The Skin and Neurologic Disease




Keywords

neurologic disorders, cutaneous lesions, rash, phakomatosis, heritable disorders, primary inflammatory disease, infections

 


This chapter provides an overview of disorders with both neurologic and cutaneous manifestations. Because the emphasis is on diagnosis, the presentation is organized around familiar neurologic syndromes rather than pathologic entities. This approach is complementary to those based on traditional pathophysiologic categories, such as phakomatoses or autoimmune and infectious disorders. Patients present to the neurologist with signs and symptoms, not with biopsies.


Usually a disease cannot be related to either a single cutaneous sign or a single neurologic syndrome. To minimize repetition while aiming for a comprehensive presentation, the text is limited to important representative diseases. Each is described only once, grouped with its most characteristic clinical presentation where possible. Secondary manifestations are mentioned in passing or in tables. Details are necessarily limited, but are supplemented with more comprehensive tables and, where applicable, annotation with the code number in the continuously updated Online Mendelian Inheritance in Man (OMIM). The discussion is limited to disorders that permit survival to adulthood.




Tumors


Earlier classifications of neurocutaneous disorders described phakomatoses, a label originally applied to two autosomal dominant disorders associated with tumors: neurofibromatosis type I and tuberous sclerosis. However, this category gradually expanded to encompass a wide variety of other neurologic disorders, including Sturge–Weber syndrome, which is not associated with tumors, and von Hippel–Lindau syndrome, associated with tumors but not with cutaneous lesions. Phakomatosis has outlived its utility as a diagnostic category.


Numerous disorders are associated with tumors, cutaneous manifestations and neurologic disease. In many cases the tumors themselves are responsible for the cutaneous or neurologic symptoms, but in others they are independent manifestations of a more complex syndrome.


Neurofibromatosis Type I


Neurofibromatosis type I (NF1; von Recklinghausen disease), an autosomal dominant disorder (OMIM 162200), is characterized by café-au-lait spots, fibromatous dermal tumors, and Lisch nodules of the iris as well as neoplasms of both the peripheral and the central nervous system (CNS). The earlier designation as peripheral neurofibromatosis (strictly speaking, a misnomer) served to distinguish this disorder from the genetically and clinically distinct central neurofibromatosis, now neurofibromatosis type 2 (NF2; OMIM 101000).


NF1 is the most common single-gene disorder of the nervous system, affecting 1 in 3,500 individuals. It results from heterozygosity for a mutant form of a large gene on chromosome 17q11.2 that encodes a cytoplasmic protein with multiple regulatory functions. The NIH consensus criteria permit unequivocal diagnosis of NF1 even without demonstration of the genetic mutation, by clinical observation of at least two of the following: (1) the presence of six or more café-au-lait macules with a diameter of≥5 mm in children younger than 6 years and≥15 mm in older people ( Fig. 21-1 ); (2) two or more neurofibromas of any type or one plexiform neurofibroma; (3) axillary or inguinal region freckling; (4) optic pathway glioma; (5) two or more Lisch nodules (whitish tumors of the iris); (6) dysplasia of the sphenoid bone or thinning of the cortex of long bones with or without pseudoarthrosis; and/or (7) a first-degree relative exhibiting these changes.




Figure 21-1


Neurofibromatosis type 1: axillary freckling—a cluster of freckle-sized café- au-lait macules.

(From Kurlemann G: Neurocutaneous syndromes. Handb Clin Neurol 108:513, 2012, with permission.)


The familiar café-au-lait spots are present at birth, as are plexiform neurofibromas and focal bone dysplasias, but axillary freckling, optic gliomas, Lisch nodules, and neurofibromas appear later in childhood. Of these, axillary freckling is the most diagnostically reliable, being present in all individuals with NF1 by the end of puberty. Café-au-lait spots alone are not diagnostic of NF1 because fewer than five spots are found frequently in individuals who are well. Café-au-lait spots as an isolated trait can be transmitted as an autosomal dominant (OMIM 114030) or as occasional features in other heritable disorders including tuberous sclerosis, the microcephalic disorders Nijmegen breakage syndrome (ataxia telangiectasia variant VI, OMIM 251260), X-linked Russell–Silver syndrome (OMIM 312780), Turcot mismatch repair cancer syndrome (OMIM 276300; polyposis coli, rhabdomyosarcomas, medulloblastomas, ependymomas and other gliomas), the rare Westerhof growth retardation syndrome (OMIM 154000), and perhaps most famously in McCune–Albright polyostotic fibrous dysplasia (OMIM 174800). The old clinical pearl that the rough border of McCune–Albright café-au-lait spots distinguishes them from the smooth borders seen in NF1 is not reliable.


Malignant neoplasms or benign tumors of the nervous system occur in 45 percent of individuals with NF1. Optic nerve gliomas develop in 15 percent. However, neurologic involvement most often results from benign neurofibromas in the root entry zone of peripheral nerves, causing radiculopathy or compression of the spinal cord. Plexiform neurofibromas, which can be nodular or diffuse, arise from nerve trunks. Diffuse plexiform neurofibromas are usually congenital and undergo transformation in about 4 percent of cases into malignant peripheral nerve sheath tumors that are severely painful, tender, and hard. The more common dermal neurofibromas are usually innocent, permitting conservative management in asymptomatic people. The incidence of non-neural tumors is also increased modestly, especially rhabdomyosarcomas of the urogenital tract and myelogenous leukemia.


