J Neurol Neurosurg 1999;66:417–430 417 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

NEUROLOGY AND

Neurology and the

Orest Hurko, Thomas T Provost

Many disorders aVect both the Five per cent to 10% of patients with HIV and the skin. The complementary—and some will develop herpes zoster radiculitis, would say—diametrically opposite—clinical with painful dermatomal , which in methods of the dermatologist and the neurolo- rare patients disseminates over the entire body gist can in these circumstances reduce an oth- (fig 1).4 Kaposi’s sarcoma has been associated erwise dauntingly large diVerential into a more with herpes type VIII. Unlike the classic indo- tractable, smaller list. Often triangulation with lent Kaposi’s sarcoma detected in elderly East- these and other clinical findings is suYcient for ern European Askenazi Jews, this rapidly accurate diagnosis, but in other cases, serologi- growing tumour is seen in young homosexuals, cal or genetic data must be considered before but not in AIDS associated with a parenteral diagnosis is secure. mode of infection (drug misuse, inadvertent We have purposely avoided traditional needle stick, etc). Rarely, disseminated infec- groupings such as phakomatoses, and immunological, infectious, or genetic . tion with cryptococcus resulting in cutaneous Such distinctions are becoming increasingly resembling obscure. Instead, we have organised the may be an AIDS defining event. Surprisingly, roughly 300 disorders with manifestations both patients with this may have few or in the skin and nervous system into clinically no systemic features. relevant groupings, as they may be first Neurological disorders related to AIDs are encountered by a practicing : neuro- reviewed elsewhere.45 , discussed cutaneous disorders associated with impaired below, is another important neurocutaneous ; ; neuropathy; or complication of AIDS. meningoencephalitis; vesicular lesions; ecchy- , non-palpable , and petechiae; cafe au lait spots; ; ; cutaneous ; photosensitivity; Neuroscience and . For disorders mentioned only Research, SmithKline in the tables, or not at all, the reader is referred http://jnnp.bmj.com/ Beecham to the encyclopaedic text of Fitzpatrick et al1 Pharmaceuticals, 23 New Frontiers Science and more specialised compendia. Park North H25/124, Third Avenue, Harlow, Neurocutaneous disorders of impaired Essex, UK O Hurko immunity AIDS Eighty five per cent of those aVected with Department of on October 2, 2021 by guest. Protected copyright. , The AIDS have skin lesions, the most common of Johns Hopkins which are infectious, the result of impaired cell University School of mediated immunity. Even such banal Medicine, 10 th Floor, 550 North Broadway, as verruca vulgaris and molluscum contagio- Baltimore, MD, USA sum are problematic. Both types of viral infec- T T Provost tion are resistant to . Giant mollusca may disseminate over the body. Correspondence to: and recurrent bacterial infections, especially Dr Orest Hurko, Neuroscience Research, Staphylococcal aureus, may occur. The most SmithKline Beecham common cutaneous manifestation, however, is Pharmaceuticals, New recalcitrant seborrheic , a chronic Frontiers Science Park North H25/124, Third Avenue, inflammation typically of the scalp and face, Harlow, Essex CM19 5AW, but which can also involve the intermammary UK. Telephone 0044 1279 region of the chest, groin, and . is 622 739; fax 00441279 622 371; email thought to result from infection by Pityrospo- [email protected] rum orbiculare, a saprophytic organism. Usu- ally, it can be successfully suppressed by Received 14 August 1998 continued use of topical . and in revised form 9 November 1998 Herpes zoster is an AIDS defining event for Figure 1 Grouped vescicles on an erythematous base in a Accepted 10 November 1998 those who test positive for infection with HIV. zonal distribution characteristic of a herpes zoster infection. 418 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

Table 1 Neurocutaneous disorders associated with stroke

Disorder Cutaneous Amyloidosis VII Behçet’s nodosum, genital and oral aphthous ulcers Cerebral cavernous malformations Rarely, mellitus lipoidica diabeticorum, poorly healing ulcers Petechiae, Osler’s nodes, splinter haemorrhages —clusters of punctate dark red to blue black non-blanching macules or ; symmetric, starting at the umbilicus and knees, then buttocks and Haemolytic-uraemic syndrome Erythematous necrotic skin lesions Hereditary haemorrhagic Homocystinuria Sparse , malar flush, livedo reticularis, diVuse Hypercholesterolaemia , xanthelasma Progeria (Hutchinson-Gilford) Aged skin, alopecia, generalised hypotrichosis, sparse or absent eyebrows, - like, thin skin, midfacial Neurocutaneous Large irregular haemangiomas, angiomas Pseudoxanthoma, multiple papules, peau d’orange skin, angioid streaks, subcutaneous calcification usually in blood vessels Systemic erythematosus Photosensitivity, malar , telangiectasia, discoid lupus, patchy alopecia, mucosal ulcers, angioneurotic oedema, Raynaud’s phenomenon, subcutaneous nodules, palpable purpura, , (rare) Takayasu’s Cutaneous necrotising venulitis—palpable purpura Werner (Pangeria) Scleroderma-like skin, graying hair and baldness, leg ulcers, progressive scalp alopecia, sparse body hair, telangiectasia, mottled pigmentation, loss of subcutaneous , subcutaneous calcification

OTHER NEUROCUTANEOUS DISORDERS WITH Neurocutaneous disorders associated IMPAIRED IMMUNITY with stroke (table 1) Similar infections and tumours are common to ANTIPHOSPHOLIPID SYNDROME other from a wide variety The antiphospholipid syndrome is of causes such as chemotherapy, lymphoma, characterised by that are thought to and in excess of 100 described heritable disor- induce hypercoagulability by neutralising ani- ders in which the is depressed, onic phospholipids on endothelial cells and including severe combined immunodeficiency . These antibodies are most commonly (Swiss or alymphocytic type agammaglobuli- seen in systemic but also naemia) with susceptibility to fungal and viral as a primary abnormality. The most common antiphospholipid antibody of pathophysiologi- as well as pyogenic infections; the X-linked cal relevance is directed against epitopes local- Wiskott-Aldrich syndrome of eczema and ised to the cardiolipin 2 glycoprotein I ; Chediak-Higashi syn- complex. Other antibodies show specificity for drome of partial and neuropathy prothrombin and annexin V.In some instances, related to of a beige-related lyso- antiphospholipid syndrome has been shown to somal traYcking regulator encoded on chro- be a familial trait.6 The two most common tests mosome 1q42; the of employed for detecting antiphospholipid anti- partial albinism with silvery hair and progres- bodies are the anticardiolipin enzyme linked sive , related to mutations of immunosorbent assay (ELISA) and a func- 5 encoded on 15q21; tel- tional assay employing the Russell viper venom angiectasia; discussed below; test (RVVT). The associated cutaneous mani- 3 and others. festations are livedo reticularis, most com- http://jnnp.bmj.com/ monly on the lower extremities (fig 2); , a Raynaud’s-like phenomenon, and rarely, Degos malignant atrophic papulo- sis. The combination of livedo reticularis with multiple resulting in dementia has been designated Sneddon’s syndrome. Antiphos- pholipid antibodies are associated with several 7 neurological syndromes, most of which result on October 2, 2021 by guest. Protected copyright. from focal ischaemia.8

