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eMedicine Journal
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Dermatology
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Internal Medicine
Dermatologic Manifestations of Neurologic Disease Synonyms, Key Words, and Related Terms: neurocutaneous disorders, neurofibromatosis type 1, NF1, von Recklinghausen disease, neurofibromatosis type 2, NF2 central neurofibromatosis, bilateral acoustic neuroma, tuberous sclerosis, Bourneville syndrome, epiloia, nevoid basal cell carcinoma syndrome, Gorlin syndrome, variegate porphyria, LEOPARD syndrome, multiple lentigines syndrome, ataxia-telangiectasia, AT, Louis-Bar syndrome, Sjögren-Larsson syndrome, SLS, incontinentia pigmenti, IP, Bloch-Sulzberger syndrome, Sturge-Weber syndrome, pellagra, varicella zoster virus, antiphospholipid syndrome, Sneddon syndrome, diabetes mellitus, lyme disease, arsenic poisoning, reflex sympathetic dystrophy, RSD, seborrheic dermatitis |
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Author Information | Introduction | Neurocutaneous Disorders With Autosomal Dominant Phenotypes | Disorders Of Autosomal Recessive, X-linked, And Congenital Origin | Neurocutaneous Syndromes With Photosensitivity | Neurocutaneous Disorders Of Viral Origin | Neurocutaneous Disorders Associated With Stroke | Neurocutaneous Disorders Associated With Peripheral Neuropathy | Neurologic Disorders With Important Dermatologic Findings | Test Questions | Pictures | Bibliography
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 | AUTHOR INFORMATION | Section 1 of 12    |
Authored by Theresa Conologue, DO, Staff, Department of Dermatology, National Capital Consortium/Walter Reed Army Medical Center
Coauthored by Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, Medicine, University of Texas Health Science Center-San Antonio
Theresa Conologue, DO, is a member of the following medical societies: American Academy of Dermatology, and Association of Military Dermatologists
Edited by Donald Belsito, MD, Program Director, Professor, Department of Internal Medicine, Division of Dermatology, University of Kansas; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey P Callen, MD, Chief, Division of Dermatology, Professor of Medicine (Dermatology), Department of Internal Medicine, University of Louisville School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; and Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
| Author's Email: | Theresa Conologue, DO |  |
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| Editor's Email: | Donald Belsito, MD |
eMedicine Journal, February 6 2007, VOLUME 8,
Number 2
| INTRODUCTION | Section 2 of 12  |
Many disorders have a combination of neurologic and dermatologic findings in patients. This chapter provides an overview of neurocutaneous disorders and organizes them into clinically relevant groupings of use to the practicing physician.
| NEUROCUTANEOUS DISORDERS WITH AUTOSOMAL DOMINANT PHENOTYPES | Section 3 of 12 |
Neurofibromatosis type 1 (NF1; also termed von Recklinghausen disease) is an autosomal dominant disorder. The gene locus is on band 17q11.2, but spontaneous mutations occur in approximately 50% of patients. As the most common genetic disorder of the nervous system, NF1 affects approximately 1 in 3000 people. NF1 occurs with equal frequency in men and women without regard to race or ethnic background.
The National Institutes of Health (NIH) consensus criteria for the diagnosis of NF1 require 2 or more of the following:
These criteria are useful in the clinical diagnosis of NF1; however, some children younger than 8 years may not appear to have NF1 because of the late onset of the characteristic features used in the classification.
Cutaneous manifestations
Cutaneous manifestations are listed in the NIH criteria.
Neurofibromas occur in almost all patients affected with NF1. Neurofibromas are benign tumors and almost always involve cutaneous, subcutaneous, or dermal tissues. They comprise Schwann cells, nerve fibers, fibroblasts, vascular elements, mast cells, and myxoid matrix. Neurofibromas are classified into 4 types.
Neurologic manifestations
Chromosome 17 encodes the tumor suppressor neurofibromin. Neurofibromin suppresses the products of ras by enhancing its guanosine triphosphatase (GTPase) activity, thus reducing the requirement for nerve growth factor or neurotrophins. The loss of neurofibromin, which is expressed in neurons, Schwann cells, the adrenal medulla, and white blood cells, may contribute to tumor progression.
Patients are at risk for developing numerous benign and malignant tumors. CNS neoplasms are of particular concern in patients with NF1. Optic gliomas are the most common CNS tumors, occur in approximately 15% of patients, and may result in blindness if left untreated. Other associated CNS neoplasms are astrocytomas, vestibular schwannomas (acoustic neuroma), and, less often, ependymomas and meningiomas.
Other manifestations
Non-CNS tumors associated with NF1 include neurofibrosarcoma, rhabdomyosarcoma, pheochromocytoma, Wilms tumor, nonlymphocytic childhood leukemia, and visceral neurofibroma.
Other complications of NF1 include congenital glaucoma, hydrocephalus, seizures, learning disabilities, psychosocial difficulties, and endocrine disturbances. Hypertension can occur in NF1 and may result from a pheochromocytoma or renal artery stenosis. Pheochromocytoma occurs in 0.1-5.7% of patients with NF1 and is more common in adults. Other endocrine disturbances, such as growth hormone deficiency, short stature, and precocious puberty, have been reported in patients with NF1.