In addition, there are neurologic sequelae not related to tumors. The most significant of these are poorly characterized T2 hyperintensities in the centrum semiovale (unidentified bright objects), the density of which correlates with mild cognitive impairment.


Neurofibromatosis Type II


This genetically distinct autosomal dominant disorder (OMIM 101000; also known as NF2, bilateral acoustic neurofibromatosis, or BANF) is characterized by tumors of the eighth cranial nerve in the cerebellopontine angle, meningiomas, and schwannomas of the dorsal roots of the spinal cord. It is less common than NF1 by an order of magnitude, affecting 1 in 25,000 live births in association with heterozygosity for a mutant form of merlin, a critical regulator of cell–cell adhesion, transmembrane signaling, the actin cytoskeleton, and resultant inhibition of proliferation. It is encoded on chromosome 8. Other mutations of this gene result in a clinically related but distinct mendelian disorder, congenital cutaneous schwannomatosis (OMIM 162091) or in some familial predispositions to meningiomas (OMIM 607174). Typically, NF2 presents in young adults, but hearing loss has been reported as early as age 6. Proposed diagnostic criteria for definite NF2 are bilateral vestibular schwannomas; or a family history of NF2 in one or more first-degree relatives plus (1) unilateral vestibular schwannomas at age less than 30 years, or (2) any two of the following: meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Bilateral acoustic neuromas occur in less than 5 percent of most series. The cutaneous manifestations are also distinct from that of NF1. Café-au-lait spots are present in about 40 percent of individuals, but only about 1 percent have six, the minimum seen in NF1. There are three types of cutaneous tumors: (1) discrete well-circumscribed, slightly raised, roughened areas of skin often pigmented and accompanied by excess hair, which are seen in about one-half of affected individuals; (2) subcutaneous well-circumscribed, nodular tumors located on peripheral nerves seen in about one-third; and (3) violaceous papillary skin neurofibromas, similar to those seen in NF1, in about one-fifth. One-third of NF2 patients have no cutaneous lesions.


Tuberous Sclerosis


This autosomal dominant neurocutaneous disorder was originally described as a phakomatosis, as had been NF1. It is characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. The characteristic brain lesions, named tubers because of their fancied resemblance to potatoes, are benign, but some 5 to 15 percent of affected individuals also develop malignant brain neoplasms, most frequently subependymal giant cell astrocytomas. These often develop at the foramen of Monro or elsewhere on the wall of the lateral ventricle or the retina. More frequent neurologic presentations are learning difficulties, behavioral problems, autism or epilepsy, often the severe West syndrome. The characteristic skin lesions are pale “ash leaf spots,” present in 90 percent of affected individuals. These are difficult to spot on light-skinned individuals unless examined with an ultraviolet Wood light ( Fig. 21-2 ). Such an examination will also facilitate the recognition of smaller confetti-like hypopigmented patches that are present in about one-third of patients, but only rarely in normal individuals. In addition to these flat hypopigmented lesions and occasional café-au-lait spots, there are three kinds of distinctive raised cutaneous lesions: shagreen patches ( Fig. 21-3 ), periungual fibromas ( Fig. 21-4 ), and facial angiofibromas. The latter can be mistaken for acne on casual inspection. There are also systemic manifestations: usually asymptomatic cardiac rhabdomyomas, present at birth and regressing in childhood, but sometimes associated with arrhythmias; renal cysts, angiolipomas and carcinomas; and pulmonary lymphangioleiomyomas.




Figure 21-2


Tuberous sclerosis: ash leaf spot in Wood light.

(From Kurlemann G: Neurocutaneous syndromes. Handb Clin Neurol 108:513, 2012, with permission.)



Figure 21-3


Tuberous sclerosis: ash leaf spot and shagreen patch.

(From Kurlemann G: Neurocutaneous syndromes. Handb Clin Neurol 108:513, 2012, with permission.)



Figure 21-4


Tuberous sclerosis: nail-fold fibroma.

(From Kurlemann G: Neurocutaneous syndromes. Handb Clin Neurol 108:513, 2012.)


Tuberous sclerosis (TSc) can result from mutation of either of two genes. About 70 percent of cases (TSc 2, OMIM 613254) result from heterozygous mutation of tuberin encoded on chromosome 16p13.3, the remainder (TSc 1, OMIM 191100) from mutations of the gene encoding hamartin on chromosome 9q34.13. Unlike the case for the phenotypically distinct NF1 and NF2, each of which results from disruption of either of two independent, non-interacting proteins, TSc 1 and TSc 2 are practically indistinguishable clinically. This is as would be predicted by the known interaction of hamartin and tuberin to form a single complex, the activity of which is disrupted by mutation of either subunit. This complex regulates the activity of the downstream pathway of the mammalian target of rapamycin (mTOR), which is disrupted by mutation in another neurocutaneous disorder, the Cowden multiple hamartoma syndrome (OMIM 158350).