FABRY’S DISEASE Fabry’s disease is an X-linked multisystem dis- order resulting from deficiency of ceramide tri- hexosidase (also known as á-galactosidase) and resultant vascular deposition of lipid.39 Af- fected males are easily recognised by a purpu- ric skin rash for which the disorder was given its other name, angiokeratoma diVusum univer- sale. There is a characteristic whorl-like corneal dystrophy of similar severity in hetero- zygotes as in hemizygous males,10 but aVected females almost never have the characteristic skin rash. Without the rash, the diagnosis is often overlooked. The cutaneous manifesta- tions of Fabry’s disease are characterised by Figure 2 Livedo reticularis involving the knees and discrete most prevalent be- thighs. There is also ulceration on the lower leg. tween the knees and nipples. Neurology and the skin 419 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

a non-specific diabetic dermopathy. The last is characterised by reddish brown macules most commonly over the extensor surfaces of the lower extremities. The more characteristic , however, is diabeti- corum. This lesion, although not absolutely specific, generally occurs in patients with long- standing diabetes mellitus. Lesions consist of sharply demarcated, yellowish brown patches located most characteristically over the anterior surface of the lower legs (fig 3). A peculiar yel- lowish hue is characteristic, as well as the pres- Figure 3 Necrobiosis lipoidica diabeticorum: sharply ence of telangiectasia. Ulceration of this lesion demarcated, yellowish-brown indurated plaques with may occur. and telangiectasias characteristically, but not exclusively, associated with diabetes mellitus. Neurocutaneous disorders with In addition to a painful small fibre neu- neuropathy (table 2) ropathy with autonomic involvement and abdominal crises, the early syndrome includes In addition to diabetes mellitus, there are many small infarctions in the and that neurocutaneous disorders associated with neu- had previously led to death by the third decade. ropathy. Although largely sparing developed However, renal transplantation has permitted nations, leprosy is perhaps the most common survival to a later stage of multiple infarctions neurocutaneous disorder and peripheral neu- of the CNS. Although women tend to survive ropathy in the world. Vulnerability to infection longer than aVected men, clinical involvement with leprae appears, in part, to can be very severe, including debilitating be determined genetically.14 It had consistently ,11 renal failure, aVected some 10 to 12 million people until the ,12 and involvement of the introduction of multidrug therapy in the CNS.13 mid-1980s. By 1991 this number had dropped Angiokeratomas can also be found in associ- to about 5.5 million, including some 2 to 3 ation with other heritable disorders.3 million who were seriously deformed.15 The characteristic abnormality is a hypaesthetic DIABETES MELLITUS: METABOLIC mononeuritis multiplex, with palpably ENCEPHALOPATHY, NEUROPATHY, RETINOPATHY, thickened nerves, beginning with burning or AND STROKE shooting nerve and progressing to com- Diabetes is arguably the most common neuro- plete anaesthesia in aVected areas, comparable logical disorder in the developed world. The with that resulting from syringomyelia or com- cutaneous manifestations of diabetes mellitus pleted nerve transection. There is invariably a include necrobiosis lipoidica diabeticorum and non-necrotising lymphocytic angiitis of the Table 2 Neurocutaneous disorders associated with http://jnnp.bmj.com/ Disorder Cutaneous AIDS Seborrheic dermatitis, verruca vulgaris, molluscum contagiosum, Kaposi sarcoma Telangiectasias, Amyloidosis (primary) Purpura skin folds or flat surfaces or eyelids, papules, sometimes alopecia, rarely bullae on skin or Dry scaly desquamation, linear of nails, Mees lines Chediak-Higashi Partial albinism, silvery blond hair Cronkhite-Canada Alopecia, skin hyperpigmentation, onychodystrophy Diabetes mellitus Necrobiosis lipoidica diabeticorum, poorly healing ulcers

Diphtheria (cutaneous) Jungle sore on October 2, 2021 by guest. Protected copyright. , familial Blotching, abnormal sweating, Fabry Disease Angiokeratoma Flynn-Aird disease Skin atrophy, , chronic ulceration Haemochromatosis Bronze pigmentation Histiocytic reticulosis Purpura, jaundice, Impaired long-chain fatty acid oxidation Congenital , ichthyosiform erythroderma Leprosy Hypopigmentation and hyperpigmentation, leonine facies, leprosum, Lucio phenomenon: arteritis of skin, Linear sebaceous nevi of Jadassohn sebaceous and epithelial nevi, linear sebaceous Target lesions Pellagra Erythematous photosensitive rash, erythema, vesicles, , malar and supraorbital hyperpigmentation, rhagades Poems syndrome Hyperpigmentation, thickening, verrucous angiomas, , Raynaud’s phenomenon -spastic paraplegia Poikiloderma: delicate, smooth, wasted skin Refsum’s disease Ichthyosis Refsum’s disease with increased pipecolicacidaemia Ichthyosis Hypohidrosis,, cicatricial alopecia; acute: erythema nodosum, vesicles, maculopapular rash; chronic lupus pernio, plaques, , Systemic lupus erythematosus Photosensitivity, malar rash, discoid lupus Thallium intoxication Ichthyosis, flexural eczema, photosensitivity, short wooly hair deficiency Black pigmentation (nail bed and matrix), oral aphthae Werner (pangeria) Scleroderma like skin, graying hair and baldness, leg ulcers, progressive scalp alopecia, sparse body hair, telangiectasia, mottled pigmentation; loss of subcutaneous fat, subcutaneous calcification pigmentosum Photosensitivity, early onset (basal cell, squamous cell, and malignant melanoma), atrophy, telangiectasia, actinic , angioma, 420 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

