eMedicine Specialties > Dermatology > Internal Medicine

Dermatologic Manifestations of Neurologic Disease

Author: Heather Kiraly Orkwis, Philadelphia College of Osteopathic Medicine
Coauthor(s): Theresa Dressler Conologue, DO, FAAD, Physician, Department of Dermatology, Geisinger Medical Center; Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Contributor Information and Disclosures

Updated: May 13, 2009

Introduction

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

Neurofibromatosis type 1

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:

• Café au lait macules larger than 5 mm in diameter in prepubertal individuals and larger than 15 mm in diameter in postpubertal individuals and numbering 6 or more
• Neurofibromas of any type or 1 plexiform neurofibroma and numbering 2 or more
• Axillary freckling (Crowe sign; Media File 1) or inguinal freckling
• Optic glioma
• Lisch nodules (iris hamartomas; Media File 2) in more than 90% of patients younger than 6 years and numbering 2 or more
• Dysplasia of the sphenoid or thinning of long bone cortex with or without pseudoarthrosis
• First-degree relative with NF1

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.

• The most common type is cutaneous neurofibromas (see Media Files 3-4). These neurofibromas are nonpainful, soft, flesh-colored tumors that can range from a few millimeters to 2 centimeters in diameter. The underlying dermal defect allows reduction of the tumor with light pressure, which is termed the buttonhole sign.
• Subcutaneous neurofibromas occur in 20% of patients and are painful, firm, rubbery tumors.
• Nodular plexiform neurofibromas comprise a large network of subcutaneous neurofibromas that occur along nerve plexuses or dorsal nerve roots. As a result of their location, these tumors cause severe neurologic deficits.
• Diffuse plexiform neurofibromas occur in approximately 5% of patients and are considered specific to NF1. They usually are congenital and may have overlying hyperpigmentation and hypertrichosis. These tumors are highly vascular and may involve deep structures that erode bone and extend to visceral areas. These tumors are like icebergs; what appears small on the outside may be extensive on the inside and involve vast regions of the mediastinum or retroperitoneum. Of plexiform neurofibromas, 5-6% can progress to malignant peripheral nerve sheath tumors or Triton tumors (a rare variant of malignant peripheral nerve sheath tumors), which are severely painful and carry a poor prognosis.

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.

Neurofibrosarcoma is the main cause of death of NF1 patients younger than 40 years. It may develop de novo or from sarcomatous degeneration of a preexisting plexiform neurofibroma. It should be suspected in patients with new onset of symptoms or in patients with changing symptoms. At imaging, neurofibrosarcoma is characterized by a large heterogeneous tumor invading adjacent structures.²

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 al³ found a 30- to 40-fold higher than expected rate for the association of NF1 with juvenile xanthogranulomas and juvenile chronic myelogenous leukemia.

Neurofibromatosis type 2

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:

• Bilateral vestibular schwannomas (visualized with CT scan or MRI)
• A first-degree relative with the disease plus a unilateral vestibular schwannoma before age 30 years
• Any 2 of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular opacity

Cutaneous manifestations

Cutaneous manifestations in NF2 are less common than NF1. Of patients with NF2, two thirds have a skin manifestation.

• Neurofibromas occur less commonly than in NF1.
• Plexiform neurofibromas are unusual, and café au lait macules tend to be fewer and lighter in pigmentation; only 8% of NF2 patients have more than 3 macules.
• Axillary or inguinal freckling is not present.
• Cutaneous and subcutaneous flat or spherical schwannomas often occur on peripheral nerves.
• Most commonly, schwannomas are superficial raised papules with overlying pigment and hair.
• Subcutaneous spherical nodular schwannomas occur on peripheral nerves of the limbs and trunk and often can be palpated.

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

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 case per 5,800 population to 1 case per 10,000 population, 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 (see Media File 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 (see Media File 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. Successful treatment of facial angiofibromas has been reported with podophyllin,⁴ but this should be considered experimental.

