondary to lymphoma or breast cancer.
Familial ALS genetic testing is commercially available. Mutations occur in the SOD1, TARDBP, FUS, FIG4, ANG, Alsin (ALS2), VAPB, OPTN, and SETX genes (see Chapter 10 Hereditary and Genetic Diseases).
Muscle biopsy may rule out myopathy. In ALS, there is chronic denervation and reinnervation.
AUTOIMMUNE DISORDERS OF THE CNS
PRIMARY AUTOIMMUNE AUTONOMIC FAILURE
Primary autoimmune autonomic failure (also known as autoimmune autonomic ganglionopathy, acute panautonomic neuropathy, or acute pandysautonomia) is an autoimmune disorder possibly due to anti-ganglionic acetylcholine receptor antibodies (AChRs) causing dysfunction of efferent sympathetic and parasympathetic pathways.
Patients present with orthostatic hypotension, anhidrosis, decreased production of saliva and tears, erectile dysfunction, and impaired bladder emptying. This disorder is responsive to plasma exchange. Antibodies to ganglionic AChR are present in about two thirds of all subacute cases and in one third of chronic cases.1–3
The differential diagnosis should include secondary causes of autoimmune autonomic failure. These are DM, amyloidosis, paraneoplastic syndromes, Lambert-Eaton syndrome, botulism, syphilis, HIV infection, collagen vascular disease, and porphyria.4
Testing varies according to the presentation and history of autonomic symptoms. Testing should be directed to differentiate between acute inflammatory demyelinating polyneuropathies (Parkinson disease, drug or toxin exposure, and hereditary etiologies) from primary autoimmune autonomic failure. Detection of antibodies binding to ganglionic nicotinic AChRs is performed by radioimmunoprecipitation and is diagnostic.1 There may also be decreased plasma norepinephrine levels.
Tests that rule out disorders that may cause autonomic symptoms include
Glycosylated hemoglobin to test for diabetes
Anti-Hu antibody titers, which may be used to test for paraneoplastic syndromes
Anti-calcium channel antibody titers for Lambert-Eaton myasthenic syndrome
Stool for botulinum by culture and detection of toxin for botulism
Serum and urine protein electrophoresis to evaluate myeloma due to amyloidosis, or genetic testing to evaluate for familial amyloidosis