nerves, either as a result of delayed hypersensi- lopathies has crudely approximated motor tivity, or, in the case of multibacillary disease, disease in some patients. Such rare direct infection of endoneurial cells by the occurrences as well as incidental seropositivity mycobacterium. The organism grows preferen- in patients aVected with these common dis- tially in cool, exposed limbs and face, giving a eases, including stoke, have suggested associa- diVerent distribution than is seen in inflamma- tions, none of which have been established.20 tory mononeuritis multiplex. In addition to In chronically aVected patients there can superficial nerves, commonly aVected are also be a non-vasculitic mononeuropathy motor function of the and sensory multiplex, perhaps mechanistically identical to function of the posterior .16 the acute form. Some untreated patients The cutaneous manifestations of leprosy are develop an indolent, indistinct diVuse the reflection of the host immune response to encephalopathy. This nondescript chronic M leprae. All forms of leprosy are associated syndrome has become seriously over- with invasion of the organism into peripheral diagnosed, in part because of the problems nerves. The tuberculoid form of leprosy, char- inherent in serological diagnosis of an immu- acterised by anaesthetic patches on the skin nologically complex spirochete, endemic in adjacent to thickened peripheral nerves, results some areas and rare in others. Inappropriate from a vigorous cell mediated immune re- diagnosis may well contribute to the belief that sponse with formation of . Severe there is a subgroup of patients with chronic destruction of peripheral nerves ensues. The Lyme disease unusually refractory to anti- lepromatous form of leprosy is characterised by biotic treatment, in contradistinction to the widespread cutaneous nodular lesions (leonine responsiveness of classic neuroborreliosis.21 22 facies) in which massive quantities of M leprae DiYculties with serological diagnosis abound. are found in the tissue. This form of leprosy, associated with an absent cell mediated re- Neurocutaneous disorders with sponse, also produces nerve destruction, but meningitis or meningoencephalitis more insidiously. Reversal reactions induced by In addition to Lyme disease, there is a wide therapy () or a natural immune variety of neurocutaneous disorders associated response to M leprae produce a very prominent with inflammation of the meninges, often with inflammatory reaction from which damage to associated cranial or peripheral neuropathies. nerves can be severe. Dermatological findings are particularly help- Although there is correlation between cuta- ful in diagnosing aseptic meningitides or those neous and nerve , it is not absolute. associated with indolent organisms. Careful examination shows that some 4% of at risk people have sensory or motor nerve BEHÇET’S DISEASE: MENINGOENCEPHALITIS AND involvement without cutaneous signs of re- SINUS versal reaction, erythema nodosum, or nerve This is an inflammatory dermatosis of un- tenderness.17 Furthermore, there can be dis- known aetiology. There is a high of crepancies in nerve and skin , showing Behçet’s syndrome in people from the Mediter- paucibacillary involvement in one, multibacil- ranean, , China, and Japan. There lary form in the other.18 is an increased frequency of HLA-B5 (Bw51 split) in aVected people. There is evidence that http://jnnp.bmj.com/ LYME DISEASE the primary association with Behçet’s syn- Lyme disease (erythema chronicum migrans) drome is not in the HLA-B1 itself, but is a chronic inflammatory disease caused by the with the newly discovered MICA gene.23 spirochete Borrelia burgdorferi. It is transmitted Behçet’s syndrome is characterised by recur- by a tick bite (Ixodes dammini). No genetic vul- rent aphthous , genital ulcers, uveitis, nerability loci have been identified. About 85% erythema nodosum, and . of patients develop a very peculiar, distinctive, Recurrent occurs in 98% cutaneous inflammatory reaction at the site of of patients with Behçet’s syndrome and is often on October 2, 2021 by guest. Protected copyright. the tick bite. Initially there is an inflammatory the initial manifestation. As many as 90% of , which over a period of weeks spreads patients with Behçet’s syndrome have a relaps- centrifugally. Central clearing occurs but a ing iridocyclitis, anterior and posterior uveitis, haemorrhagic, papular, vesicular lesion may or retinal vasculitis. Optic atrophy may occur remain at the site of the tick bite. Multiple and blindness may result. Pathergy (the devel- lesions of erythema chronicum migrans occur opment of pustulation at the site of trauma) is if the disease process is untreated. a characteristic feature. Vesicles, pustules, Borrelia burgdorferi aVects the joints, the , , and acneiform erup- , and the nervous system. The typical tions, as well as necrotising vasculitis have also presentation is of a painful patchy mononeuri- been described. tis multiplex in association with mild lym- Neurological manifestations are the least phocytic meningitis. The mononeuritis can frequent but most feared aspect of this take the form of cranial neuropathies, particu- disorder, aVecting 2.2% of those in a recently larly of the facial nerve, or a painful radiculopa- reported series.24 Most often, this takes the thy, or brachial or lumbar plexitis.19 Less often, form of a recurrent or chronic aseptic meningi- there can be a myositis. Involvement of the tis. In about 10% of patients there is a menin- CNS can mimic roughly some common goencephalitis or meningomyelitis, which may neurological disorders. Patchy demyelination respond to early and aggressive treatment with sometimes suggests an atypical distribution of steroids, immunosuppressive drugs, and col- . with radicu- chicine. There is a high incidence of dural sinus Neurology and the skin 421 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

Figure 5 Characteristic copper coloured lesions over the palms in secondary syphilis.

SYPHILIS After a period of diminishing prevalence, there has been a 10-fold rise in the incidence of pri- mary and secondary syphilis, some 20/100 000 in the United States and 360/100 000 in parts of Africa. Inflammatory CSF is found in 10%- 20% of those with primary syphilis, 30% to 70% of cases of secondary syphilis (2–4 months after infection), and falling to 10%- 30% of cases of latent syphilis. In these early Figure 4 of primary syphilis. stages mild meningism can be associated with cranial nerve involvement, particularly of the optic, facial,and acoustic nerves.28 thrombosis, aVecting about 25% of all those The cutaneous manifestations of syphilis with neuroBehçet’s syndrome.25 Psychiatric characteristically are initiated by a primary disturbances and isolated trigeminal chancre most commonly on the genitalia, but have also been described. sometimes on the lips or in the throat. This is a painless, indurated, rubbery lesion generally occurring within 2 weeks of infection (fig 4). It SARCOIDOSIS: CRANIAL NEUROPATHIES AND is also characterised by painless swelling of the ASEPTIC MENINGITIS draining (bubo). Serological test- Sarcoidosis is a chronic granulomatous disease ing (Venereal Disease Research Laboratory of unknown aetiology. Some 20% to 35% of test) may be negative during the early phase, patients with systemic sarcoidosis have cutane- but invariably becomes positive within 1 month ous disease. The cutaneous features include of infection. The fluorescent Treponema anti- skin coloured papules, nodules, and annular body test, however, is generally positive within lesions. The annular lesions are most common 2.5 weeks of the onset of infection. The in people of African descent. In addition to primary chancre may go untreated or unrecog- being skin coloured, the lesions of sarcoidosis nised (most common in women with a cervical http://jnnp.bmj.com/ may be brownish red or violaceous. They are primary chancre) allowing the secondary phase often detected on the face, especially around of syphilis to occur. This can occur while the the nostrils. On occasion, they may become primary chancre is still present. It is character- confluent, forming erythematous plaques. ised by mucous membrane patches and a The angiolupoid form of sarcoidosis is a rare patchy alopecia, as well as copper coloured cutaneous lesion occurring most often in lesions on the palms and soles (fig 5). women. These lesions are soft, well demar- In adults, it is only during the early cated, orange-red or reddish brown, with a livid meningeal phases of the illness that cutaneous on October 2, 2021 by guest. Protected copyright. hue secondary to prominent telangiectasia. abnormalities are present. About 10% of those Lupus pernio is characterised by large, bluish with early syphilitic meningitis have a rash. red, dusty, violaceous infiltrated nodules and Cutaneous abnormalities resolve by the time of plaques, which generally appear on the cheeks, the later stages of neurosyphilis: meningovas- ears, fingers, and nose. On rare occasions, sar- cular, which peaks after 4 to 7 years; general coidosis may present as an erythrodermic paresis, 10 -15 years; and , 15–25 lesion characterised by red scaling patches years. There is considerable overlap in the extending and merging into brownish red, con- times of incidence. Cutaneous nodules or fluent areas. Ulceration is rare, but most com- plaques of late syphilis are distinctly rare.29 monly seen in those of African descent. Prenatal syphilis is lethal in utero or shortly Clinically recognisable disease of the nerv- after birth in about half the cases. Early prena- ous system occurs in 5% to 10% of patients tal syphilis, with manifestations occurring with sarcoidosis.26 In half of these patients, before the age of 2, corresponds to secondary neurological signs were the presenting syphilis, whereas the signs of late prenatal feature.27 The most common findings were syphilis do not appear until after the age of 2, cranial neuropathies, chiefly of the facial nerve. rarely as late as 30. Half of early cases have Also encountered were parenchymatous le- cutaneous manifestations, typically copper red sions of the nervous system including the macules and papules on the palms, soles, and hypothalamus, , peripheral neu- perineum. Fissures of the lips or anus “rha- ropathy, and myopathy. gades” aVect 75% of aVected infants. Less 422 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

