http://www.heparininducedthrombocytopenia.com/ Royal College of Obstetricians and Gynecolog ists: http://www.rcog.org.uk See also Renal replacement therapies in acute kidney injury, p. 328 Hemodialysis, hemo \201 ltratio n, and hemodia \201 ltration, p. 494 CKD in pregnant women, p. 476 S GUPTA & G. JOHNSTON 450 Dermatologic disorders in chronic kidney disease \200 \200 Introduction Cutaneous disorders are common in patients with ESRD, 50 \200\223100% of patie nts having at least one dermatologic con- dition. By contrast, skin changes are rare in acu te kidney injury (AKI). Improvements in early diagnosis and treat- ment of renal disease me an that some dermatologic condi- tions such as uremic frost are now rarely seen. possible increase in tissue mast cells; dryness of skin is a contributing factor but not so le cause; correlation with predialysis blood urea levels not estab- lished; an increase in dialysis dose may not improve symptoms; possible correlation with hyperphosphatemia due to secondary hyperparathyroidism but symptoms may recur after subtotal parathyroidectomy. Anemia Pallor of the skin and conjunctivae is a common early cuta- neous sign in ESRD. Deve lopment of anemia in CKD is multifactorial: \200 \200 \200 \200 Treatment Dif \201 cult. A long list of published treatment options bears witness to the l ack of a consistently effective therapy. anemia of chronic disease; decreased erythropoiesis; increased hemolysis; significant reduc tion in cutaneous blood flow on dialysis. General measures \200 \200 \200 \200 Removal of cause, where possible. Paraf \201 n-based emollients. Topical steroids. Physica l methods to cool the skin, including use of cot- ton clothing and avoidance of wool. Treatment involves the use of: \200 \200 erythropoetin; IV iron dextran. Speci \201 c measures \200 \200 \200 \200 \200 Phototherapy (narrow band Ultraviolet B). Oral cholestyramine and activated charcoal. Thali domide. Erythropoetin. Opioid antagonists: based on reports of elevated plasma levels of op ioid peptides and serotonin (e.g. oral naltrex- one, oral ondansetron). Lowering magnesium concentration of dialyzate may help. Cutaneous hyperpigmentation Occurs in 25 \200\22370% of patients on dialysis with incidence increasing with duration of renal disease. It is seen equally in hemodialysis (HD) and per itoneal dialy- sis (PD) patients although a yellowish hue is more preva- lent in patients o n HD. Patients have a distinctive gray-yellow hue with diffuse hyperpigmentation of sun-exp osed skin. Purpura This is a common cutaneous \201 nding in ESRD especially in those patients on HD. Patients may have: \200 \200 \200 Etiology \200 Deposition of melanin (possibly due to impaired renal processing of melanocyte-stimulating hormone, MSH). Accumulation of carotenoid and nitrogenous pigments in dermis. petechiae or ecchymoses (bruising); mucosal bleeding; also re \202 ected in poor wound hea ling in dialysis patients. Dry skin (xerosis) 50 \200\22375% of dialysis population have excessively dry skin. The inc idence of xerosis in patients with CKD is unknown. Patients will have dry roughened skin, s ometimes with \201 ne scaling. Etiology \200 \200 Mild thrombocytopenia and platelet dysfunction. Malnutrition. Half-and-half nails These will be present in up to 50% of patients with ESRD. The incidence increases with duration of dialysis. It is more prevalent in patients on HD. Patients have whitish or normal-colored proximal portion of the nail plate, with abnormally brown/red di stal portion. Latter comprises more than one-third of nail plate. Etiology \200 \200 \200 Reduction in the size of eccrine sweat glands. High dose diuretic treatment. Fluid restrict ion. Treatment \200 \200 \200 Regular use of paraf \201 n-based bland emollients. Urea-containing emollients. Emollient- based soap substitutes. Etiology An increased level of MSH causes increased melanin pig- ment within the nail plate . Pruritus Clinically signi \201 cant pruritus affects 50 \200\22390% of the dialysis popula tion and is more prevalent in patients on HD. Pruritus is unusual in AKI. Treatment There is no speci \201 c treatment but it may disappear with successful renal tr ansplantation. Etiology Exact pathogenesis is unknown and likely to be multi- factorial: \200 Skin cancer Squamous cell and basal cell carcinomas are the common- est types of skin cance rs seen in CKD and ESRD. patients receiving dialysis with less permeable mem- branes experience more severe pruritus ; CHAPTER 11.13 Dermatologic disorders in chronic kidney disease 451 Cutaneous calci \201 cation Benign nodular calci \201 cation is not uncommon and devel- o ps in the setting of CKD complicated by prolonged sec- ondary and tertiary hyperparathyroid ism. Large calcium deposits may be found in the skin and subcu- taneous tissue, particularl y periarticular sites. The number and size correlate with severity of hyperphos- phatemia. It is usually asymptomatic except for the pressure they can place on surrounding structures . The incidence rises with increased time on dialysis. Lesions are distinct from the multiple dysplastic and frankly malignant skin lesions which can develop in the immuno- suppressed patient with a renal transplant. Clinical features Excessive wrinkling and yellowing of skin, especially over the neck. Seni le lentigines (liver spots, age spots). Vascular dilatations (telangiectases). Actinic kera toses: \200 \200 Etiology Disruption of normal calcium regulatory pathways can lead to \200\230metastatic \200\231 calci \201 cation and/or