Cutaneous Manifestations and Neurological Diseases

Our skin and nervous system are tightly connected. Numerous dermatomes on our skin provide sensory information to the brain. Because skin changes can occasionally be the first sign of a neurological problem, understanding skin alterations is crucial as it can indicate early about the underlying condition, which can affect the prognosis of the disease. In these cases, the dermatologists' and neurologists' skills are complementary to each other. In this article, we have categorized diseases with neuro-cutaneous manifestations under different headings, such as infections, metabolic diseases, connective tissue disorders, genodermatoses, nutritional deficiency, and the diagnostic criteria of some commonly encountered diseases. Through tabulation, it has been observed that this categorization can serve as a useful reference for managing day-to-day patients who are either diagnosed with the diseases mentioned above or suspected to have the conditions.


Introduction And Background
The central nervous system and skin are intimately linked.There are many diseases which involve the nervous system and the skin simultaneously.In these cases, the dermatologists' and neurologists' skills are complementary to each other.The neural crest gives rise to melanocytes, an essential skin component, and has similar embryonic origins to the nerve tissues found in the brain and spinal cord.Cutaneous dermatomes receive sensory input from C fibers, alpha fibers, beta fibers, and delta fibers, which end in the sensory apparatus of the skin.The eccrine sweat gland, hypodermic vascular tone, and piloerection are all under the control of sympathetic and parasympathetic nerves.Numerous central and peripheral nervous disorders have cutaneous symptoms of neurology and neuroendocrinology that are clinically relevant and may be physiologically significant [1][2][3][4].

Review Methodology
The following keywords were used in Embase, Scopus, Cochrane, Google Scholar, and advanced PubMed searches: cutaneous, genodermatosis, neurocutaneous, and neurological disorders.The search yielded 437 articles, of which 76 research publications were selected for research.The methodology of the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) method is shown in Figure 1.Genodermatoses, such as neurofibromatosis, tuberous sclerosis, and ataxia-telangiectasia, may present cutaneous manifestations followed by systemic manifestations.This necessitates that neurologists, physicians, and dermatologists be well-versed in these conditions.Upon reviewing the literature, we attempted to categorize a few common conditions into groups: infections, metabolic diseases, connective tissue disorders, genodermatoses, and nutritional deficiencies.These categorizations are as follows: a) Infections, cutaneous and neurological manifestations, b) Metabolic diseases, cutaneous and neurological manifestations, c) Connective tissue disorders, cutaneous and neurological manifestations, d) Genodermatoses, Café au lait cutaneous lesions and neurological manifestations, e) Nutritional deficiencies, cutaneous and neurological manifestations.As a dermatologist, the disorders encountered daily in the OPD are listed below.These can be diagnosed through their clinical features and additional diagnostic methods, as outlined below.
Various tests for the varicella-zoster virus are utilized, including detecting IgM antibodies specific to varicella-zoster in the blood and observing multinucleated giant cells on the Tzanck smear of vesicular fluid.Additional methods involve polymerase chain reaction testing of vesicular fluid and direct fluorescent antibody testing [7][8][9][10][11].

Leptospirosis
Skin manifestations in leptospirosis largely result from vasculitis, where the inflammation of small blood vessels precipitates skin hemorrhages and petechiae.Diagnosis might involve a variety of tests; the microscopic agglutination test is one primary method.Further, comprehensive blood work may encompass renal and liver function tests, a complete blood count, and coagulation studies.Cerebrospinal fluid can be analyzed, typically obtained via a lumbar puncture, especially when aseptic meningitis is suspected in the immunological phase.Additionally, due to the potential involvement of numerous organ systems, chest Xrays might also be requisitioned to provide a thorough assessment of the patient's condition [12][13][14][15][16][17][18][19][20].

Syphilis
Dark-field microscopy and serological tests are utilized for diagnosing syphilis, with the latter being bifurcated into treponemal and non-treponemal types.The non-treponemal assays, such as the rapid plasma reagin test (RPR) and venereal disease research laboratory test (VDRL), are screening tests that look for antibodies to cardiolipin in blood but lack specificity for syphilis.A treponemal test that identifies particular serum antibodies to Treponema pallidum must be used to confirm positive non-treponemal testing.Notable examples of these tests include the fluorescent treponemal antibody absorption assay (FTA-ABS) and Treponema pallidum particle agglutination assay (TP-PA) [21][22][23][24][25][26][27].