often, there are bullae or a bright red nasal dis- Ecchymoses, purpura, and petechiae charge “snuZes”.29 As in secondary syphilis of Ecchymoses, petechiae, and purpura result adults, meningoencephalitis is the most com- from extravasation of blood into the skin or mon neurological presentation. Neurologists subcutaneous tissues. Such can occur must be wary of the “pseudoparalysis of after significant trauma in people who are oth- Parrot”—failure to move a limb because of a erwise well. However, subcutaneous haemor- painful osteochondritis at the epiphysis of a rhages occurring after trivial trauma indicate long bone. either a coagulopathy or disorder of platelets or blood vessels. All of these may concurrently aVect the nervous system, disorders OTHER NEUROCUTANEOUS DISORDERS WITH perhaps less so than the others. MENINGITIS OR MENINGOENCEPHALITIS

In addition to Behçet’s disease and neurosar- CHILD ABUSE: THE SHAKEN BABY SYNDROME coidosis, aseptic meningitis with uveitis can —delivered either by a frustrated occur in infantile multisystem inflammatory caregiver trying to stop an infant’s crying, or by disease and in the rare Vogt-Koyanagi-Harada someone deliberating trying to inflict harm—is syndrome. In the last, a prodromal meningoen- the leading cause of serious head in cephalitis precedes uveitis and the final phase infants,34 accounting for 95% of serious intrac- with the characteristic dermatological findings ranial . Intracranial pathology may of alopecia, , and leukoderma with occur in the setting of bone fractures and the symmetric patches of vitiligo involving the mucocutaneous manifestations described 30 head, , shoulders, and eyelids. above. However, the “shaken baby syndrome” There is a large diVerential for meningitis or can occur in the absence of skeletal or cutane- meningoencephalitis with cutaneous manifes- ous manifestations of trauma. Infants present tations (table 3). comatose or convulsing with retinal haemor- rhages and anaemia from intracranial extrava- sation of blood into the subdural or subarach- noid space. The clinical triad of the “tin ear Neurocutaneous disorders with vesicular syndrome”: unilateral ear bruising, ipsilateral lesions cerebral oedema, and retinal haemorrhage is HERPES VARICELLA ZOSTER said to be , but bilateral sub- The varicella zoster causes two distinct dural haematomas are seen most often.35 In syndromes: a primary infection () more severe cases there may be lacerations or and a recurrent infection (shingles) after reac- other intraparenchymal brain lesions. Up to tivation of virus that has lain dormant in the 60% of children either succumb or become dorsal root ganglia for years after the primary profoundly mentally retarded, blind, or tetra- infection.31 The most common nervous system paretic with residual encephalomalacia, poren- complication of primary infection is a self lim- cephalic , and chronic subdural fluid iting cerebellar ataxia and aseptic meningitis, collections.36 Less often rhabdomyolysis and that typically occurs around 21 days after the myoglobinuric renal failure ensue. eruption of cutaneous vesicles. About 0.1% to The diVerential diagnosis for the neurocuta- 0.2% of infected children develop . neous manifestations includes haemophilia http://jnnp.bmj.com/ About 2% of patients with childhood chick- and vitamin K deficiency of infancy. Multiple enpox will reactivate the virus to develop shin- bone fractures after trivial trauma can occur in gles, usually in the 6th through to the 8th dec- osteogenesis imperfecta type 3 or 4 (resulting ade. Excruciating dermatomal pain, typically in from mutations in the encoding thoracic or high lumbar dermatomes precedes 1A or 2A)3 Wormian bones in these disorders by 2–3 days the development of a maculopapu- can simulate the multiple skull fractures which lar rash that quickly matures into a vesicular are now considered almost pathognomonic for eruption that may take 2–4 weeks to resolve child abuse. Careful radiographic examination on October 2, 2021 by guest. Protected copyright. completely. , however, of bones usually permits distinction of osteo- may persist indefinitely. Reactivation of the genesis imperfecta from child abuse.37 38 virus in the distribution of the VIIIth cranial nerve results in a characteristic mononeuritis: THROMBOTIC Ramsay Hunt herpes zoster oticus. Deep local Thrombotic thrombocytopenic purpura is a pain is followed several days later by vesicles in rare acute or subacute disorder that chiefly the external auditory meatus, and later hearing aVects young women, sometimes in association loss, with or without vertigo.32 with systemic lupus erythematosus, Sjögren’s In some patients there is symptomatic men- disease, or scleroderma. Petechiae are less fre- ingitis. Reactivation of the virus in the ophthal- quent than in the unrelated disorder, idiopathic mic branch of the results in thrombocytopenic purpura, in which there is herpes zoster ophthalmicus. Vasculitic stroke is no involvement of the nervous system. Jaundice most common with eruptions in the distribu- can result from the severe haemolysis that is a tion of the first division of the trigeminal nerve, hallmark of this disease. A severe encephalopa- but may occur from shingles elsewhere.33 In thy with , focal deficits,39 and coma rare circumstances there may be transverse occur in about 90% of patients that succumb to or granulomatous angiitis of the CNS. the disease, usually as a result of cerebral or The risk of widespread dissemination is greater renal involvement. However, patients success- in the immunocompromised host, but is rarely fully treated with plasmapheresis will go on to fatal. complete neurological recovery.40 Neurology and the skin 423 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