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.

• Retinal hamartomas (phacomata) are white streaks on the retina seen on funduscopic examination.
• Renal involvement usually begins in infancy, and 75% of patients have angiomyolipomas.
• Simple renal cysts may appear spontaneously.
• Oral pathology consists of enamel pits and gingival fibromas.
• Effects on the musculoskeletal system are seen in phalangeal cysts and periosteal thickening.
• Lung cysts may occur.
• Rhabdomyomas occur in 50% of patients, usually in infancy, and may regress spontaneously with age.
• Pulmonary lymphangiomyomatosis, a proliferation of smooth muscle cells, can occur in women with tuberous sclerosis.
• A few reports exist of infants with a white forelock who later were diagnosed with tuberous sclerosis.

Recommendations

The NIH-sponsored Tuberous Sclerosis Consensus Conference categorized the evaluation and management of tuberous sclerosis patients into the following 3 types:

• Recommendations for newly diagnosed patients
  • Neurodevelopmental testing
  • Ophthalmologic evaluation
  • If seizures present, EEG
  • If cardiac symptoms present, echocardiography
  • Renal ultrasonography
  • Cranial CT scanning or MRI
  • Chest CT scanning
• Recommendations for established patients
  • Neurodevelopmental testing before school and as needed
  • Ophthalmologic examinations as needed
  • EEG to monitor seizure treatment
  • If cardiac symptoms present, echocardiography
  • Renal ultrasonography for those aged 1-3 years
  • Cranial CT scanning or MRI for those aged 1-3 years, up to and during adolescence
  • If pulmonary symptoms present, chest CT scanning
• Family members: Consider cranial CT scanning, renal ultrasonography, and genetic testing

Nevoid basal cell carcinoma syndrome

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

Epidemiologic studies have demonstrated that sunlight, and particularly UV radiation, are key risk factors for developing basal cell carcinomas. This explains the low frequency of these lesions in African Americans, owing to the protective action of melanin pigmentation.⁵

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

• Protect these children from the sun and closely monitor them throughout life. Radiography and radiotherapy are contraindicated, since they induce new basal cell carcinomas. This may present difficulties if medulloblastoma is treated with radiation therapy before the syndrome is diagnosed.
• If basal cell carcinomas are treated early and no other malignancies develop, patients can live a normal life span.

Variegate porphyria

Variegate porphyria is an autosomal dominant acute hepatic porphyria, due to a deficiency of protoporphyrinogen oxidase (PPO) activity, the penultimate enzyme in the heme biosynthetic pathway. The disease is termed variegate because it can manifest with neurological symptomatology, cutaneous photosensitivity, or both.⁶

Variegate porphyria (mixed, South African) has been 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 (see Media File 9).

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 (see Media File 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.

• Advise patients about precipitating drugs, such as barbiturates, estrogen, griseofulvin, sulfonamides, and alcohol.
• Educate patients with variegate porphyria about sun avoidance and the use of opaque sunscreens such as titanium dioxide.
• Beta-carotene may decrease symptoms.
• Advise patients to avoid long periods of fasting.
• Patients may require referral to a nutritionist for education on eating small carbohydrate meals that maintain stable glucose levels.
• Consult a neurologist for seizure management and pain control.
• Avoid acute attacks, which are life threatening and may result in further neurologic damage.

LEOPARD syndrome

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.

This disease was also known as multiple lentigines syndrome, cardiocutaneous syndrome, Moynahan syndrome, lentiginosis profuse, and progressive cardiomyopathic lentiginosis. About 200 patients have been reported worldwide, but the real incidence of LEOPARD syndrome has not been assessed.⁷

Mutations in the PTPN11 gene, known to be mutated in persons with Noonan syndrome, has been demonstrated in patients with LEOPARD syndrome.^8,9

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 (see Media File 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.

Neurologic manifestations

Hypotonia is common in the newborn and can result in delayed psychomotor development. Mild learning difficulties are reported in about 30% of the cases.⁷

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.