Case reports of NF1 and juvenile xanthogranulomas have been associated with juvenile chronic myelogenous leukemia. Zvulunov et al found a 30- to 40-fold higher than expected rate for the association of NF1 with JXG and juvenile chronic myelogenous leukemia.
Neurofibromatosis type 2 (NF2; central neurofibromatosis, bilateral acoustic neuroma) is an autosomal dominant disorder caused by mutation in the schwannoma tumor suppressor gene on bands 22q11-13.1. This gene codes for schwannomin/merlin proteins, which are membrane-organizing proteins and may affect tumor suppressor activity at the cell membrane level. Evidence for interfamilial clinical variability and spontaneous mutations exists in 50-70% of patients. NF2 is less common than NF1, occurring in 1 in 35,000 live births without regard to sex, race, or ethnic background. The neurologic hallmark of NF2 is the development of bilateral vestibular schwannomas (acoustic neuromas) that are not associated with NF1.
The NIH Consensus Developmental Conferences provide guidelines for use of the term neurofibromatosis type 2. They suggest the term vestibular schwannoma in place of the term acoustic neuroma to reflect the anatomic site of the tumor. Evidence suggests that 2 subtypes of NF2 exist, which are (1) a milder variant (Gardner) resulting from missense and splice-site germ-line mutations and (2) a severe variant (Wishart) resulting from frameshift and nonsense mutations. Onset of the disorder frequently appears at age 15-30 years.
Diagnostic criteria for NF2 include the following:
Cutaneous manifestations
Cutaneous manifestations in NF2 are less common than NF1. Of patients with NF2, two thirds have a skin manifestation.
Neurologic manifestations
The most common neurologic finding is the presence of vestibular schwannomas; however, schwannomas may occur on any of the cranial nerves except for the olfactory nerve. Pressure on the vestibulocochlear and facial nerve complex can cause symptoms of hearing loss with intermittent tinnitus, unsteady gait, and facial weakness. Advise patients to avoid swimming under water, especially alone, because of the association with underwater disorientation.
Other tumors of the CNS occur in NF2, such as intracranial and spinal meningiomas, astrocytomas, and ependymomas.
Other manifestations
Ocular manifestations include juvenile posterior subcapsular lenticular opacity, retinal hamartomas, optic disk glioma, and optic nerve meningioma. Lisch nodules are not associated with NF2.
Tuberous sclerosis (Bourneville syndrome, epiloia) is an autosomal dominant disorder in approximately 50% of patients; in the remaining 50% of patients, the disorder occurs as a result of spontaneous mutation. In 1908, Vogt first described tuberous sclerosis as a triad of mental retardation, epilepsy, and adenoma sebaceum; however, this triad is present in less than one third of patients. The term epiloia indicates epilepsy, low intelligence, and adenoma.
In tuberous sclerosis, 2 gene loci have been identified, TSC1 and TSC2. TSC1 has been mapped to band 9q34, which codes for a 130-kd protein (termed hamartin) and is a probable tumor suppressor gene. TSC2 has been mapped to band 16q13.3 and codes for an amino acid protein (termed tuberin), which has a region of homology with the GTPase-activating protein GAP3. GTPase regulates cell proliferation, and current studies suggest tuberin may mediate this activity. The genetic heterogeneity produces subtle differences in the phenotype. This may be explained by the function of hamartin and tuberin as part of the same intracellular pathway. Prevalence has been estimated to range from 1 per 5800 to 1 per 10,000, occurring equally between males and females of all races. Expression is highly variable among families.
Cutaneous manifestations
Cutaneous manifestations associated with tuberous sclerosis may be present at birth. In approximately 87% of patients, congenital hypopigmented macules are found. These ash-leaf macules are the earliest and most characteristic finding and can be accentuated on Wood lamp examination. Polygonal macules are the most common type. Another type is Confetti macules, which are 1- to 3-mm, hypopigmented, and spotlike macules commonly located on the pretibial area. Melanocytes are present in the macules; however, their transfer and synthesis are impaired.
Shagreen patch, a connective tissue nevus, may occur on the trunk, most often in the lumbosacral region (Image 11). Shagreen patch is a 1- to 10-cm, flat, flesh-colored plaque with an orange peel appearance. Facial angiofibromas (eg, adenoma sebaceum) are diagnostic of tuberous sclerosis and usually appear in children aged 4-10 years (Image 10). These typically are firm, smooth, red-to-pink papules consisting of hyperplastic blood vessels and collagen, occurring on the nasolabial folds, cheeks, and chin.
Subungual and periungual fibromas (Koenen tumors) are firm flesh-colored fibromas in the nail matrix or bed that result in destruction of the nail plate. Koenen tumors are common in tuberous sclerosis, and surgical excision is curative (Image 12). Other associated cutaneous findings include fibrous plaques on the face, café au lait macules, and port-wine hemangiomas.