Melanoma


In most instances, involvement of the nervous system by melanoma is by metastasis from a primary cutaneous lesion first to a local regional lymph node, then to the lung whence it metastasizes further to brain, bone or liver. Unlike the usual solitary brain metastases from more common primaries such as lung, breast, and kidney, brain metastases of melanoma are characteristically multiple. The other two types of primary cutaneous neoplasms, the more common basal cell carcinoma and the more invasive squamous cell carcinoma, do not metastasize to the brain.


Furthermore, tumors of the nervous system (including gliomas, medulloblastomas, ependymomas, meningiomas, and acoustic neurilemmomas) have an increased likelihood as secondary tumors in patients with cutaneous melanoma as well as in their family members. The molecular bases underlying these associations are only partially understood.


An increased incidence of cutaneous melanomas is seen in a more complex heritable neurocutaneous syndrome, xeroderma pigmentosa (OMIM 610651). This autosomal recessive disorder is characterized by increased sensitivity to sunlight as well as widespread neurologic involvement. Signs include microcephaly, mental retardation, ataxia, ventriculomegaly, cerebellar atrophy, basal ganglia calcification, and disordered central and peripheral myelination.


In addition to those syndromes in which melanoma originates in the skin, there is also the rare neurocutaneous melanosis (OMIM 249400), in which there is a primary melanoma of the CNS in over 50 percent of cases, but no malignant melanoma in the periphery. In this disorder there are large multiple pigmented skin nevi (>20 cm) ( Fig. 21-5 ), as well as cranial nerve palsies from histologically benign melanocytic invasion of the meninges, Dandy Walker malformation, and suprasellar calcifications. Death usually occurs in childhood.




Figure 21-5


Neurocutaneous melanosis.

(From Jones, K: Smith’s Recognizable Patterns of Human Malformation. Saunders, Philadelphia, 2005, with permission.)




Stroke


A number of neurocutaneous disorders are associated with either ischemic or hemorrhagic stroke, or both. The underlying mechanisms range from intrinsic vascular disease to cardiac or paradoxical embolization and to coagulopathies or platelet disorders, as summarized in Table 21-1 .



Table 21-1

Ischemic or Hemorrhagic Stroke with Cutaneous Manifestations








































































































Disease Cutaneous Lesions Neurologic Features
Antiphospholipid syndrome Livedo reticularis Ischemic stroke, chorea, neuropsychiatric symptoms, relapsing-remitting central vasculitis, myelopathy
Behet diseaseç Erythema nodosum, genital and oral aphthous ulcers Brainstem meningoencephalitis, dural sinus thrombosis, ischemic stroke, peripheral neuropathy (rare)
Bone fragility with contractures, arterial rupture, and deafness (OMIM 612394) Ecchymoses, blistering of fingers, toes, pinnae Cerebral hemorrhage, developmental delay
Cerebral cavernous malformations; CCM (OMIM 116860 & 603284) Angiomas, hyperkeratotic cutaneous vascular lesions Small, localized intracranial hemorrhages
Diabetes mellitus Necrobiosis lipoidica diabeticorum, poorly healing ulcers Lacunar stroke, peripheral neuropathy, retinopathy, metabolic coma
Endocarditis Petechiae, Janeway lesions, Osler nodes, splinter hemorrhages Septic embolic strokes
Fabry disease (OMIM 301500) Angiokeratoma starting at the umbilicus and knees, spreading to buttocks and scrotum Ischemic stroke, seizures, peripheral neuropathy, autonomic dysfunction, acral paresthesias, painful crises
Factor XIII subunit A deficiency (OMIM 613225) Ecchymoses Intracranial hemorrhage
Glanzmann thrombasthenia (OMIM 273800) Easy bruisability, purpura Intracranial hemorrhage
Hemolytic-uremic syndrome (OMIM 235400) Erythematous necrotic skin lesions Seizures, coma, hemiparesis, cognitive defects, visual defects, dysphasia
Hereditary hemorrhagic telangiectasia of Osler–Weber–Rendu (OMIM 187300, 600376, 601101, 610655) Telangiectasia Ischemic and hemorrhagic stroke
Homocystinuria due to cystathionine β-synthase deficiency (OMIM 236200) Malar flush, livedo reticularis, hypopigmentation Ischemic stroke, seizures, mental retardation, psychiatric disorders, depression, personality disorder
Familial hypercholesterolemia (OMIM 143890) Xanthomas, xanthelasma Ischemic thromboembolic stroke
Hereditary neurocutaneous angiomas (OMIM 106070) Large irregular flat hemangiomas Spinal angiomas and cerebral thin-walled angiomas
Hyper-IgE recurrent infection syndrome, autosomal recessive (OMIM 243700) Severe eczema, atopic dermatitis, recurrent skin abscesses Ischemic infarctions, subarachnoid hemorrhage
Malignant atrophic papulosis (OMIM 602248) Multiple asymptomatic papules with atrophic white centers surrounded by telangiectatic lesions Ischemic infarctions
Prothrombin deficiency, congenital (OMIM 613679) Ecchymoses, easy bruising Intracranial hemorrhage
Pseudoxanthoma elasticum (OMIM 264800) Pseudoxanthoma, multiple papules, peau d’orange, angioid streaks, subcutaneous calcification usually in blood vessels Stroke, retinopathy
Pseudoxanthoma elasticum, forme fruste (OMIM 177850) Small, yellow papules, peau d’orange, elastosis perforans serpiginosa Cerebral hemorrhage, retinopathy
Schimke-type immuno-osseous dysplasia (OMIM 242900) Hyperpigmented macules Moyamoya, cerebral infarctions
Systemic lupus erythematosus Photosensitivity, malar rash, telangiectasia, discoid lupus, patchy alopecia, mucosal ulcers, angioneurotic edema, Raynaud phenomenon, subcutaneous nodules, palpable purpura, gangrene, erythema multiforme Ischemic and hemorrhagic stroke, encephalopathy, chorea, peripheral neuropathies
Takayasu arteritis Palpable purpura Ischemic stroke
Thrombophilia due to protein C deficiency, autosomal dominant (OMIM 176860) Warfarin-induced skin necrosis Cerebral thrombosis
Thrombocytopenia–absent radius syndrome (OMIM 274000) Nevus flammeus on forehead, dysseborrheic dermatitis Intracranial hemorrhage, absent corpus callosum, spina bifida