Tuberculosis
The Mantoux test, involving skin testing with PPD, is a customary diagnostic approach for tuberculosis.In all cases when a screening test is positive, a chest x-ray is advised to either rule out or confirm the existence of active illness.Additional diagnostic and confirmatory tests, such as Ziehl-Neelsen Acid Fast Staining and culture, are also pivotal.The advent of Nuclear Amplification and Gene-Based Tests, which employ Deoxyribonucleic acid-based molecular techniques to detect the bacteria or its particles, marks the latest advancements in tuberculosis testing.Notable among these are the GeneXpert and tests for Drug-resistant Mycobacterium tuberculosis.The newest molecular-based procedures are quicker and allow for precise, quick diagnosis.According to histopathology, the granuloma is recognized as the histological hallmark of tuberculosis [27][28][29][30][31][32][33][34][35].

Diabetes Mellitus
The American Diabetes Association (ADA) establishes that a diabetes diagnosis can be confirmed through any of the following criteria: an HbA1c (glycated hemoglobin) level of 6.5% or higher; a fasting plasma glucose level of 126 milligrams per deciliter (mg/dL) or 7.0 millimoles per liter (mmol/L) or greater, ensuring no caloric intake for at least eight hours; a 75-gram oral glucose tolerance test revealing a two-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher.Additionally, a patient exhibiting symptoms of hyperglycemia (such as excessive thirst, frequent urination, insatiable hunger, and weight loss) or undergoing a hyperglycemic crisis, with a random plasma glucose measurement of 200 mg/dL (11.1 mmol/L) or above, can be diagnosed with diabetes [42].

Arsenic Poisoning
A history of acute gastroenteritis followed by hypotension, as well as a risk of occupational or environmental hazards, should make practitioners more cautious.Signs of persistent exposure may include hyperpigmentation, peripheral neuropathy, or recurrent gastroenteritis.A higher-than-normal arsenic level in a 24-hour urine collection is the best sign of arsenic exposure.Urine testing on the spot is potential in emergencies.Arsenic exposure is considered to have occurred at a concentration of 50 micrograms/liter or more.In cases of unknown chronic exposure, hair and nail clippings should be collected for laboratory investigation [43][44][45][46][47].

Systemic Lupus Erythematosus
Manifestations of systemic lupus erythematosus are due to immune complex deposition and subsequent inflammation.Diagnosis and classification of SLE typically require meeting at least four out of the eleven criteria stipulated by the 1997 American College of Rheumatology.It is identified based on a combination of signs and symptoms, indicators, and relevant laboratory tests.Additionally, histology and imaging are important.Key indicators can include malar rash, Raynaud's phenomenon, photosensitivity, oral/nasal ulcers, discoid rash, alopecia, non-erosive arthritis in two or more peripheral joints, and serositis (pleura or pericardium inflammation).Additionally, renal disease (evidenced by daily proteinuria exceeding 500 milligrams or cellular casts), hematologic abnormalities (such as a platelet count under 100,000/cubic millimeter in the absence of platelet-lowering drugs, or a white blood cell count under 4,000/cubic millimeter on two or more occasions), seizures, and psychosis without alternative explanation can also be indicative.Immunologic conditions might involve the presence of antiphospholipid antibodies, determined by either an abnormal serum level of IgM or IgG anticardiolipin antibodies, a positive test result for lupus anticoagulant, anti-deoxyribonucleic acid antibody, or anti-Smith antibody, or a false-positive syphilis test using the Venereal Disease Research Laboratory test or rapid plasma reagin.Moreover, antinuclear antibody positivity must be established in the absence of medications known to induce drug-induced lupus [48][49][50][51][52][53][54].