Neurologic manifestations
Neurologic symptoms often are the first presenting sign and begin as focal or generalized seizures. Infantile spasms, tonic-clonic seizures, and complex partial and myoclonic seizures are the most common forms. Of children with infantile spasms, 10% have tuberous sclerosis.
Cortical tubers are characteristic to tuberous sclerosis. These are potatolike nodules of glial proliferation occurring anywhere in the cortex, ganglia, or ventricle walls. Other CNS findings include mental retardation, subependymal hamartomas, paraventricular calcifications, and giant cell astrocytomas. Over time, subependymal nodules and cortical tubers can become calcified.
Other manifestations
Tuberous sclerosis is a multisystemic disease.
Recommendations
The NIH-sponsored Tuberous Sclerosis Consensus Conference categorized the evaluation and management of tuberous sclerosis patients into the following 3 types:
Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is an autosomal dominant disorder with a gene locus at bands 9q22-31 and a variable expressivity. The disorder begins at birth with obvious frontal bossing, hypertelorism, bifid ribs, and bone abnormalities of the spine and fingers. As the child ages, jaw cysts, palmar pitting, and basal cell carcinomas become apparent. Nevoid basal cell carcinoma syndrome results from mutation causing an inactivation of the patched gene, a tumor suppressor gene, in the hedgehog pathway.
Cutaneous manifestations
Multiple basal cell carcinomas present as tan-brown papules on the face, neck, and trunk. Palmoplantar pits are 2- to 3-mm erythematous pits occurring on the palms and soles. Other cutaneous findings are epidermoid cysts and milia.
Neurologic manifestations
Key neurologic abnormalities are calcification of the falx cerebri, hydrocephalus internus, agenesis of the corpus callosum, medulloblastoma, and occasionally, mental retardation.
Other manifestations
Common features include odontogenic keratocysts, jaw cysts (usually occurring in the maxilla), ovarian fibromas, fibrosarcoma, strabismus, and congenital blindness. An unusual finding of combined hamartoma of the retina and retinal pigment epithelium also has been reported.
Recommendations
Variegate porphyria (mixed, South African) is an autosomal dominant disorder recently cloned and mapped to the protoporphyrinogen oxidase gene on bands 1q22-23. The disorder is termed South African porphyria because it occurs frequently in white South Africans of Boer descent with an incidence of 1 case per 330. Genealogic studies show that all are descendants of Gerrit Jansz (Dutch settler) and Ariaantje Jacobs (orphan from Rotterdam) who married at the Cape of Good Hope in 1688. Similar founder effects explain the high prevalence of variegate porphyria in Finland, and links have been hypothesized to the houses of Stuart, Hanover, and Prussia.
Symptoms begin in the second or third decade of life as a result of a deficiency of protoporphyrinogen oxidase, the enzyme that catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX in the heme pathway. This results in the accumulation of protoporphyrinogen, porphyrins, and porphyrin precursors.
Cutaneous manifestations
Cutaneous manifestations are present in 80% of patients. The extent of skin findings varies (hence the name) and is identical to findings in porphyria cutanea tarda. Vesicles, bulla, and ulcers are found primarily on light-exposed skin. Increased skin fragility with chronic scarring, milia on fingers and hands, hyperpigmentation in photodistributed patterns, sclerodermoid plaques, dystrophic calcifications, photo-onycholysis, and hypertrichosis are common (Image 9).
Neurologic and other manifestations
Acute attacks are seen in approximately 50% of patients and cause neuropsychiatric, gastrointestinal, and cardiovascular manifestations as a result of the increase in porphobilinogen (PBG) and aminolevulinic acid (ALA). Acute attacks also are associated with other hepatic porphyrias, such as acute intermittent porphyria and hereditary coproporphyria. During attacks, symptoms include delirium, colicky abdominal pain, dark urine, axonal neuropathy that can mimic Guillain-Barré syndrome, seizures, coma, tachycardia, and hypertension.
Attacks in all 3 porphyrias are precipitated by increases in hepatic ALA synthase, eg, by drugs that increase cytochrome P450 or by starvation dieting.
Laboratory analysis in variegate porphyria can be helpful. ALA and PBG can be found in the urine only during acute attacks and fluoresce a pink-to-red color (Image 8). Accordingly, the Watson-Schwartz test for PBG is positive only during acute attacks. Stool porphyrin levels are elevated markedly (including between attacks), with protoporphyrin in greater proportion than coproporphyrin. Plasma porphyrin levels are elevated, and fluorescence at 626 nm is diagnostic.
Recommendations
LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia in males, retardation of growth, and sensorineural deafness) syndrome (multiple lentigines syndrome) is an autosomal dominant disorder with high penetrance and variable expressivity. Gorlin first described the condition.
Mutations in the PTPN11 gene, known to be mutated in persons with Noonan syndrome, has been demonstrated in patients with LEOPARD syndrome.
Cutaneous manifestations
The most prominent cutaneous findings in LEOPARD syndrome are the lentigines that begin at birth and increase with age. These lentigines are multiple 1- to 2-mm, flat, dark-brown patches in a general distribution, sparing mucous membranes (Image 13). Areas of hypopigmentation in places where previous lentigines existed also may be a key feature. Unlike freckles, the lentigines have an increased number of melanocytes and large pigment granules that are unrelated to sun exposure. Some patients lack lentigines, which makes the diagnosis difficult.