Fabry Disease


Fabry disease is an X-linked neurocutaneous disorder (OMIM 301500) characterized by stroke, peripheral neuropathy, and progressive renal and cardiac failure. These sequelae occur both in hemizygous males as well as in heterozygous females, albeit later and with less severity. A pathognomonic whorl-like corneal dystrophy is seen with equal severity in both sexes. Affected males are easily recognized by a purpuric skin rash: discrete angiokeratoma, most prevalent between the knees and nipples. Females, having two X chromosomes, are twice as likely to have the pathogenic mutation of α-galactosidase (also commonly known as ceramide trihexosidase). Nevertheless, affected female heterozygotes frequently remain undiagnosed because they rarely have the characteristic cutaneous lesions, even though they can have severe neurologic, cardiac and renal manifestations.


Stroke is a late manifestation of the vascular deposition of lipid in Fabry disease. It was underappreciated until renal transplantation and, now, enzyme-replacement therapy, prolonged survival. A painful small-fiber neuropathy with autonomic dysfunction and episodic severely painful abdominal crises, reminiscent of those of the hepatic porphyrias, occurs early in the disease. Other early manifestations are small infarctions in the retina and kidneys. The latter lead to renal failure, which had previously caused death of affected hemizygotes by the third decade.


Although Fabry disease is also referred to as angiokeratoma diffusum, these skin lesions are not pathognomonic. They are also manifestations of other mendelian neurocutaneous disorders associated with mental retardation: aspartylglucosaminuria (OMIM 208400; seizures), fucosidosis (OMIM 230000; seizures and peripheral neuropathy), lysosomal beta A mannosidosis (OMIM 248510), Ramon syndrome (OMIM 266270; a posterior cerebral leukoencephalopathy), Kanzaki disease (OMIM 609242), and Bannayan–Riley–Ruvalcaba syndrome (OMIM 153480; megaencephaly, meningioma, pseudopapilledema).


Hereditary Hemorrhagic Telangiectasia


Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder also known eponymously as Osler–Weber–Rendu syndrome, is a vascular dysplasia that gives rise to hemorrhagic and ischemic strokes. These arise from a diverse set of peripheral as well as central vascular abnormalities, ranging from ischemic strokes and brain abscesses from paradoxical emboli passing through pulmonary venous malformations to intracerebral vessels, and subarachnoid hemorrhages from cerebral arteriovenous malformations. It is important to search for previously unsuspected pulmonary arteriovenous malformations before assuming local vascular pathology as a cause of stroke, because these pulmonary lesions can be effectively obliterated by embolization. The mucocutaneous telangiectasias for which the disorder is named are most often found on the tongue, lips, palate, fingers, face, conjunctiva, trunk, nail beds, and fingertips. Similar systemic vascular malformations are responsible for frequently problematic recurrent epistaxis, hepatic cirrhosis, and gastrointestinal hemorrhage later in life. Depending on the vascular anatomy, there may be either a polycythemia or an anemia.


This disorder is genetically heterogeneous. HHT type 1 (OMIM 187300) results from heterozygosity for a mutation of the gene on chromosome 9q34.11 encoding endoglin, a homodimeric membrane glycoprotein expressed mostly on the vascular endothelium, a component of the transforming growth factor–beta receptor complex; and HHT type 2 (OMIM 600376), from heterozygosity for mutation of the gene on chromosome 12q13.13 encoding activin receptor–like kinase 1. HHT type 3 (OMIM 601101) has been mapped to chromosome 5q31.3-q32) and HHT type 4 (OMIM 610655) to chromosome 7p14. The genes mutated in the latter two entities have not yet been identified.


Homocystinuria


Homocystinuria is a feature of several different neurologic disorders, only one of which, homocystinuria due to cystathionine β-synthase deficiency (OMIM 236200), is associated either with cutaneous lesions or with stroke. In this disorder cutaneous hypopigmentation, malar flush, and livedo reticularis are not as striking as the Marfan-like disproportionate tall stature and ectopia lentis, which provide the most evident clues to diagnosis. Neurologic features include ischemic thromboembolic strokes in about 25 percent of homozygotes, as well as mild mental retardation, seizures, and a variety of psychiatric disturbances that include personality disorders and depression. Diagnosis is critical, because over half of affected individuals respond to simple treatment with pyridoxine, vitamin B 6 . Furthermore, even pyridoxine non-responders benefit from dietary modification to reduce methionine and increase cysteine as well as supplementation with betaine.