Other neurocutaneous disorders with autosomal dominant phenotypes

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 (see Media File 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.

Disorders of Autosomal Recessive, X-linked, and Congenital Origin

Ataxia-telangiectasia

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

• Avoid using radiography, radiotherapy, and radiomimetic agents, such as bleomycin, in AT patients because of their inability to repair damaged DNA and the increased sensitivity of fibroblast DNA to ionizing radiation.
• Patients are more sensitive to UV light.
• Screen family members, since heterozygote carriers reportedly share the defect in repairing radiation-induced damage. In addition, family members have as much as 5 times the risk for cancer, particularly breast cancer in female heterozygotes.
• How the ATM gene results in ataxia remains unclear; however, recent evidence suggests an effect on intracellular vesicle or protein transport mechanisms.
• Therapy is supportive and prognosis is poor. Most patients are confined to a wheelchair by their teens.
• Death occurs in the first decade as a result of infection or malignancy.
• Studies have shown some clinical improvement with fetal thymus transplants, administration of thymic products, and use of intravenous IgG.
• Current evidence suggests that patients with AT are under a constant state of oxidative stress and that treatment with antioxidants, such as N -acetyl cysteine, may decrease the development of lymphoma. Trials of N -acetyl cysteine in patients with AT are ongoing.¹⁰

Sjögren-Larsson syndrome

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by a triad of intellectual disability, spastic diplegia or tetraplegia, and congenital ichthyosis with associated ocular features, which include pigmentary changes in the retina.¹¹ Linkage to arm 17q has been reported in Swedish pedigrees. Lacour et al¹² show linkage of chromosome 17 in families from different ethnic origins; thus providing evidence of a single gene locus.

SLS is caused by mutations in the ALDH3A2 gene, causing a deficiency in fatty alcohol oxidoreductase, which catalyzes the oxidation of medium- and long-chain fatty acids.¹³

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 and signs appear during the first 1-2 years of life and consist of delay in reaching motor milestones due to spastic diplegia or, much less commonly, spastic tetraplegia. Approximately half the patients are nonambulatory, and most others require braces or crutches to walk. Seizures occur in about 40% of patients. Cognitive deficits are equally divided among those with mild, moderate, or profound retardation, but rare patients have been found with normal intellect. Delayed speech and dysarthria are common. A distinctive ophthalmologic finding is the presence of retinal crystalline inclusions, so-called glistening white dots, surrounding the fovea. Although all SLS patients do not have the retinal inclusions, their presence is pathognomonic for SLS. Photophobia and myopia are also often present. Brain MRI reveals white matter disease and MR spectroscopy identifies an unusual lipid peak in myelin.¹³

Recommendations

• Prognosis is guarded and depends on the extent of neurologic involvement. Currently, no effective treatment exists.
• Dietary restriction of long-chain fatty acids with medium-chain triglyceride oil supplementation may help.
• Research by Willemsen et al¹⁴ showed leukotriene B4 (LTB4) in the urine of patients affected with SLS, unlike healthy control subjects. In addition, in vivo studies demonstrated a defect in the inactivation of leukotriene B4. Although it is uncertain if this inactivation has a pathophysiologic role in SLS, it may be responsible for the severe pruritus and provides evidence for further studies and possible therapeutic trials of leukotriene synthesis inhibitors.
• Inhibition of LTB4 synthesis by zileuton, which improves the disturbing pruritus in some patients, is one example of targeted therapy. Stimulation of ALDH3A2 transcription by bezafibrate, a PPAR agonist, increases residual enzyme activity in fibroblasts from SLS patients with certain missense mutations.¹³

Other neurocutaneous syndromes with autosomal recessive phenotypes

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

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.