Other key dermatologic findings include café noir and café au lait spots.
Neurologic manifestations
Neurologic deficits associated with LEOPARD syndrome often are not recognized at birth. Sensorineural deafness occurs in 15-25% of reported cases and can be profound. Once the diagnosis is made, screen the child for sensorineural deafness and start appropriate therapy as soon as possible to avoid later difficulties with speech and phonation. Mild mental retardation, disturbed EEG wave activity, and diffuse encephalopathy also may be present.
Recommendations
Refer patients with LEOPARD syndrome to a cardiologist for a complete workup. ECG conduction abnormalities usually are present and may result from right or left ventricular hypertrophy. Cardiovascular findings include aortic stenosis, obstructive cardiomyopathy associated with significant mortality, and sudden cardiac arrest. Other findings associated with the disorder include triangular facies and pectus excavatum or pectus carinatum.
Many other disorders exist with neurocutaneous findings and autosomal dominant phenotypes.
In Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) patients have multiple telangiectasias on the face, hands, palmoplantar, and subungual regions (Image 6). Epistaxis is common in approximately 80% of patients, and neurologic complications include vascular lesions of the brain and/or spinal cord. The mutated genes are HHT1 and HHT2; both endoglin and activin are tumor growth factor-beta receptors that play a role in vessel wall integrity.
Piebald trait with neurologic defects presents as a white forelock and depigmented patches with spots of hyperpigmentation on the anterior body, sparing the hands and feet. Patients have cerebellar ataxia, varying degrees of mental retardation, and possible hearing loss.
| DISORDERS OF AUTOSOMAL RECESSIVE, X-LINKED, AND CONGENITAL ORIGIN | Section 4 of 12 |
Ataxia-telangiectasia (AT; Louis-Bar syndrome) is an autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, abnormalities in cellular and humoral immunity, and recurrent viral and bacterial infections. The gene for AT has been localized to bands 11q22-23 and is termed the ATM gene. The disorder occurs with equal frequency in males and females and in approximately 1 in 80,000-100,000 live births.
Cutaneous manifestations
Patients present with distinctive cutaneous manifestations. Telangiectasias develop when patients are aged 3-6 years and are noted first on the bulbar conjunctiva and ears. Later, they appear on the flexor surface of the arms, eyelids, malar area of the face, and upper chest. Granulomas, café au lait macules, graying hair, and progeria can occur.
Neurologic manifestations
The presenting symptom is cerebellar ataxia beginning in the second year, when the child begins to walk. Choreic and athetoid movements, progressive nystagmus, slurred speech, dystonia, dysarthria, oculomotor apraxia, impassive facies, decreased deep tendon reflexes, and distal muscular atrophy develop gradually. Intelligence may be normal in early childhood but progressively deteriorates.
Other manifestations
Immunodeficiency (from deficient thymic development) results in an inability to mount sufficient immune response. Recurrent viral and bacterial infections (eg, sinus infections, bronchiectasis, pneumonia) occur in 80% of patients and are the most common cause of death resulting from respiratory failure. Patients lack helper T cells, but suppressor T cells are normal. Immunoglobulin A (IgA) is absent in 75% of patients, immunoglobulin E (IgE) in 85%, and immunoglobulin G (IgG) is low. Alpha-fetoprotein and carcinoembryonic antigen are elevated and may be useful in the diagnosis.
Endocrine disorders associated with AT include ovarian agenesis, testicular hypoplasia, and insulin-resistant diabetes.
The ATM gene is a nuclear protein important in the detection and repair of damaged DNA. Defects in the gene result in an increased susceptibility to malignancy. Malignant neoplasms occur in 10-15% of AT patients; most common are lymphoreticular neoplasm and leukemia.
Recommendations
Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder. Linkage to chromosome arm 17q has been reported in Swedish pedigrees. Lacour et al show linkage of chromosome 17 in families from different ethnic origins; thus providing evidence of a single gene locus. SLS is caused by a deficiency in fatty alcohol oxidoreductase, which catalyzes the oxidation of medium-chain and long-chain fatty acids.
Cutaneous manifestations
The disorder begins at birth with generalized ichthyosis and erythroderma. As the child ages, the scale becomes darker without erythema and is more pronounced around the umbilicus, neck, and flexures, typically sparing the face. Hyperkeratosis of the palms and soles and marked pruritus are common. Atypical retinal pigment degeneration in the macula (glistening dots) usually is seen after the first year.
Neurologic manifestations
Neurologic symptoms consist of spastic diplegia or tetraplegia, scissor gait, seizures, mental retardation, and speech deficits. Progressive spasticity can result in confinement to a wheelchair during childhood.
Recommendations
Autosomal recessive phenotypes typically are more severe than those with autosomal dominant traits and commonly are associated with enzyme deficiency.