Table 3 Meningitis or meningoencephalitis with cutaneous manifestations

Disorder Cutaneous Neurological Adams-Oliver type III Scalp defect at the vertex, hypoplastic nails, tortuous scalp Acute bacterial meningitis from skull defect , cutis marmorata telangiectatica, haemangioma AIDS Seborrhoea, herpes zoster, tinea corporis, S Aureus, Transient meningitis during seroconversion molluscum contagiosum, Kaposi sarcoma, Amyloidosis V (Meretoja) Cutis laxa Cranial and peripheral neuropathies Behçet’s disease Erythema nodosum, genital and oral aphthous ulcers (not Chronic or recurrent meningitis, meningoencephalitis, as painful as recurrent aphthae) 1-5 ulcers <10 mm, 4-14 dural sinus thrombosis days duration, papules, purpura, pustules, dermatographia, pyoderma Hyperplastic granulomatous microabscesses Very rarely: chronic meningitis or cerebral Brill-Zinser Macular rash Meningoencephalitis Chagas disease Romana’s sign, inflammation of lacrimal glands, erythema Encephalitis multiforme Coccidiomycosis Erythema nodosum, draining sinus, subcutaneous Meningitis common; sometimes from parameningeal focus in vertebral osteomyelitis Cryptococcosis Macules and nodules in only 10 -15% of aVected Chronic meningitis individuals Haemophilus influenza Typically single indurated area on face, neck, upper chest, Acute purulent meningitis or Histiocytic reticulosis (autosomal recessive) Purpura, jaundice, erythroderma Chronic aseptic meningitis, neuropathy Infantile multisystem inflammatory disease Evanescent rash, uveitis , optic atrophy, mental retardation, aseptic meningitis Scleral conjunctival injection; maculopapular rash of trunk Subacute meningitis in 50% of cases, jaundice Leukaemia Erythema nodosum, Sweet’s syndrome (acute febrile Meningeal leukaemia is common form of relapse, neutrophilic dermatosis— painful raised red plaques especially in all commonly on face and extremities) Listeria Generalised erythematous papules or petechiae in infants; Subacute meningitis veterinarians with tender red papules of hands Lyme borreliosis Target lesion Early aseptic meningitis, , delayed Lymphoma Erythema nodosum Subacute meningitis, cerebral or vertebral metastasis Lymphoma, cutaneous () Scaly erythematous patches, leonine facies, poikiloderma, Subacute meningitis, vertebral metastases hypopigmented and hyperpigmented patches with atrophy and telangiectasia Meningococcaemia Typically small and irregular petechiae with smudged Fulminant meningitis appearance, usually on extremities and trunk; initially can mimic a viral Axillary rash, macular rash of upper abdomen, shoulders, Headache, encephalopathy, and nuchal rigidity without chest meningitis Neurocutaneous Melanosis; large multiple pigmented skin nevi (> 20 cm), Meningeal enhancement secondary to melanosis of no malignant melanoma other than CNS; primarycns pia-arachnoid; cranial nerve palsies, Dandy Walker melanoma in over 50% of cases malformation, suprasellar calcification; Reticulosis, familial histiocytic Purpura, jaundice, erythroderma Chronic meningitis, peripheral neuropathy Rocky mountain spotted Characteristically progressing rash begins (1) on the fourth Vasculitic meningoencephalitis, choreoathetosis, day of fever with pink macules on wrists, ankles, forearms; deafness, hemiplegia (2) after 6 to 18 hours, on palms and soles, then centrally (3) after 1-3 days deep red macules; (4) after 2-4 days, non-blanching petechiae Sarcoidosis Dry skin, hypohidrosis, decreased sweating, cicatricial Chronic meningitis with cranial neuropathies, distal alopecia; acute: erythema nodosum, vesicles, neuropathy and proximal myopathy; leukopathy,

maculopapular rash; chronic: lupus pernio, plaques, scars, hypothalamic involvement http://jnnp.bmj.com/ keloids Sjögren’s syndrome Purpura, Raynaud’s phenomenon, , , Aseptic meningitis, dorsal ganglionopathy with sensory dental caries ataxia, dural sinus thrombosis Syphilis Primary: chancre; secondary maculopapular non-pruritic Aseptic meningitis in secondary phase; late scaling rash (acral), hair: patchy alopecia, condyloma lata, meningovascular syphilis; tabes dorsalis mucous patches, erythema multiforme, hyperpigmentation on healing; split papules, palm and sole lesions Cutaneous tuberculosis is rare; primary tuberculosis Chronic meningitis; Pott’s disease of vertebrae; CNS chancre; warty tuberculosis verrucosa cutis from tuberculomas reinfection, postprimary , , erythema nodosum, erythema multiforme on October 2, 2021 by guest. Protected copyright. Varicella-zoster (chickenpox) Vesicles with oral lesions Meningitis with cerebellar ataxia Vogt-Koyanagi-Harada Vitiligo type macules, poliosis and alopecia in convalescent Meningoencephalitis in first phase of illness, preceding third phase uveitis Yersinia pestis (bubonic ) Erythema multiforme, bubos then petechiae and Meningitis can complicate all three types: bubonic, ecchymoses bubonic-septicaemic, pneumonic

Cafe au lait spots (4) optic pathway ; (5) two or more TYPE 1 Lisch nodules (whitish tumours of the iris); (6) Neurofibromatosis is the most common single dysplasia of the sphenoid bone or thinning of gene disorder to aVect the nervous system, the cortex of long bones with or without pseu- aVecting about 1/3500 people.41 The NIH doarthrosis; and (7) a first degree relative consensus criteria42 for the diagnosis of neu- exhibiting these changes. rofibromatosis type 1 (von Recklinghausen’s Among the most pressing management neurofibromatosis) require at least two of the issues in neurofibromatosis type 1 are those following: (1) the presence of six or more café pertaining to tumours, usually histologically au lait macules with a diameter of 5.0 mm in benign.41 43 Neurological involvement most children younger than 6 years and >15 mm in often results from benign neurofibromas older people (fig 6); (2) two or more neurofi- arising in the root entry zone, causing radi- bromas of any type or one plexiform neurofi- culopathy or compression of the spinal broma; (3) axillary or inguinal region freckling; cord. Plexiform neurofibromas, which can be 424 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