• Stage 1: The vesicular stage occurs from birth to 2 weeks. Infants present with inflammatory vesicles and bullae in a linear pattern on the extremities, trunk, and scalp. Recurrent crops of erythematous macules and papules may erupt for weeks. Skin biopsy at this stage reveals increased eosinophils.
• Stage 2: The verrucous stage occurs from 2-6 weeks, with hyperkeratotic streaks, pustules, and papules occurring exclusively on the extremities.
• Stage 3: The hyperpigmentation stage occurs from 3-6 months and is characterized by marbled swirls of hyperpigmentation along Blaschko lines (see Media File 7).
• Stage 4: The hypopigmentation stage occurs in adult women, when follicular atrophy and hypopigmentation replace hyperpigmented swirls.

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

• Lee et al¹⁵ reported changes in the retinal vasculature may serve as markers for CNS disease; therefore, abnormalities of the retinal vasculature found in one eye, should prompt examination of the other eye and evaluation for CNS disease.
• Carefully screen mothers of patients with IP because of an increased risk of breast carcinoma.

Sturge-Weber syndrome

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 (see Media File 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 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

• When port-wine stains with the V1 distribution are seen, refer the patient to an ophthalmologist for close follow-up care. Ocular complications occur in 30-60% of patients. Glaucoma can begin as early as 2 years; therefore, closely monitor intraocular pressures. The most common ocular manifestation is diffuse choroidal angioma, usually occurring ipsilateral to the nevus.
• Initiate laser treatment early in port-wine stains to avoid complications such as soft tissue swelling and hypertrophy. Flashlamp-pumped pulsed-dye laser can result in partial-to-complete resolution.
• Laser treatment of port-wine stains is based on the premise of selective thermolysis, resulting in "irreversible" injury to blood vessels without damaging other skin constituents. The generated heat damages red blood cells and vessel endothelium but does not allow heat dissipation and damage to the surrounding fibroblasts and collagen. It can produce good cosmetic results, with a low incidence of adverse skin changes and other adverse effects.¹⁶
• Antiepileptic drugs are used to control seizures.
• For almost 20% of patients with medically refractory epilepsy, surgical treatment may offer an excellent therapeutic option.

Neurocutaneous Syndromes With Photosensitivity

Pellagra

Pellagra is caused by dietary deficiency of niacin, resulting in the 4 D 's: 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 United States. Because of intensive fortification efforts in the United States, 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 United States 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 easily treated. The condition has been reported in fad dieters and persons infected with HIV.¹⁷

Cutaneous manifestations

Cutaneous manifestations occur in a photodistributed pattern.

• Hand erythema in a glove distribution is one of the first signs, and patients may complain of pruritus and burning, especially after sun exposure.
• Early facial lesions are erythematous scaly papules and pustules and may resemble the malar rash seen in lupus erythematous.
• As the disorder progresses, lesions become hard, dark, and thick plaques with painful fissures.
• Note that a striking demarcation exists between affected and normal skin.
• A symmetric ring of lesions around the neck (Casal necklace) is a late finding (see Media File 20).

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

Herpes varicella zoster

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 United States 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 (see Media File 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.

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.

• Ramsay-Hunt syndrome is the reactivation of the virus in the seventh cranial nerve, causing one-sided facial weakness combined with lesions of the ipsilateral external ear, herpes zoster oticus, or zoster of the hard palate.
• Ophthalmoplegia (most commonly of cranial nerve III), optic neuritis, and other cranial neuropathies may develop.
• Arm weakness and, less frequently, diaphragmatic paralysis may occur with cervical zoster.
• Leg weakness with bladder and bowel dysfunction may occur with lumbosacral zoster.
• Rarely, myelitis or encephalitis occurs after the development of skin lesions.
• Recently, studies have shown that infection of blood vessels by the virus causes encephalitis.
• Granulomatous arteritis (causing encephalitis) results from large vessel arterial disease and occurs mainly in immunocompetent patients.
• Encephalitis resulting from small vessel disease occurs exclusively in immunodeficient patients.
• Long-term use of low-dose steroids may cause an increased susceptibility to myelitis and encephalitis.