Multiple sulfatase deficiency is a neurodegenerative disorder that progresses to death early in childhood. Children with this disorder are unable to degrade various sulfatases (in particular steroid sulfatase), which results in mild ichthyosis. Neurologic complications result from myelin deterioration, causing unsteady gait, deterioration in speech, and blindness.
Hartnup disease is a disorder of amino acid transportation with resulting decreased absorption of tryptophan. Cutaneous manifestations include photosensitivity and the pellagralike skin changes of photodistributed erythema and scale. Progressive cerebellar ataxia and psychiatric disturbances are common. Urinalysis shows aminoaciduria and tryptophan derivatives.
Tangier disease is a rare autosomal recessive deficiency syndrome. The disease results from a deficiency of high-density lipoproteins, causing orange-yellow papules, xanthomatous papules, and recurrent neuropathy.
Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is an X-linked dominant disorder lethal to male patients. The disorder has been linked to the gene locus Xq28 in a number of studies. Recently, mutations in the NEMO/IKKy have been found to cause expression of the disorder. Few affected males have been documented, and most had Klinefelter syndrome (47,XXY). The disorder was described as early as 1906; Bloch and Sulzberger were credited with fully describing IP in 1928. Skin lesions arranged in a linear pattern, ocular defects, dental, and neurologic abnormalities characterize IP.
More than 700 cases have been reported, with a 97% female predominance.
Cutaneous manifestations
Characteristic cutaneous findings begin at birth and occur in 4 stages.
Of patients, 50% present in stage 1 at birth and 90% by age 2 weeks. Stage 2 lesions occur in approximately 70% of patients. In a small percentage of patients, the hyperpigmentation is present at birth. Other cutaneous findings include scarring alopecia in 30% of patients, nail dystrophy in 5-10%, and peg teeth in 66%. Subungual tumors (resembling keratoacanthomas), keratotic tumors, and more rarely, squamous cell carcinoma also have been reported.
Neurologic manifestations
CNS findings occur in more than 30% of patients; seizures are the most common. Other findings include cerebral ischemia, cerebral edema, brain atrophy, and gyral dysplasia. Gross neurologic findings associated with IP include mental retardation, spastic paralysis, cortical blindness, and paresis.
Other manifestations
Ocular manifestations occur in 25-35% of patients and include strabismus, cataracts, retinal detachments, optic atrophy, retrolental mass, and vitreous hemorrhage. In particular, note the retinal vascular abnormalities with secondary blindness.
Recommendations
Sturge-Weber syndrome (craniofacial or trigeminocranial angiomatosis with cerebral calcification) is not an inherited disorder, but it has been reported to show prevalence among relatives. Sturge-Weber syndrome is characterized by congenital facial port-wine stains and leptomeningeal vascular angiomatosis. Sporadic malformations most commonly occur in the leptomeninges, facial capillaries, and ocular vessels. Leptomeningeal angiomatosis can present clinically as epilepsy, mental retardation, and hemiplegia.
Cutaneous manifestations
Newborns with port-wine stains have a 5-8% risk of Sturge-Weber syndrome. In patients with Sturge-Weber syndrome, the port-wine stain usually involves the ophthalmic (V1) and maxillary (V2) division of the trigeminal nerve (Image 5). The macule is deep red, irregular-shaped, and of vascular origin. The lesion's size varies, and it may involve the eyelid, face, and trunk. Although striking, the size of the nevus does not predict the degree of neurologic impairment.
Neurologic manifestations
Neurologic complications can begin as early as age 5 months with partial motor seizures later progressing to more generalized seizures. Most neurologic complications, such as spastic hemiparesis, sensory defects, and homonymous hemianopia, appear later in childhood and are contralateral to the nevus. At approximately age 6-7 years, skull radiographs reveal curved double outlines of the parietooccipital cortex, which is the classic tram-track calcification. Mental retardation is present in approximately 55-92% of cases.
Recommendations
| NEUROCUTANEOUS SYNDROMES WITH PHOTOSENSITIVITY | Section 5 of 12 |
Pellagra is caused by dietary deficiency of niacin, resulting in the 4 Ds: diarrhea, dermatitis, dementia, and eventually, death. Niacin can be ingested or synthesized from large quantities of dietary tryptophan. In the early 1900s, pellagra was prevalent, and during the years 1928-1929, it became the eighth-to-ninth highest cause of death in the US. Because of intensive fortification efforts in the US, pellagra has become uncommon; however, it remains a public health issue in Africa, India, and China, and recent outbreaks were reported in Angola at an asylum camp dependent on food distribution.
Pellagra continues to occur in the US and commonly is associated with alcoholism and isoniazid therapy. Other possible causes include carcinoid tumors, Hartnup disease, hookworms, and medications such as azathioprine and 5-fluorouracil. Recognizing the clinical manifestations associated with pellagra is important, since the disorder is treated easily.
Cutaneous manifestations
Cutaneous manifestations occur in a photodistributed pattern.
Neurologic manifestations
Episodes of mania, aggressive behavior, and severe mood swings may occur. Neurologic symptoms may be predominant in late stages of the disease. Patients may experience paresthesia, muscle weakness, and headaches. Death occurs within 4-5 years if the patient remains untreated.