Rheumatoid Arthritis
The 2010 diagnostic criteria for rheumatoid arthritis, outlined by the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR), encompass four distinct domains.The size of the affected joints: one to three small joints equal to two points (metacarpophalangeal joints, second to fifth metatarsophalangeal joints, proximal and thumb interphalangeal joints, and wrists), four to ten small joints equal to three points (ankles, knee, hip, shoulder, elbow), more than 10 joints, plus at least one minor joint, equals five points.Serological testing for anti-citrullinated peptide/protein antibodies or rheumatoid factor is assigned two points for a low positive and three points for a high positive.Raised erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) equals one point.Lastly, a minimum of six weeks of symptoms equals one point.The patient is diagnosed as having rheumatoid arthritis if their total score is equal to or greater than six [54][55][56][57][58][59][60][61][62][63][64][65].

Neurofibromatosis 1
The abnormal growth of neural crest-derived cells is thought to be the cause behind these manifestations of neurofibromatosis 1.To diagnose according to the accepted clinical National Institutes of Health (NIH) criteria, at least two or more of the following conditions must be met: six or more café-au-lait macules, ranging from five to fifteen millimeters in maximum diameter; at least one plexiform neurofibroma or two or more neurofibromas of any type; freckling in the inguinal or axillary regions; optical gliomas; a minimum of two Lisch nodules; bony lesions, such as pseudoarthrosis or sphenoid dysplasia; and a first-degree relative with the condition [66].The following is a list of the Revised Diagnostic Criteria issued in 2021.The following should be present in a patient without any family history in two or more cases: six or more café au lait macules measuring over 5 mm before puberty and over 15 mm after; freckling in the inguinal or axillary regions; one plexiform neurofibroma or two or more neurofibromas of any type; an optic nerve pathway tumor; two or more iris choroidal anomalies; a distinct osseous condition, like pseudoarthrosis of a long bone, tibial bowing, or sphenoid dysplasia; or a hazardous Neurofibromatosis 1 variant.For a child with a supportive family history, only one or more of the conditions in section A need to be present [67][68][69][70][71].

Pellagra
To validate the findings, laboratory testing, including measurements of tryptophan, nicotinamide adenine dinucleotide phosphate, and niacin levels, should be carried out.The diagnosis of pellagra is based on the patient's therapeutic response to niacin treatment and the characteristic symptoms [72].

Vitamin B12
A complete blood count, along with a peripheral smear, serum B12, and serum folate levels, serve as indicators for vitamin B12.Once a B12 deficiency is confirmed, its cause must be identified and addressed.In cases of B12 insufficiency, serum methylmalonic acid and serum homocysteine should be elevated.Moreover, these laboratory findings can assist in differentiating between a folate deficiency and a B12 deficiency.In the context of folate insufficiency, homocysteine levels are elevated, while methylmalonic acid levels remain normal [73][74][75][76].
All cutaneous and neurological manifestations are summarized in Table 1

Conclusions
The article explores the intricate relationship between the skin and the nervous system.It underscores the significance of recognizing dermatological changes as potential indicators of underlying neurological conditions.This understanding is paramount for early diagnosis and prognosis, bridging the expertise of dermatologists and neurologists.The review methodically categorizes diseases with neuro-cutaneous manifestations, encompassing infections, metabolic disorders, connective tissue abnormalities, genodermatoses, and nutritional deficiencies.This categorization provides a valuable reference tool for healthcare professionals dealing with patients exhibiting symptoms in these domains.However, it is worth noting that while this article provides a solid foundation for understanding neuro-cutaneous diseases, further research and clinical studies are needed to expand our knowledge in this field.More detailed insights into the mechanisms underlying these conditions, as well as advancements in diagnostic tools and treatment options, would enhance the depth of this article.Furthermore, the article delves into the diagnostic criteria for several commonly encountered diseases.It elucidates the diagnostic processes for conditions such as herpes zoster, leptospirosis, syphilis, tuberculosis, primary amyloidosis, diabetes mellitus, arsenic poisoning, systemic lupus erythematosus, rheumatoid arthritis, neurofibromatosis 1, pellagra, and vitamin B12 deficiency.While these diagnostic criteria serve as valuable guidelines, ongoing research may refine and expand upon these parameters, leading to even more accurate and efficient diagnoses in the future.
In essence, this article serves as a strong foundation for understanding the intersection of dermatology and neurology.However, it also highlights the need for continuous research and clinical advancements to improve our knowledge and ultimately enhance patient care in this critical medical field.

FIGURE 1 :
FIGURE 1: PRISMA model for search strategy.PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses. .