The classic syndrome associated with homozygosity for mutations in the gene cystathionine β-synthetase is rare, but heterozygotes—encountered more commonly—are also at greater risk of ischemic stroke than the general population. Lacking the characteristic cutaneous or systemic signs, these individuals can only be detected by biochemical or genetic screening. As is always the case with rare autosomal recessive disorders, the vast majority of heterozygotes will not have an affected homozygous relative to prompt suspicion of the diagnosis.


Endocarditis


Septic emboli leading to ischemic or hemorrhagic stroke or intracranial hemorrhage from rupture of mycotic aneurysms occur in 40 percent of individuals with bacterial endocarditis. In developed countries, acute endocarditis commonly occurs because of unhygienic self-administration of intravenous drugs; infections of surgically implanted artificial cardiac valves are another important cause. In the developing world, secondary infection of unrepaired congenital valvular abnormalities or those damaged by rheumatic fever are also an important cause of infective endocarditis.


The classic cutaneous findings associated with infective endocarditis are subungual splinter hemorrhages, Janeway lesions, and Osler nodes. Splinter hemorrhages (1- to 3-mm, red to reddish-brown, longitudinal hemorrhages appearing under the nail plate) are commonly seen also as a response to repetitive trauma in otherwise healthy individuals, such as manual laborers or elderly individuals using walkers. In addition they have been reported as occasional findings in antiphospholipid syndrome, another neurocutaneous syndrome associated with stroke.


The more diagnostic Janeway lesions are nontender, large, irregular, flat macules that appear on the palms or the soles, frequently on the planar surface of a toe. These are culture-positive sites of septic emboli. In contrast, Osler nodes are tender, purple, slightly raised nodules ranging in size from 1 to 10 mm. These are typically seen on the tips or sides of toes or fingers. Unlike the Janeway lesions, they are sites of vasculitis, not embolization. Both of these lesions can appear on the thenar or hypothenar eminences.


The presence or absence of neurologic complications dictates the optimal timing of surgery for both native and prosthetic valve endocarditis, as do cardiac function and the control of the infection. In the absence of embolic events or rapidly deteriorating cardiac function, cardiac surgery is best delayed for 1 or 2 weeks of antibiotic treatment before subjecting the patient to the risks of surgery, not the least of which is cardiac bypass and attendant anticoagulation. However, if there is a stroke or transient ischemic attack, and intracranial hemorrhage has been excluded by scanning, surgery is recommended without delay.


Antiphospholipid Syndrome


The twin hallmarks of antiphospholipid antibody syndrome are either a thrombotic event, such as a stroke, or a complication of pregnancy seen in association with high titers of certain antibodies. Sometimes misleadingly referred to as lupus anticoagulants, these are thought to induce hypercoagulability by neutralizing anionic phospholipids on endothelial cells and platelets. This syndrome can be seen either as a primary abnormality or in the setting of a number of different neurocutaneous disorders: primary inflammatory diseases such as systemic lupus erythematosus, systemic sclerosis, Behçet disease, Sjögren syndrome and rheumatoid arthritis, or infections such as syphilis, Lyme borreliosis, and human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). In some instances, antiphospholipid syndrome has been shown to be a familial trait (OMIM 107320).


Cutaneous manifestations may be the initial clinical manifestation of the antiphospholipid syndrome. These include livedo reticularis, most commonly on the lower extremities; acrocyanosis, a Raynaud-like phenomenon; necrotizing vasculitis, with cutaneous ulceration and necrosis; erythematous macules; purpura, ecchymoses, and subungual splinter hemorrhages; and rarely, Degos malignant atrophic papulosis. The combination of livedo reticularis with multiple strokes has been designated as Sneddon syndrome. Antiphospholipid antibodies are associated with several neurologic syndromes, including stroke, transverse myelitis, and chorea. Many of these might be plausibly attributed to focal ischemia.


Takayasu Arteritis


Stroke in a young woman of Asian descent should prompt consideration of Takayasu arteritis (aortic arch syndrome or pulseless disease). The cutaneous manifestation is erythema nodosa, which occurs at an early phase in the disease. Fever and synovitis also develop prior to the large-vessel vasculopathy that defines the disorder. Neurologic involvement results from ischemic stroke from inflammation or stenosis of a proximal carotid or vertebral artery. Such strokes occur in about 20 percent of affected individuals. More commonly, involvement of the subclavian arteries leads to claudication and pulse asymmetries or frank loss of palpable pulses in the upper extremities.


The etiology of this disorder appears to be autoimmune, with modest associations both to HLA-B52 and to elevations of serum levels of certain matrix metalloproteinases. The latter normalize after clinical improvement resulting from treatment with immunosuppressants.




Meningitis and Meningoencephalitis


A large number of disorders can present both dermatologic abnormalities and meningitis or meningoencephalitis, which can be acute, subacute, relapsing-remitting, or chronic. A few characteristic disorders are presented in detail, the others in Table 21-2 .