Recommendations
Focus treatment on dietary correction and daily supplements of 100-300 mg of nicotinic acid. Once therapy has begun, skin lesions begin to heal within 24 hours.
| NEUROCUTANEOUS DISORDERS OF VIRAL ORIGIN | Section 6 of 12 |
Varicella zoster virus is a herpes virus that causes a primary infection of varicella (ie, chickenpox). The virus is latent in cranial nerve and dorsal root ganglia and can reactivate years later as herpes zoster (shingles). More than 300,000 cases of zoster are seen in the US every year. Crops of diffuse, painful, pruritic vesicles and papules that occur in a dermatomal distribution characterize zoster. The disease is self-limiting and usually resolves within 2-3 weeks.
Cutaneous manifestations
Cutaneous manifestations are present in almost all cases of zoster. The phrase "dewdrops on a rose petal" describes the appearance of the vesicles on an erythematous base (Image 17). The affected dermatome is painful to the touch, and prodromal pain may precede the development of visible lesions. Although zoster can occur anywhere along the neural axis, thoracic dermatomes are affected most commonly, followed by the face.
Neurologic manifestations
Southern blot analysis and in situ hybridization has detected the virus in human trigeminal and thoracic ganglia. Polymerase chain reaction (PCR) analysis further confirms the clinical findings of thoracic and trigeminal dermatomes as the most common site of reactivation.
Zoster occurring in the ophthalmic division of the trigeminal nerve may result in keratitis, a potential cause of blindness. Immediately refer these patients to an ophthalmologist for slit lamp examination. Of patients with ophthalmic nerve zoster, two thirds have eye involvement, especially when vesicles occur on the side of the nose, indicating involvement of the nasociliary nerve (Hutchinson sign).
Other complications can develop following varicella or zoster infections.
Recommendations
| NEUROCUTANEOUS DISORDERS ASSOCIATED WITH STROKE | Section 7 of 12 |
Antiphospholipid syndrome is a hypercoagulable state resulting from antibodies that neutralize anionic phospholipids on endothelial cells and platelets. It is a multisystemic disorder, and patients may present with a wide range of neurologic manifestations, fetal loss (usually second trimester), mild thrombocytopenia, valvular heart disease, and livedo reticularis. Antiphospholipid syndrome is associated strongly with systemic lupus erythematosus (SLE) and patients with SLE are considered to have secondary antiphospholipid syndrome. The term primary antiphospholipid syndrome is reserved for cases of unknown etiology.
The disorder is characterized by high titers of antiphospholipid antibodies (APLA), ie, lupus anticoagulant and anticardiolipin antibodies. Recent studies suggest that antibodies are not directed against phospholipids but are directed at phospholipid-binding proteins such as B2-glycoprotein I and prothrombin.
Cutaneous manifestations
The cutaneous manifestations most commonly seen include livedo reticularis and leg ulceration. Livedo reticularis is a mottled, bluish, netlike discoloration that changes from red-blue to deep blue on cold exposure (Image 23). This nonspecific reaction pattern has been reported in other disorders, such as polyarteritis nodosa, cryoglobulinemia, disseminated intravascular coagulation, and endocarditis. Other cutaneous manifestations, including acrocyanosis (Raynaudlike phenomenon) and Degos malignant atrophic papulosis, are rare findings.
Neurologic manifestations
Neurologic complications may be misdiagnosed as multiple sclerosis (MS). Clinical findings include multiinfarct dementia, focal deficit, epilepsy, and recurrent stroke. Transitory weakness, vertigo, ataxia, and dysarthria may occur. Neurocognitive defects including dementia, atypical migraines, depression, and delusional states also have been reported.
Recommendations
Research to predict outcome in patients with antiphospholipid syndrome has shown that patients with elevated IgG have increased risk of recurrent thrombotic events. Tektonidou et al predicted that risk of a second event was highest in patients with B2-glycoprotein I antibodies in whom autoimmune hemolysis was the first event. Patients without antibodies, who had recurrent abortions as their first event, were at lowest risk. The study reported that recurrent events are of the same type as the presenting symptom. Therefore, initial clinical features can help predict the prognosis of the disorder. Specific clinical features tend to cluster during the course of the disease.
A variety of therapies have been tried.
Sneddon syndrome is characterized by livedo reticularis and multiple strokes resulting in dementia. Antiphospholipid antibodies and anti–B2-glycoprotein antibodies also have been detected in some patients with this disorder. The cutaneous manifestation of livedo reticularis may precede the cerebrovascular episodes, thus alerting the clinician.
| NEUROCUTANEOUS DISORDERS ASSOCIATED WITH PERIPHERAL NEUROPATHY | Section 8 of 12 |
Diabetes mellitus is the most common systemic endocrine disorder; an increasing number of patients are diagnosed each year. Neurologic complications of type 1 and type 2 diabetes mellitus are similar; the most common is peripheral neuropathy. Other important complications of diabetes result from accelerated atherosclerosis that places patients at high risk for cerebrovascular accidents, hypertension, and cardiovascular disease. Associated cutaneous manifestations of diabetes include necrobiosis lipoidica diabeticorum (NLD), acanthosis nigricans, and bullous diabeticorum.