Recommendations

• Treatment of zoster includes the following:
  • Analgesic (eg, Tylenol with codeine q6h) and famciclovir (500 mg tid)
  • Valacyclovir (1000 mg tid) or oral acyclovir (800 mg 5 times per d) for 7 days to decrease new lesions
  • Treatment ideally started within 3 days of rash appearance¹⁸
• Zoster is common in older patients, especially those older than age 60 years. Of patients who have had chickenpox, 2% develop zoster. Patients who develop chickenpox younger than age 1 year are predisposed to develop zoster before age 60 years.
• Millions of children worldwide have received the varicella vaccine, and vaccination is recommended by the American Academy of Pediatrics.
• Vaccine prevents the primary infection; however, the virus remains latent, and vaccination does not prevent later development of zoster. Pediatric herpes zoster has been reported in children who received the vaccine or who had clinical chickenpox at a very young age.
• A vaccine (Zostavax) has been approved by the US Food and Drug Administration for the prevention of herpes zoster in individuals age 60 years and older. In a randomized, double-blinded controlled trial, the zoster vaccine reduced the burden of illness by 61.1%, decreased the incidence of postherpetic neuralgia by 66.5%, and reduced the incidence by 51.3%.¹⁹
• The most common complication of zoster is postherpetic neuralgia (defined as presence of pain >6 wk after skin lesions heal). Pain often is debilitating and can persist indefinitely. A prognostic factor is age, and this complication usually does not occur in immunocompetent patients younger than 50 years. After age 60 years, more than 40% of patients develop postherpetic neuralgia. Optimal therapy for prevention has not been established. Although controlled trials have not shown oral antiviral drugs to be effective, such medications are administered empirically to patients older than 60 years.
• Studies of other therapeutic options have been initiated to discover how to prevent postherpetic neuralgia and include steroids, interferon alfa-n3, amantadine hydrochloride, adenosine monophosphate, and levodopa with benserazide.
• Different therapies have been tried to treat postherpetic neuralgia. Tricyclic antidepressants (eg, amitriptyline) and anticonvulsants (eg, carbamazepine, phenytoin) have provided relief to some patients.
• Steroids may help by reducing inflammation.
• Topical aspirin, capsaicin, and anesthetic agents may help relieve pain.

Neurocutaneous Disorders Associated With Stroke

Antiphospholipid syndrome

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. 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 (see Media File 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 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 al²⁰ 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.

• Use of long-term anticoagulants to maintain the international normalized ratio (INR) at 3 or greater may help prevent recurring thromboembolism.
• Aspirin is of clinical benefit and may help decrease the incidence of fetal loss in some patients.
• Plasmapheresis and cyclophosphamide have been used.
• Ancrod (purified pit viper venom) has been used successfully in one patient.
• A review of clinical and laboratory characteristics of 50 patients by Asherson et al²¹ described a 70% (14 of 20) survival rate in patients treated with anticoagulation, steroids, and treatments that decrease antiphospholipid antibodies, such as plasmapheresis and/or intravenous IgG.
• Statins have been used in antiphospholipid syndrome because of their antithrombotic, anti-inflammatory, and pleiotropic effects on vascular endothelium. Statins may block the antiphospholipid-induced endothelial cell activation, which is thought to be a mechanism of thrombus formation in antiphospholipid syndrome.²²
• Additional research is needed to establish the best treatment guidelines for this uncommon but potentially life-threatening condition.