Table 21-2

Meningitis with Cutaneous Manifestations




























































































































Disorder Cutaneous Lesions Neurologic Features
Adams–Oliver aplasia cutis congenita type III (OMIM 614814) Scalp defect at the vertex, cutis marmorata telangiectatica, hemangioma Acute bacterial meningitis from skull defect
AIDS Seborrhea, herpes zoster, tinea corporis, S aureus infection, molluscum contagiosum, Kaposi sarcoma, cryptococcosis Transient meningitis during seroconversion
Amyloidosis V (Meretoja, Finnish) (OMIM 105120) Cutis laxa Cranial and peripheral neuropathies
Behet disease Erythema nodosum, genital and oral aphthous ulcers, papules, purpura, pustules, dermatographia, pyoderma Chronic or recurrent meningitis, meningoencephalitis, dural sinus thrombosis
Blastomycosis Hyperplastic granulomatous microabscesses Rarely, chronic meningitis or cerebral abscess
Brill–Zinser epidemic typhus Macular rash Meningoencephalitis
Chagas disease Romana sign, inflammation of lacrimal glands, erythema multiforme Encephalitis
Coccidiomycosis Erythema nodosum, draining sinus, subcutaneous cellulitis Meningitis common
Cryptococcosis Macules and nodules (in 10–15% of cases) Chronic meningitis
Haemophilus influenzae infection Typically a single indurated area on face, neck, upper chest, or arm Acute purulent meningitis
Histiocytic reticulosis (autosomal recessive) (OMIM 267700) Purpura, jaundice, erythroderma Chronic aseptic meningitis, neuropathy
Leptospirosis Scleral conjunctival injection, maculopapular rash of trunk (in 50% of cases), jaundice Subacute meningitis
Leukemia Erythema nodosum, Sweet syndrome (acute febrile neutrophilic dermatosis—painful raised red plaques, commonly on face and extremities) Meningeal leukemia is common form of relapse, especially in acute lymphocytic leukemia
Listeriosis Generalized erythematous papules or petechiae in infants; veterinarians with tender red papules on hands Subacute meningitis
Lyme borreliosis Target lesion Early aseptic meningitis, polyneuropathy, delayed demyelinating disease
Lymphoma Erythema nodosum Subacute meningitis, cerebral or vertebral metastases
Lymphoma, cutaneous (T cell) Scaly erythematous patches, leonine facies, poikiloderma, hypopigmented and hyperpigmented patches with atrophy and telangiectasia Subacute meningitis, vertebral metastases
Meningococcemia Petechiae, usually on extremities and trunk; initially can mimic a viral exanthem Fulminant meningitis
Murine typhus Axillary rash, macular rash of upper abdomen, shoulders, chest Headache, encephalopathy, and nuchal rigidity without meningitis
Neurocutaneous melanosis Melanosis; large multiple pigmented skin nevi (>20 cm), no malignant melanoma other than CNS; primary CNS melanoma in over 50% of cases Meningeal enhancement secondary to melanosis of pia-arachnoid, cranial nerve palsies, Dandy–Walker malformation, suprasellar calcification
Reticulosis, familial histiocytic Purpura, jaundice, erythroderma Chronic meningitis, peripheral neuropathy
Rocky Mountain spotted fever Progressive rash begins on the fourth day of fever with pink macules on wrists, ankles, forearms; after 6–18 hours, on palms and soles, then centrally after 1–3 days; after 2–4 days, non-blanching petechiae Vasculitic meningoencephalitis, choreoathetosis, deafness, hemiplegia
Sarcoidosis Dry skin, hypohidrosis, cicatricial alopecia; acute : erythema nodosum, vesicles, maculopapular rash; chronic : lupus pernio, plaques, scars, keloids Chronic meningitis with cranial neuropathies, peripheral neuropathy, proximal myopathy, hypothalamic involvement
Sjögren syndrome Purpura, Raynaud phenomenon, xerostomia, candidiasis Aseptic meningitis, sensory neuronopathy, dural sinus thrombosis
Syphilis Primary : chancre. Secondary : maculopapular non-pruritic scaling rash (acral), patchy alopecia, condyloma lata, mucous patches, erythema multiforme, hyperpigmentation on healing, split papules, palm and sole lesions Aseptic meningitis, late meningovascular syphilis, tabes dorsalis
Tuberculosis Cutaneous tuberculosis is rare; primary tuberculous chancre; warty tuberculous verrucosa cutis from reinfection, postprimary lupus vulgaris, scrofuloderma, erythema nodosum, erythema multiforme Chronic meningitis, Pott disease of vertebrae, CNS tuberculomas
Varicella zoster (chickenpox) Vesicles with oral lesions Meningitis with cerebellar ataxia
Vogt–Koyanagi–Harada Vitiligo-type macules, poliosis and alopecia in convalescent third phase Meningoencephalitis in first phase of illness, preceding uveitis
Yersinia pestis (bubonic plague) Erythema multiforme, bubos then petechiae and ecchymoses Meningitis can complicate all three types: bubonic, bubonic-septicemic, pneumonic


Meningococcal Meningitis


Meningococcal meningitis is a fulminant disorder with a high mortality rate and serious sequelae (sensorineural hearing loss, seizures, motor deficits, hydrocephalus, cognitive abnormalities, and behavioral problems) in treated survivors. Fever, headache, and meningeal irritation develop over the course of 24 hours. The distinguishing feature of meningococcal disease is the concomitant evolution of a rapidly evolving petechial rash, usually over the trunk and lower extremities, but which can also develop on the face, mucous membranes, and arms ( Fig. 21-6 ). These cutaneous lesions can coalesce or develop into vesicles or bullae. In contrast, the cutaneous lesion associated with meningitis from infection with Haemophilus influenzae , previously the most common type of bacterial meningitis in children, is typically a solitary indurated area on the face, neck, upper chest, or arm. The meningococcal rash must also be distinguished from that of other disorders in Table 21-2 , notably Rocky Mountain spotted fever.