Cutaneous manifestations
NLD occurs in 0.3% of patients, and one study by Little et al reported a 0.8% prevalence in 82% of patients with type 1 diabetes. NLD is 3 times more common in women, and 60% of patients with NLD have diabetes.
Recommendations in NLD are as follows:
Acanthosis nigricans can be seen in a variety of disorders. More severe forms are associated with malignant disease, and milder forms can occur in obesity and in patients with insulin resistance, despite the absence of overt diabetes. Characteristic skin changes include velvety hyperpigmented plaques in the neck and axillary regions, and patients often complain of dirty skin (Image 15). More severe forms of acanthosis nigricans can become generalized over the knuckles, extensor surfaces, and may involve mucosal surfaces.
A rare cutaneous finding in diabetes is bullous diabeticorum (Image 14). These tense bullae can arise spontaneously on the distal extremities. The bullae are subepidermal, with the plane of separation at the basement membrane zone above the basal lamina, and heal without scarring. They may be chronic and recurrent, especially in older patients. Only 100 cases have been reported in the past 70 years, but according to a report by Lipsky et al of 12 patients in an 8-year period, this disorder may be underdiagnosed.
Lyme disease was first described in 1975 in Lyme, Connecticut. Currently, more than 90% of cases occur in the northern hemisphere. Lyme disease is a multisystemic disorder caused by the spirochete Borrelia burgdorferi transmitted by a tick bite (Ixodes scapularis). During the bite, the risk of transmission increases with the duration of the tick's attachment. The degree of engorgement seen in the tick is a rough measure of the risk of transmission.
Cutaneous manifestations
Cutaneous manifestations occur in 65-80% of patients. Erythema chronicum migrans (ECM) begins as a small papule, commonly at the site of the tick bite. The lesion progresses centrifugally over weeks and can become large. Central clearing gives the lesion the typical bull's-eye appearance (Image 21). The area can irritate the patient, and regional lymphadenopathy may develop.
Secondary lesions have been reported and usually are multiple erythematous macules with central clearing, similar to ECM but smaller. A bluish-red solitary nodule (borrelial lymphocytoma) may develop at the site of the tick bite or at a distant location such as the ear, nose, scrotum, or areola region. Acrodermatitis chronica atrophicans consists of atrophic, edematous, bluish-red plaques on the extensor aspect of the lower legs and elbows and most commonly occurs in women. These may resemble scleroderma or lichen sclerosus.
Neurologic manifestations
More than 50% of patients have a migrating peripheral neuropathy, usually occurring 2-3 months after the onset of infection. The term neuroborreliosis describes the many neurologic complications that occur, such as lymphocytic meningitis, cranial neuritis, facial palsy, ophthalmoplegia, trigeminal neuralgia, vestibular neuritis, and paralysis. Neurologic complications cannot be excluded on the basis of a negative cerebral spinal fluid antibody analyses. Late complications, occurring after 1 year, are chronic peripheral neuropathy, MS-like demyelinating disease, dementia, and extreme fatigue.
Other manifestations
Arthritis in one to a few large joints is a common manifestation and develops in as many as 70% of untreated patients. Patients with human leukocyte antigen D4 (HLA-D4) haplotype may be at increased risk for chronic arthritis resulting from Lyme disease. Carditis, conduction abnormalities, and heart blocks also may occur.
Recommendations
Antibiotics are 90% curative in the early stages but become less effective as the disease progresses.
Arsenic is a tasteless and odorless substance and often is used in insecticides, fabric dyes, the tanning of animal hides, and certain printing processes. Contaminated drinking water can be a common source of chronic exposure. At one time, arsenic was used medically to treat disorders such as psoriasis. Many cases of arsenic poisoning occur each year as a result of accidental or industrial mishaps, and its characteristics and availability make it a popular choice for intentional poisoning.
Cutaneous manifestations
Cutaneous manifestations include hyperpigmentation occurring in a guttate pattern (which occasionally may be generalized) with increased pigment in the areola and inguinal folds. Mees lines are transverse bands of leukonychia and can occur 2-3 weeks after an acute poisoning or in persons with chronic exposure (Image 22).
Neurologic manifestations
Associated neurologic effects include subacute sensorimotor polyneuropathy, convulsions and, in severely affected patients, coma and death.
Recommendations
Treatment begins by removing the offending agent and by chelating with British antilewisite.
| NEUROLOGIC DISORDERS WITH IMPORTANT DERMATOLOGIC FINDINGS | Section 9 of 12 |
Reflex sympathetic dystrophy (RSD) is a poorly defined disorder often difficult to diagnose. Symptoms of intolerable pain (out of proportion to clinical picture) develop following an injury. In 50% of patients, the initial injury is a fracture, usually of the distal extremity. The sympathetic nervous system is believed to be a mediating factor in the early stages of the disorder, but the exact role is unclear.
Cutaneous and neurologic manifestations
RSD can be divided into 3 stages, and each stage is characterized by dermatologic and neurologic findings.