ing or eliminating the requirement for nerve growth factor or neurotrophins.50 About a third of aVected people have no family history.51 New mutations can occur in any of several locations in this very large gene. Because so many of the mutations are novel, DNA based diagnosis is currently not clinically practicable in many instances. However, a truncation assay can detect about 70% of all mutations52 and can be useful in conjunction with other tests.43 Figure 6 Two café au lait macules on the skin of a patient Other mutations in the neurofibromin gene with neurofibromatosis. These are adjacent to two small give rise to the Watson pulmonary neurofibromas. syndrome,53 in which there is also macro- cephaly, axillary freckling, intellectual dullness, nodular or diVuse, arise from nerve trunks. and axillary freckling, but in which Lisch nod- DiVuse plexiform neurofibromas are usually ules are uncommon and the neurofibromas congenital and undergo transformation in visceral or retroperitoneal. about 4% of cases into44 malignant peripheral nerve sheath tumours that are severely painful, tender, and hard. The more common dermal NEUROFIBROMATOSIS, TYPE 2(NF2): BILATERAL neurofibromas are usually innocent, permitting ACOUSTIC NEUROFIBROMATOSIS conservative management in asymptomatic The neurological hallmark of this clinically and people. Incidence of non-neural tumours is genetically distinct disorder is the appearance also increased, albeit to a modest degree, espe- of bilateral vestibular , tumours cially rhabdomyosarcomas of the urogenital that are not associated with neurofibromatosis tract and myelogenous leukaemia.45 type 154 55 The diagnostic criteria for definite In addition to involvement of the peripheral neurofibromatosis type 2 are either bilateral nervous system, there is also involvement of the vestibular schwannomas or a first degree CNS. Increasing awareness of CNS pathology relative with the disease plus a unilateral led to abandonment of the old name for this vestibular appearing before the disorder—peripheral neurofibromatosis—for age of 30 or any two of the following: meningi- the current neurofibromatosis type 1). Of the oma, glioma, schwannoma, and juvenile poste- central tumours, of the optic pathway rior subcapsular lenticular opacity/juvenile are the most frequent, occurring in about 15% cortical .43 Neurofibromatosis type 2 of those aVected. , and, less often, was formerly named central neurofibromatosis and medulloblastomas also because the cafe au lait spots and dermal neu- occur. rofibromas characteristic of neurofibromatosis Not all neurological manifestations result 44 type are less abundant and often absent. How- from tumours. Indeed, the most frequent ever, the terms central and peripheral are neurological manifestation of neurofibromato- unfortunate and have been abandoned, in as sis type 1 is a learning problem.46 Other mani- much as both neurofibromatosis type 1 and festations unrelated to tumour are megalen- type 2 each have central and peripheral http://jnnp.bmj.com/ cephaly, , and hydrocephalus.44 manifestations.56 Two thirds of patients with can result either from pheochro- type 2 have some sort of skin lesion, but cafe au mocytomas or fibromuscular dysplasia of the lait spots are less frequent than in type 1. Only renal . Rarely, there can be a peripheral neuropathy, fibromuscular dysplasia, or fusi- 8% of patients with neurofibromatosis type 2 form of an intracranial . have more than three café au lait spots. In a Brain MRI often demonstrates T2 bright large clinical study palpable subcutaneous lesions—“unidentified bright objects” or tumours attached to large nerves were found in 57 on October 2, 2021 by guest. Protected copyright. UBOs. Typically they arise in the basal ganglia, 43% of patients, violaceous subcutaneous brainstem, and cerebellum47 and do not show neurofibromas in 27%, and well circumscribed mass eVect. However, they can only be pigmented and often hairy patches of skin in distinguished reliably from low-grade astrocy- 48%. There are no Lisch nodules but posterior tomas by careful follow up. Thought by some capsular are typical. In addition to the to represent aberrant myelination or gliosis, the characteristic vestibular schwannomas, there majority of these can be distinguished from can be meningiomas, gliomas, and generalised by their spontaneous resolution neuropathy. This autosomal dominant disorder by adulthood, after a peak incidence between 8 occurs less often than does neurofibromatosis and 16 years.. These are for the most part type 1 It is caused by mutations in the clinically silent, although their presence in gene on chromosome 22, which also multiple sites has correlated with cognitive dis- seems to be involved in the pathogenesis of turbance in some studies48 though not others.49 some cases of what had initially been described Neurofibromatosis type 1 is caused by as neurolemmomatosis58 59 and is now called of an unusually large gene (spanning schwannomatosis.60 In this disorder, there are 350 kb of genomic DNA) on chromosome 17 multiple schwannomas, but no other manifes- which encodes a novel tumour suppressor, tations of neurofibromatosis type 2 in most neurofibromin. Neurofibromin is thought to family members.61 There may also be a distinct inactivate the tumour suppressor Ras by form of schwannomatosis unrelated to neurofi- enhancing its GTPase activity and thus reduc- bromatosis type 2.62 Neurology and the skin 425 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

neous Fanconi syndrome369 in which mental retardation is associated with , deafness, thumb anomalies, and pancytopenia. Rarely, cafe au lait spots as well as hypo- pigmented patches are seen in the von Hippel-Lindau syndrome: autosomal domi- nant retinal angiomas; hemangioblastomas of the and ; renal and pancreatic cysts and carcinomas; as well as pheochromocytomas.37071 However, cutane- ous manifestations are decidedly rare in this Figure 7 Shagreen patch over the back of a patient with . This is a resulting from common autosomal dominant disorder that subepidermal fibrosis. results from mutations in a gene on chromo- some 3p26-p25. This gene encodes a novel OTHER NEUROCUTANEOUS SYNDROMES tumour suppressor protein that both regulates ASSOCIATED WITH CAFE AU LAIT SPOTS AND exit from the cell cycle and the expression of TUMOURS several -inducible genes, including vas- Cafe au lait spots are also seen in other neuro- cular endothelial growth factor.3 More often, cutaneous tumour syndromes, which can be café au lait spots have been seen in Turcot’s easily distinguished both clinically and geneti- syndrome,372 a rare autosomal dominant syn- cally. In tuberous sclerosis the distinguishing drome of brain tumours, usually medulloblas- cutaneous manifestations are not café au lait tomas, colon cancer associated with poplypo- spots but adenoma sebaceum, periungual sis, thyroid carcinoma, and bone cysts. These angiokeratomas, Shagreen patches (fig 7), and phenomena result from certain germ line hypopigmented ash leaf spots, best appreciated mutations of the adenomatous polyposis coli under Wood’s lamp.63 The neuro- gene.3 logical manifestations vary from severe mental retardation and infantile spasms to normal NEUROLOGICAL DISORDERS ASSOCIATED WITH intelligence. Cardiac and olfactory hamarto- CAFE AU LAIT SPOTS BUT NOT TUMOURS mas are characteristic of severely aVected Very large, unilateral and segmental café au lait infants. Large hamartomas called tubers are spots are characteristic of McCune Albright often found on neuroimaging and can only be polyostotic fibrous dysplasia. Although it was distinguished from astrocytomas, also associ- commonly understood that the rough border of ated with tuberous sclerosis, by serial scanning. these cutaneous lesions distinguished them The characteristic tumours are ganglioneuro- from the smoother contour seen in neurofi- mas that give a candle guttering appearance to bromatosis, this does not permit the reliable the ventricular wall. Other associated lesions distinction aVorded by the rest of the are ependymomas, Wilms’ tumour, retinal syndrome.373 The osseous and endocrine phakomas, clinically silent renal cysts, and abnormalities result from somatic mosaicism angiolipomas, as well as, less often, renal cell for constitutively lethal mutations the GNAS1 carcinoma.364This autosomal dominant disor- gene (guanine nucleotide binding protein, der is genetically heterogeneous: tuberous scle- á-stimulating activity polypeptide 1), that http://jnnp.bmj.com/ rosis I is caused by mutations of the hamartin encodes a GTP binding subunit of adenylate gene on chromosome 9q34, and tuberous scle- cyclase. Neurological manifestations are lim- rosis II, with a higher risk of mental retarda- ited to brainstem compression and syringomy- tion, by mutations of the tuberin gene on chro- elia resulting from severe .74 mosome 16p13.3.365 Previous reports of Cafe au lait spots are associated are associ- additional tuberous sclerosis 3 and 4 loci on ated with mental retardation in several clini- chromosomes 11 and 12 have proved cally distinguishable syndromes: the rare West- incorrect.3 erhof syndrome in which growth retardation is on October 2, 2021 by guest. Protected copyright. Cafe au lait spots are sometimes found in associated with congenital hypopigmented and some of the many autosomal recessive neuro- hyperpigmented patches,75 as well as in chil- cutaneous disorders associated with defective dren with ring 14 and ring 17 chromosomal DNA repair. Some early compendia had asso- anomalies. Microcephaly but usually normal ciated ataxia telangiectasia with café au lait intelligence are typical of Russell-Silver dwarf- spots.66 However, the association is not with the ism, a growth retardation syndrome with a classic disorder but with what had been called characteristic lateral body asymmetry.376 ataxia telangiectasia variant VI. This geneti- Finally, it is important to remember that cally distinct disorder is now known as the autosomal dominant of café au Nijmegen breakage syndrome of microcephaly lait spots can be seen in the absence of other with (usually) normal intelligence, immunode- abnormalities.3 Some,77 although not all78 such ficiency, and lymphoreticular malignancies.367 cases result from mutation in the neurofibro- Facial telangiectasias are also typical in Bloom min gene. syndrome,368 in which susceptibility to infec- tions and neoplasia result from mutations in Amyloidosis DNA ligase I encoded on chromosome Amyloidosis refers to extracellular deposition 15q26.1. There is dolichocephaly and light of insoluble protein fibrils. The pattern of sensitivity, with mild learning disability as the cutaneous, neurological, or visceral involve- only neurological manifestation. Leukaemia is ment is to some extent related to the type of a fatal complication of the genetically heteroge- protein that is being deposited.79 Slightly raised 426 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