Sneddon syndrome

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

Diabetes mellitus

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 al²³ 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:

• Screen patients with NLD for diabetes. Lesions start as sharply demarcated erythematous papules that become well circumscribed and annular and most commonly occur pretibially (see Media File 16). Lesions progress to form shiny yellow-brown plaques with central atrophy and telangiectases.
• Control of diabetes does not necessarily result in remission of NLD.
• Treatment consists of occlusive dressing, topical steroids, aspirin, dipyridamole, pentoxifylline, and whirlpool therapy.
• Intralesional steroids have been used but can cause tissue breakdown.
• Reports have shown marked improvement using 0.05% tretinoin cream (Renova) applied before bed.²⁴
• Topically applied bovine collagen also may enhance wound healing.²⁵
• New treatment strategies include cyclosporin A, infliximab, or tacrolimus, which can be used topically or systemically.²⁶

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 (see Media File 15). More severe forms of acanthosis nigricans can become generalized over the knuckles, extensor surfaces, and may involve mucosal surfaces.

Lyme disease

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 (see Media File 21). The area can irritate the patient, and regional lymphadenopathy may develop.

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.

• Consider prescribing doxycycline (100 mg bid) or amoxicillin (500 mg tid) for 14-21 days, or 28 days if arthritis is present.
• For patients with carditis or neurologic complications, ceftriaxone (2 g IV qd) for 14-21 days is recommended.
• In pregnant patients, use amoxicillin (500 mg PO tid) for 21 days. If they are allergic to penicillin, use azithromycin (500 mg PO qd) for 7-10 days.

Arsenic poisoning

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 (see Media File 22).²⁸

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 (BAL).

BAL (2,3-dimercaprol) is a traditional chelating agent that has been used clinically in arsenic poisoning since 1949. In humans and experimental models, the antidotal efficacy of BAL has been shown to be most effective when administered immediately after the exposure.²⁹

Neurologic Disorders With Important Dermatologic Findings

Reflex sympathetic dystrophy

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.

• Early or acute stage: Patients are in severe pain, which often is described as a burning throbbing sensation. The key finding is pain beyond that expected for the injury sustained. The pain can be induced easily by minor stimuli such as blowing air, stress, and certain textures. In approximately 20% of patients, associated skin findings are edema, erythema, and warmth.
• Second or dystrophic stage: This stage occurs approximately 3 months after the injury and can last as long as 6 months. Pain begins to spread from the initial site and can occur spontaneously. Skin becomes cool, clammy, and pale. A faint cyanosis, decreased capillary refill, and/or livedo reticularis can be present. If the affected area involves the nails, they can become dry and brittle. Hair in the area may become darker and grow faster.
• Third or atrophic stage: This stage occurs approximately 8 months after the initial injury and can be chronic. Patients may experience constant burning and increasing pain, resulting in disruption of sleep. Depression and anxiety may develop. Tissue damage progresses, and the skin appears shiny, dry, and mottled. Atrophic changes occur, and the patient may lose hair in the areas of previous increased growth. Ridging of the nails and Beau lines may be present. Diffuse osteoporosis (Sudeck atrophy) may occur because of increased absorption of bone.

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

• Treatment begins with prevention. Promptly immobilize patients with distal injuries.
• Once diagnosed, no single effective therapy exists, and patients respond differently to proposed treatments.
• Patients may benefit from intensive physical therapy, sympathetic blockade, calcitonin, or alpha-blockers and beta-blockers.
• Kemler et al³⁰ reported spinal cord stimulation to be safe and effective in decreasing pain associated with RSD.
• According to van Hilten et al³¹ intrathecal baclofen, a type B GABA-receptor agonist, has relieved pain and decreased spasms and dystonia in some patients.

Seborrheic dermatitis

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 (see Media File 19). Blepharitis is a common finding.

• Patients with Parkinson disease can have severe cases of seborrheic dermatitis, usually involving the scalp and face.
• Facial paralysis resulting from stroke or injury can result in seborrheic dermatitis, usually occurring on the corresponding side.
• Other disorders (eg, quadriplegia, poliomyelitis, syringomyelia) have an increased incidence of seborrheic dermatitis.
• Immunocompromised patients (eg, HIV patients) are especially at risk.
• Seborrheic dermatitis is more common and more severe in persons infected with HIV, particularly in those with CD4 counts below 400 cells/μ L, than in uninfected persons, and it may regress with highly active antiretroviral therapy. In HIV-infected patients, lesions are widespread and markedly inflamed and oozing. The skin condition is rare in African blacks; when it occurs in this population, it raises concern about HIV infection.³²
• Seborrheic dermatitis has been reported to be associated with several conditions, including neuroleptic-induced parkinsonism, familial amyloidosis with polyneuropathy, and trisomy 21, but these associations have been poorly documented.³²
• Hyperinsulinism also has been associated with seborrheic dermatitis and supports the mycologic origin of the disorder.