Diagnosis is primarily clinical; therefore, cutaneous manifestations can help the diagnosis in patients without classic findings.
Some advocate sympathetic nerve block as a diagnostic test. In chronic stages, a bone scan can reveal osteoporosis and a 3-phase scan often reveals abnormal absorption of bone.
Recommendations
Seborrheic dermatitis is a common disorder in the general population but has increased incidence in certain neurologic disorders. Erythematous greasy scales and yellow plaques on the scalp, eyebrows, nasolabial folds, ears, and sternal area are characteristic (Image 19). Blepharitis is a common finding. The etiology is unknown, but studies have described Pityrosporum ovale (Malassezia furfur) as the causative agent. P ovale is lipophilic yeast, and patients with seborrheic dermatitis have significantly higher amounts of it, as well as increased skin lipids. Some associated disorders are as follows:
Recommendations
No cure exists; however, effective treatments are available.
| TEST QUESTIONS | Section 10 of 12 |
CME Question 1: A 27-year-old woman presents with a week-old enlarging lesion on her abdomen. The patient states that at first the lesion was a small red bump noticed after hiking in the woods. The lesion has grown to cover her entire side. Upon further questioning, the patient states that she has had a low-grade fever for the past 3 days, a headache, and is tired constantly. Physical examination reveals a large erythematous patch with central clearing resembling a bull's eye. The physician should take which of the following actions?
A: Instruct her to take 2 aspirins and call in the morning.
B: Prescribe a mid strength topical steroid.
C: Perform a punch biopsy of the outer edge of the lesion.
D: Prescribe Keflex 500 mg PO qid for 10 days.
E: Prescribe doxycycline 100 mg PO bid for 14 days.
The correct answer is E: A diagnosis of Lyme disease is based on the clinical picture. Serology can aid in the diagnosis but is limited in the early stages of the disease. As tests, enzyme-linked immunosorbent assay and indirect immunofluorescence assay for Borrelia burgdorferi are used most often. Patients also may have an elevated sedimentation rate and serum immunoglobulin M; however, these are associated more frequently with disseminated infection. Other treatments are amoxicillin, clarithromycin, or cefuroxime axetil.
CME Question 2: A 30-year-old woman presents to the physician's office for follow-up care. She was seen 1 week ago in the emergency department because of colicky abdominal pain following a cocktail party. Her current medications are ibuprofen and birth control pills (recently initiated). She denies any past medical history and past surgical history. Her family history is significant for psychiatric disorders and hypertension. Physical examination reveals scarring and small milia on the dorsal aspect of her hands and fingers, which she blames on her gardening hobby. Chemistry, CBC, pregnancy, and CT scan of the abdomen and pelvis were negative. She is distressed because she thinks someone at work may be trying to poison her. The physician should take which of the following actions?
A: Reassure the patient and continue the ibuprofen prn for pain.
B: Obtain a urine sample and check to see if it fluoresces with a pink-to-red color.
C: Refer the patient to a psychiatrist because of obvious paranoid tendencies and personality disorder.
D: Obtain a stool sample to test for elevated porphyrin levels.
E: Obtain a urine sample to test for elevated porphyrin levels.
The correct answer is D: The patient may have variegate porphyria. Urine porphyrin levels are elevated only during the acute attack. Stool porphyrin levels are elevated between attacks and therefore, may help with the diagnosis. Plasma porphyrin levels also are elevated, and fluorescence at 626 nm is diagnostic. Once the diagnosis is made, counsel the patient to avoid precipitating factors, such as estrogen, alcohol, sulfonamides, barbiturates, and griseofulvin, and warn her to practice sun avoidance and use opaque sunscreens.
Pearl Question 1 (T/F): Pellagra does not occur in the United States.
The correct answer is False: Although now uncommon, cases still occur in the US and are associated with alcoholism, isoniazid therapy, restrictive diets, and carcinoid tumors.
Pearl Question 2 (T/F): Herpes varicella zoster viral infection of the ophthalmic division of the trigeminal nerve is termed the Hutchinson sign and is an ophthalmologic emergency.
The correct answer is True: Zoster infection of the ophthalmic division of the trigeminal nerve may result in keratitis, which is a potential cause of blindness.
Pearl Question 3 (T/F): All patients with necrobiosis lipoidica diabeticorum have diabetes.
The correct answer is False: Necrobiosis lipoidica diabeticorum occurs in 0.3% of patients with diabetes; however, 60% of patients with necrobiosis lipoidica diabeticorum have diabetes mellitus and another 20% have glucose intolerance or a family history of diabetes. Therefore, promptly screen for diabetes upon a diagnosis of necrobiosis lipoidica diabeticorum.
Pearl Question 4 (T/F): Upon diagnosis, evaluate livedo reticularis further, since it can be an early manifestation of disorders associated with stroke.
The correct answer is True: Livedo reticularis is associated with antiphospholipid syndrome and Sneddon syndrome, both of which have increased incidence of stroke. Carefully evaluate patients to establish the best treatment.
| PICTURES | Section 11 of 12 |
| BIBLIOGRAPHY | Section 12 of 12 |
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