cutaneous papules clustered in skin folds of the pathology in patients with scleroderma oc- axilla or perineum are characteristic of amy- curred in those who had systemic features loidosis (AL type), resulting from deposition of overlapping with those of Sjögren’s syndrome fragments of immunoglobulin light chains. or systemic lupus erythematosus. There is a painful small fibre peripheral An unusual form of localised scleroderma is neuropathy, with prominent autonomic in- seen in the Parry-Romberg syndrome of volvement. A similar small fibre neuropathy in progressive hemiatrophy of the face with the absence of cutaneous lesions is associated contralateral focal and trigeminal with autosomal dominant mutations of the neuralgia.89 transthyretin gene.80 In familial amyloidosis type VII cutis laxa is Palpable purpura: cutaneous vasculitis associated with an episodic encephalopathy Raynaud’s phenomenon is also the most com- and amyloid deposition in leptomeningeal and mon cutaneous manifestation of Sjögren’s syn- retinal blood vessels.81 In amyloidosis type V, drome, a very heterogeneous rheumatic disease cutis laxa and lattice corneal dystrophy are associated with characteristic dryness of the associated with multiple cranial neuropathies, eyes and mouth. This common disease aVects but not autonomic dysfunction.82 - 3% to 5% of elderly women, some 30% of like erythema and benign recurrent meningitis whom have anti-La(SS-B) or anti-Ro(SS-a) similar to Mollaret’s83 are the neurocutaneous antibodies. Peripheral neuropathy occurs in features of familial Mediterranean fever, asso- about 10% of those with Sjögren’s syndrome. ciated with mutations in the pyrin gene84 an The most distinctive neurological manifesta- autosomal dominant disorder that leads to tion of Sjögren’s syndrome is a amyloid deposition in the kidneys. associated with lymphocytic infiltration of the dorsal root ganglia.90 Other neurological mani- Rheumatoid arthritis festations have been attributed to Sjögren’s The characteristic cutaneous findings in rheu- syndrome but the strength of these associations matoid arthritis are subcutaneous nodules. In has yet to be determined.91–93 There is cutane- some patients there may be painful intracuta- ous vasculitis manifesting either as palpable neous papules of the finger pulp, bright red purpura of the lower extremities or urticaria- “ palms”, or a vivid washable yellow like vasculitic lesions in as many as 25% of discoloration of the skin from inspissated anti-Ro(SS-a) antibody positive patients with sweat. Rheumatoid nodules characteristically Sjögren’s syndrome. Palpable purpura, the occur at sites of trauma: extensor surfaces of hallmark of cutaneous vasculitis can also be forearms, ears, and posterior scalp. seen in other vasculitides7 including polyarteri- The most serious neurological complication tis nodosa, Henoch-Schönlein purpura, essen- commonly encountered in rheumatoid arthritis tial , some cases of giant cell is a high cervical myelopathy, most often arteritis, and Churg-Strauss allergic attributed to horizontal atlantoaxial instability, granulomatosis,94 as well as the autosomal but recently discovered to be as frequent in dominant syndrome of retinal vasculopathy patients with vertical translation of the dens with cerebral leukodystrophy.95 and a normal atlantoaxial interval.85 Systemic necrotising arteritis indistinguishable from Photosensitivity http://jnnp.bmj.com/ polyarteritis nodosa aVects fewer than 1% of Exaggerated sensitivity of the skin to sunlight is people with rheumatoid arthritis. Nevertheless, a feature of several neurocutaneous disorders it is among the most common causes of of diVuse aetiology: two autoimmune disor- mononeuritis multiplex associated with necro- ders, systemic lupus erythematosus and der- tising vasculitis, second only to classic polyar- matomyositis; nutritional deficiency of niacin; teritis nodosa.86 Peripheral nerve involvement as well as several heritable disorders of results from occlusion of the vasa nervorum. intermediary metabolism or DNA repair. Less often there can be a necrotising vasculitis on October 2, 2021 by guest. Protected copyright. 87 of the CNS. SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus is a chronic Scleroderma relapsing and remitting multisystem inflamma- The defining cutaneous abnormality of pro- tory disorder thought to result from impaired gressive systemic sclerosis is , but control of . The genetics of lupus all patients also have Raynaud’s phenomenon. is complex, susceptibility being associated with About two thirds have proximal scleroderma, certain HLA class II alleles3; homozygosity for telangiectasias, or digital pitting scars of the deficiency of several complement genes as well fingers. About half exhibit calcinosis. Although as a demonstrated but uncharacterised suscep- scleroderma is thought to be the least likely of tibility locus on chromosome 1.96 the disorders to be associated Photosensitivity is the most common cutane- with neurological dysfunction, a systematic ous manifestation of systemic lupus erythema- survey found the frequency of both peripheral tosus, usually manifested as a malar rash. Less and CNS involvement in scleroderma to be often there is a discoid rash and oral ulceration. comparable with that in systemic lupus ery- Neurological complications are frequent and thematosus and Sjögren’s syndrome, although diverse in systemic lupus erythematosus, af- the types of pathology diVer.88 In that survey fecting 70% of those with the disease.788Events one third of patients with scleroderma had predominate in the CNS. This may in part be peripheral involvement, including trigeminal an artefact of disease definition. and neuralgia and brachial . Most CNS seizures are each elements of the American Neurology and the skin 427 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

andadiVerent spectrum of autoantibodies.100 Both disorders can be part of overlap mixed connective tissue disorders, but an increased frequency of malignancy is a feature of , particularly of adult onset. Among the more striking is a 16-fold to 32-fold increase in the rate of ovarian cancer.101