Recommendations

No cure exists; however, effective treatments are available.

• Selenium sulfide, ketoconazole, and tar shampoos control symptoms well.
• Corticosteroid scalp solutions can help decrease the inflammation that commonly occurs.
• Calcineurin inhibitors, such as tacrolimus ointment (Protopic), work well for treatment of the face.
• Warm compresses and gentle cleaning with mild baby shampoo help relieve blepharitis.
• Mild steroids, and in infection, steroids in combination with antimicrobial preparations, are effective.
• Ultraviolet B phototherapy is sometimes considered as an option for extensive or recalcitrant seborrheic dermatitis, but it has not been studied in randomized trials.³²

Multimedia

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Media file 1: Crowe sign, axillary freckling, in neurofibromatosis type I.

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Media file 2: Lisch nodule, iris hamartomas, in a patient with neurofibromatosis type 1.

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Media file 3: Segmental neurofibromatosis.

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Media file 4: A large cutaneous neurofibroma.

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Media file 5: A port-wine stain in a patient with Sturge-Weber syndrome.

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Media file 6: Osler-Weber-Rendu disease with sublingual telangiectasias. Courtesy of Dirk M. Elston, MD.

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Media file 7: Whirls and swirls of hyperpigmentation in an infant with incontinentia pigmenti. Courtesy of military teaching file.

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Media file 8: Fluorescence of urine in a patient with porphyria. Note the pink-to-coral red fluorescence of urine compared to a control sample. Courtesy of Dirk M. Elston, MD.

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Media file 9: Chronic scarring and milia on the dorsal aspect of the fingers and hand in a porphyria patient. Courtesy of Dirk M. Elston, MD, and James H. Keeling, MD.

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Media file 10: Angiofibromas on the chin in a patient with tuberous sclerosis. Courtesy of Dirk M. Elston, MD.

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Media file 11: A connective tissue nevus (Shagreen patch) in a patient with tuberous sclerosis. Courtesy of Dirk M. Elston, MD.

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Media file 12: Koenen tumor in a patient with tuberous sclerosis. Courtesy of Dirk M. Elston, MD.

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Media file 13: Multiple 1- to 2-mm, flat, dark-brown lentigines in a patient with LEOPARD syndrome (also termed multiple lentigines syndrome).

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Media file 14: Bullous diabeticorum. Courtesy of military teaching file.

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Media file 15: Acanthosis nigricans. Courtesy of Dirk M. Elston, MD.

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Media file 16: Necrobiosis lipoidica diabeticorum. Courtesy of Dirk M. Elston, MD.

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Media file 17: Herpes varicella zoster in a dermatomal distribution of the chest. Courtesy of Dirk M. Elston, MD.

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Media file 18: Tzanck smear of the base of a herpetic blister showing multinucleated giant cells. Courtesy of Dirk M. Elston, MD.

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Media file 19: Seborrheic dermatitis of the face. Courtesy of Dirk M. Elston, MD.

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Media file 20: Casal necklace in a patient with pellagra.

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Media file 21: The classic bull's-eye appearance of erythema chronicum migrans. Courtesy of Dirk M. Elston, MD.

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Media file 22: A transverse band of leukonychia termed Mees lines. Courtesy of Dirk M. Elston, MD.

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Media file 23: Mottled, bluish, netlike discoloration in livedo reticularis. Courtesy of Dirk M. Elston, MD.

Keywords

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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