Figure 21-6


Early cutaneous lesions of meningococcemia.

(From Tyring S, Lupi O, Hengge U: Tropical Dermatology. Courtesy of Dr. Luc Van Kaer. Churchill Livingstone, New York, 2005, with permission.)


In the 10 to 30 percent of cases of meningococcemia that develop too rapidly to seed the choroid plexus and meninges, the prognosis is even worse than in those cases with meningitis. Early treatment at the first recognition of the short febrile prodome and rash is critical. Although most cases of meningococcemia, either with or without meningitis, occur in children, young adults in cramped quarters, including college students and military recruits, are also at risk.


The incidence of some meningococcal infections has been reduced significantly by the introduction of a vaccine, as has the incidence of the other two most common types of acute bacterial meningitis, resulting from infection with Haemophilus influenzae or Streptococcus pneumoniae . However, the currently available meningococcal vaccine is only effective against the C serotype of the causative organism, Neisseria meningitidis , a serotype that has nearly been eliminated in developed countries. Furthermore, even this vaccine is not available in the poor countries of the “meningitis belt” in Africa. Worldwide, meningococcal infections remain one of the leading causes of meningitis in children. New vaccines are being developed for Neisseria serogroups A and B, but there are other serotypes of Neisseria for which development is required.


Lyme Borreliosis


The characteristic “target lesion” ( erythema chronicum migrans ) that spreads centrifugally from the site of a prolonged bite by a tick infected with the spirochete Borrelia burgdorferi is pathognomonic of early-stage Lyme disease. This cutaneous lesion first develops within a few days to weeks after the infecting bite by the tiny tick, Ixodes dammini . The characteristic cutaneous lesion is so named because of the fancied resemblance to a target. The erythematous circumference of the lesion advances over the course of days to weeks up to a diameter of 5 cm, leaving behind a trailing central area of clearing and a persistent erythematous papule at the very center, the site of the original tick bite ( Fig. 21-7 ). This lesion develops in about 85 percent of infected individuals, facilitating clinical diagnosis for the subsequent syndrome of migratory arthralgias and later neurologic dysfunction. However, a high degree of clinical suspicion and the use of a serologic test are necessary for diagnosis in the substantial minority of patients that do not develop the characteristic target lesion.




Figure 21-7


Large 5-cm targetoid patch with central clearing, bright-red expanding border and central bite inflammation, characteristic of the erythema migrans rash of Lyme disease.

(From Habif T, Campbell J, Chapman MS, et al: Dermatology DDX Deck. Saunders, Philadelphia, 2006, with permission.)


Although neurologic signs can develop while the erythema migrans is still present, typically they do not appear until the cutaneous signs have resolved, after 6 to 12 months of migratory arthralgia that occasionally evolves into arthritis with an effusion in a large joint. The most common neurologic syndrome, affecting about 70 percent of untreated individuals, is a mild aseptic meningitis, with a mononeuritis multiplex or typical cranial nerve palsies. The latter include unilateral or bilateral facial palsies or lesions of the oculomotor, trigeminal, abducens or eighth cranial nerve. Alternatively there may be a painful radiculopathy or plexitis. Other lesions reported less frequently include a myositis, patchy demyelination mimicking multiple sclerosis, or myelopathy with radiculopathies that could be mistaken for amyotrophic lateral sclerosis. Some untreated patients later develop an indolent diffuse encephalopathy. Further discussion is provided in Chapter 40 .


Syphilis


As in Lyme borreliosis, dermatologic and neurologic manifestations are also temporally discordant in syphilis, which is related to infection with Treponema pallidum . The cutaneous manifestations are limited to the painless, indurated, rubbery genital chancre of primary syphilis in the days after infection, and the flat copper-colored lesions of the palms and soles, patchy alopecia, and mucous membrane patches seen in secondary syphilis, 2 to 4 months later ( Figs 21-8 and 21-9 ). Secondary syphilis is associated with a mild meningitis, sometimes with involvement of cranial nerves, typically the optic, facial or acoustic.




Figure 21-8


Secondary syphilis: disseminated papular lesions.

(From Tyring S, Lupi O, Hengge U: Tropical Dermatology. Courtesy of Dr. Luc Van Kaer. Churchill Livingstone, New York, 2005, with permission.)



Figure 21-9


Secondary syphilis: hyperkeratotic lesions on palms and soles.

(From Tyring S, Lupi O, Hengge U: Tropical Dermatology. Courtesy of Dr. Luc Van Kaer. Churchill Livingstone, New York, 2005, with permission.)


In contrast, cutaneous lesions will have resolved by the time of meningovascular syphilis, peaking 4 to 7 years after infection, and the neurologic manifestations of late-stage syphilis, namely the dementia (general paresis of the insane) and tabes dorsalis ( Chapter 40 ). Thus the only exception to the temporal discordance of cutaneous and neurologic manifestations is their invariable association in secondary syphilis, in prenatal syphilis, and the rare occurrence of cutaneous nodules in late syphilis.