PORPHYRIA Heritable disorders of porphyrin metabolism are clinically divisible into two general types: the cutaneous porphyrias, most of which have no neurological involvement, and the hepatic porphyrias, most of which have no Figure 8 DiVuse erythema on the dorsal hand of a patient cutaneous involvement. The hallmarks of with photosensitive dermatomyositis. Typical hand lesions of hepatic porphyrias are metabolic crises with dermatomyositis are injections of the cuticle nail fold, erythema over the PIP,DIP,and MCP joints (Gottron’s delirium, abdominal pain, and sometimes an sign) or inflammatory papules over these joints (Gottron’s axonal neuropathy, the rapid evolution of papules). which can clinically simulate Guillain-Barré syndrome.3 102 Only two of the porphyrias Rheumatological Association’s diagnostic exhibit both cutaneous and neurological fea- scheme, whereas polyneuropathy and myositis tures. Variegate (South African) porphyria are not. A diVuse encephalopathy is a frequent typically results in severe photosensitivity with manifestation, as is optic neuropathy. The bullae, scars, erosions, and leather-like thicken- initial presentation if systemic lupus erythema- ing of sun exposed skin. Infrequently, photo- tosus is often a psychosis that develops months sensitivity with some blistering is found in before other aspects of the disorder. Both large coproporphyria. In both of these disorders, and small vessel strokes occur, either as a neurological crises are triggered by a wide vari- manifestation of vasculitis, embolisation from ety of drugs including , car- Libman-Sachs endocarditis, or secondary to a bamazepine, valproic acid, and ergot coagulopathy. There may be an associated alkaloids.102 antiphospholipid syndrome, as described above. Distal axonal neuropathy, mononeuritis PELLAGRA AND HERITABLE NEUROCUTANEOUS multiplex, myopathy, and myasthenia gravis DISORDERS WITH SIMILAR RASH occur less often. Pellagra is a chronic wasting neurocutaneous disorder characterised by dermatitis, dementia, DERMATOMYOSITIS and diarrhoea. It results from niacin (a B vita- Dermatomyositis is a distinctive disorder in min that can be synthesised from large quanti- which myositis and dermatitis usually coexist, ties of dietary tryptophan) deficiency. Both but both are suYciently distinctive to permit niacin and tryptophan are in short supply in accurate diagnosis in the absence of the other. maize. The rash is characteristically symmetric, The characteristic dermatological manifesta- hyperkeratotic, hyperpigmented, and desqau- http://jnnp.bmj.com/ tion is photosensitivity. In addition to the char- mated in sun exposed areas.103 acteristic heliotrope rash of the eyelids, a pho- A similar rash occurs intermittently during tosensitive erythematous rash often develops bouts of metabolic encephalopathy in two dis- over sun exposed areas: malar, the “shawl” of tinct autosomal recessive disorders: Hartnup the neck and shoulders, and the exposed ante- disease,3 a mild disorder resulting from altered rior “V” of the chest. Unlike in systemic lupus transport of tryptophan and other neutral erythematosus, there is a tendency for the amino acids that aVects some 1/14 000 eczematous rash to localise over knuckles, people104 with emotional instability and inter- on October 2, 2021 by guest. Protected copyright. malleoli, and other joints (fig 8). In about two mittent ataxia that occasionally progresses to thirds of paediatric cases, there is also sub- stupor, and hydroxykynureninuria105 a very cutaneous calcification. There can also be peri- rare, severe aZiction of tryptophan metabolism orbital and perioral oedema and cicatricial alo- in which episodic metabolic crises are superim- pecia. Sometimes the characteristic cutaneous posed on a congenital encephalopathy with photosensitivity occurs in the absence of marked hypertonia and deafness. A pellagra- myositis.97 like rash can also occur in the Contrary to popular thinking, dermatomy- syndrome, in which tryptophan is catabolised ositis is not “polymyositis with a rash.” Both at abnormally high rates. disorders are rare with a combined annual incidence of 1/100 000. Although a subacute or AND OTHER insidious steroid responsive proximal myopa- DISORDERS OF DNA REPAIR thy is common to both, dermatomyositis is dis- Xeroderma pigmentosum3 is a rare condition tinct from polymyositis. Histologically, der- aVecting about 1/100 000 people. However, the matomyositis is a vasculitis, with perimysial insights provided by this and related autosomal and perivascular infiltration by CD4+ T cells recessive neurocutaneous syndromes make and B cells, unlike the endomysial infiltration their heuristic value greater than their by CD8+ T cells and typical of frequency. The hallmark of xeroderma pig- polymyositis.98 99 Furthermore, each disease is mentosum is extreme sensitivity to sunlight associated with a characteristic HLA genotype with progressive atrophy of the skin, irregular 428 Hurko, Provost J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.4.417 on 1 April 1999. Downloaded from

pigmentation, telangiectasias, keratoacantho- fair skinned people, there is evidence for other mas, , and high onset of skin genetic susceptibility factors.112 Primary tu- cancer, including melanoma, basal cell, and mours of the CNS are seen in increased squamous cell carcinomas. It is genetically frequency in family members of probands with heterogeneous, as was originally suspected cutaneous melanoma.113 The melanoma- from complementation studies of DNA repair syndrome segregates as an auto- with fibroblasts from aVected patients. Patients somal dominant trait.114 are also in some complementation groups,106 although seen in association with more complex neuro- not others, have progressive degeneration of cutaneous syndromes, such as xeroderma the nervous system: characteristically spastic pigmentosum. In the rare neurocutaneous ataxia, often associated with microcephaly, melanosis syndrome malignant transformation peripheral neuropathy, dementia, chore- of a hypermelanotic leptomeninges leads to oathetosis and sensorineural deafness. Some of death in childhood.115 these patients had previously been described as having the De Sanctis-Cacchione syndrome, a Summary term that has outlived its usefulness and is As knowledge of pathophysiology grows, so best abandoned. One form of xeroderma does the refinement of diagnoses. Sometimes pigmentosum (complementation group G) is increased knowledge permits consolidation allelic with phenotypically distinct Cockayne and unification. Unfortunately, at our present syndrome,107 108 characterised by a triad of pre- level of understanding, it usually demands pro- cocious senility beginning in infancy, salt and liferation of diagnostic categories. As tedious as pepper retinopathy with optic atrophy and sen- this diagnostic splintering may seem, such is sorineural deafness, as well as photosensitive the price currently exacted of both the investi- dermatitis. Neurological deficits in Cockayne gator and the clinician who seek to optimise syndrome include dementia, peripheral neu- management. ropathy as well as ataxia. Increased diagnostic refinement often re- is itself genetically heterogeneous. Other com- quires inquiry into matters outside the bounds plementation groups of xeroderma pigmento- of one’s specialty. Most often we turn to the sum (B and D) are allelic with trichothiodys- radiologist or to the laboratory to narrow the trophy, a syndrome with brittle hair and nails, diVerential diagnosis generated from the his- as well as photosensitive ichthyotic skin and tory and neurological examination. As we have mental retardation.109 shown, a useful intermediate step is extension However, photosensitivity is not a feature of of the to organs such as all neurocutaneous disorders associated with the skin, which are not the traditional preserve defects in DNA repair. In ataxia of the neurologist. That any text could confer telangiectasia,366 cutaneous findings are lim- the sophistication required for expert dermato- ited to the diagnostic oculocutaneous tel- logical diagnosis is an unrealistic expectation. angiectasias that appear after the development However, we hope that this review will encour- of oculomotor apraxia and ataxia.110 Severe age careful examination of the skin, hair, and progressive neurodegeneration leads to chore- nails by the neurological practitioner, with oathetosis and peripheral neuropathy. 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