Fortunately, the late stages of syphilis have become quite rare. There had also been a period of diminishing prevalence of primary and secondary syphilis, although a 10-fold increase in incidence to 20 per 100,000 has occurred recently in the United States and to 360 per 100,000 in parts of Africa. Much of this increase has occurred in association with HIV-AIDS, which has also contributed to an altered natural history, including an occasional novel presentation that mimics that of herpes simplex encephalitis (but is responsive to treatment with penicillin), with focal lesions in the temporal lobe and status epilepticus or periodic lateralized discharges in the electroencephalogram.


Careful studies have also brought to light previously under-recognized syndromes of otologic syphilis, characterized by early sensorineural hearing loss and occasionally by vestibular dysfunction as well; and of ocular syphilis, mostly an early posterior uveitis affecting the choroid, retina, and pigmentary retinal epithelium. Involvement of the uveal tract also characterizes several other neurocutaneous disorders. Uveomeningitis is an occasional presentation of sarcoid, Behçet disease, and systemic lupus erythematosus, described in the following sections. It is also typical of the rare Vogt–Koyanagi–Harada syndrome, in which a prodromal meningoencephalitis precedes uveitis as well as the characteristic dermatologic findings of leukoderma with symmetric patches of vitiligo (involving the head, neck, shoulders, and eyelids), alopecia, and poliosis.


Sarcoidosis


Both the cutaneous and neurologic manifestations of sarcoidosis (discussed in Chapter 49 ) are notoriously variable, complicating early diagnosis. Indeed, only 20 to 30 percent of patients with sarcoid have cutaneous lesions, and only 5 to 10 percent have neurologic manifestations. The most typical neurologic presentation is that of a mild aseptic meningitis, with or without cranial nerve palsies. Typically these are unilateral or bilateral facial nerve palsies, but optic, auditory or vestibular neuropathies may occur as well. Neurosarcoidosis is the initial presentation of sarcoid in about 50 percent of cases, prompting a large and difficult differential. A wide variety of other neurologic manifestations also occur ( Chapter 49 ).


The cutaneous manifestations of sarcoid are more frequent but are also highly variable. There can be acute lesions such as erythema nodosum, vesicles, and maculopapular rash. These annular lesions, papules, or nodules are either skin-colored, violaceous, or brownish-red, often appearing on the face. Chronic lesions include lupus pernio (large, bluish red, dusty, violaceous infiltrated nodules and plaques, which generally appear on the cheeks, ears, fingers, and nose), plaque, scars, and keloids. The rare angiolupoid form of sarcoidosis consists of orange-red or reddish-brown soft, well-demarcated lesions.


Behçet Disease


This poorly understood inflammatory disease is characterized by a triad of recurrent oral and genital ulceration and uveitis, most commonly seen in populations along the old “Silk Road.” The majority of patients have additional cutaneous abnormalities including papillopustular lesions, erythema nodosum, and a pathergy reaction (pustulation at the site of trauma). The classic triad forms the basis of the current criteria for diagnosis, which is entirely clinical: recurrent oral ulceration (at least three times in a year) plus two of the following: (1) recurrent genital ulceration; (2) ocular lesions (uveitis, retinal vasculitis or cells in the vitreous); and (3) skin lesions (erythema nodosum, pseudofolliculitis). Other common manifestations are arthritis, present in up to half of individuals; subcutaneous thrombophlebitis in about a quarter; and, in Japan, gastrointestinal lesions that affect about one-third. In contrast, neurologic complications affect only 10 percent or less of patients with Behçet disease, either as parenchymal or neurovascular disease. These two categories are not mutually exclusive; both parenchymal and neurovascular disease can affect a substantial minority of these patients. The pathology of the parenchymal disease is a “perivasculitis” rather than a vasculitis. There are infiltrates of polymorphonuclear leukocytes, eosinophils, lymphocytes and macrophages without infiltration of blood vessel walls or necrosis of endothelial cells. The typical MRI picture of brainstem meningoencephalitis is that of a unilateral T2-enhancing lesion of the upper brainstem. Less frequent manifestations of parenchymal disease are seizures, transverse myelopathy, diffuse encephalopathy, or, much less commonly, an optic neuro-pathy. In some instances, the MRI appearance may resemble that of a glioma. Movement disorders and peripheral neuropathy are rare. Although venous occlusion is common, stroke resulting from arterial occlusions is rare, occurring in about 1 percent. Intracranial venous sinus thrombosis presents as increased intracranial pressure, a presentation that also sometimes occurs in the absence of radiographically demonstrable sinus or venous occlusion.


This disorder usually presents in young men, aged 20 to 40 years, but women are also affected, albeit less often. Most patients respond to treatment with corticosteroids, although about 20 percent are left with significant residual neurologic impairment and 10 percent succumb within a decade of diagnosis. Some practitioners supplement treatment of sinus thrombosis with anticoagulants after ruling out a pulmonary aneurysm, whereas others find cortico-steroid treatment to be adequate. The course may be monophasic, relapsing remitting, or, most ominously, progressive.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Aug 12, 2019 | Posted by in NEUROLOGY | Comments Off on The Skin and Neurologic Disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access