ossi \201 cation of skin: \200 \200 \200 precancerous lesions; red spots with a rough surface (easier to feel (rough) than see); fou nd on sun-exposed surfaces. impaired renal phosphate clearance; impaired synthesis of 1,25-(OH) vitamin D3; decreased a bsorption of calcium from intestine with resulting hypocalcemia; increased parathyroid horm one and mobilization of calcium and phosphate from bone; solubility product of calcium \227 phosphate exceeded. Nonhealing enlarging skin lesions suggest cancer. Etiology Acceleration of cutaneous aging is a function of time on dialysis. Individuals at higher risk include: \200 \200 \200 \200 \200 fair skin that burns easily; light-colored eyes; red hair; numerous freckles; past history of heavy sun exposure. Treatment Phosphate binders. Surgical excision of symptomatic lesions. Calciphylaxis Vascular calci \201 cation is a common incidental \201 nding in ESRD. Rare ly vascular calci \201 cation may lead to cutaneous necro- sis or gangrene as a result of thrombosed vessels, an entity known as calciphylaxis (calci \201 c uremic syndrome). In co ntrast to benign nodular calci \201 cation, this condition is a medical emergency and carr ies a poor prognosis. 1 \200\2234% of patients with ESRD develop calciphylaxis. Incidence h as increased over the last decade, possibly due to the increased use of parenteral vitamin D and iron dextran. It is more common in: \200 \200 \200 \200 \200 Treatment Sun protection advice Prevention is the best course of action: \200 cover up with sun hat, long sleeves and trousers in sunny weather; stay in shade particular ly between 11:00 and 15:00; apply sun-block of sun protection factor (SPF) \211 25 every 3 h; do not use sunbeds. \200 Active management Excision of suspected skin tumors under local anesthetic. Cryotherapy (fr eezing the lesion with liquid nitrogen). Topical 5- \202 uorouracil or imiquimod cream. Ph otodynamic therapy. Reduce/stop immunosuppression in aggressive skin cancers. females (3:1); Caucasians; diabetics; obese; longstanding ESRD and renal replacement therap y. Lesions develop suddenly and progress rapidly. Early lesions appear as violaceous mottling, livedo reticula- ris or erythematous purpuric papules. Later, lesions have a stellate purp uric con \201 guration with central cutaneous ulceration and necrosis. Less commonly, lesi ons present as blisters or subcutaneous erythematous nodules. Intense pain is a constant \201 nding. 90% of lesions occur on lower extremities. More proximal lesions occur in 44 \200\22368% of cases, predomi- nantly on thighs, buttocks and lower abdomen. Multiple lesio ns of variable age may be present. Visceral involvement is not uncommon. Intact pulses help distinguish calciphylaxis from atheroscle- rotic peripheral vascular disease. Hypertrichosis lanuginosa This is a common \201 nding in patients with CKD and ESRD. Ther e is a uniform increase in growth of \201 ne hair over the cheeks and thickening of the e yebrows. The etiology is unknown. Some cases are iatrogenic: \200 \200 \200 corticosteroids; ciclosporin; penicillamine. Uremic neuropathy and neuropathic skin ulcers Up to 60% of patients with ESRD or on long-te rm HD develop some degree of peripheral neuropathy. Neuropathy is mainly sensorimotor and c an lead to pres- sure ulcers. This will be compounded in patients with ESRD due to conditio ns independently associated with development of peripheral neuropathy, e.g. diabetes and am yloidosis. S GUPTA & G. JOHNSTON 452 Etiology Reported triggering factors include: \200 recent and sudden weight loss; \200 infusion of medications such as iron dextran, corticos- teroids; concurrent use of warfarin . Allopurinol: xanthine oxidase inhibitor. Partial/complete resolution of tophi when serum ur ic acid normalized. Cryotherapy, intralesional corticosteroids or surgical exci- sion of in dividual symptomatic tophi. Secondary oxalosis (hyperoxaluria) Insoluble calcium oxalate may be deposited in the skin a nd other organs in CKD and ESRD, particularly in those patients on long-term HD. Tiny mille t seed-like (miliary) deposits can be found on \201 n- gers and palmar surfaces. Livedo r eticularis with peripheral cyanosis is rare. Investigations Parathyroid hormone is usually markedly elevated. Serum calcium, phosphate a nd calcium \227 phosphate are likely to be high. Skin biopsy shows nonspeci \201 c change s with calcium depo- sition in vessel walls. There is risk of subsequent ulceration at biop sy site. Investigations Serum oxalate levels. Skin biopsy shows birefringent crystals in vessel wall s. Treatment Analgesia. Urgent normalization of serum calcium and phosphate, which may require daily dialysis. Careful wound care and aggressive treatment of wound infection lowers risk of systemic sepsis. Surgical debridement of necrotic painful lesions. Parathyroidectomy. A necdotal success has been reported with hyperbaric oxy- gen and low calcium dialysis. Treatment Where possible improvements in hydration and urine alka- linization may be bene \201 cial. Arteriovenous \201 stula Cutaneous complications affecting the limb in which the hemodial ysis AV \201 stula is situated include: \200 \200 \200 \200 infection; phlebitis; hematoma; irritant and contact allergic dermatitis. Secondary hyperuricemia (gout) This may present as: \200 \200 acute monoarthritis; tophi in chronic gout. Venous hypertension syndrome, with or without ulcera- tion, together with pseudo-Kaposi \200\231s sarcoma is rare. Acute monoarthritis: \200 \200 Acquired perforating dermatoses This can occur in up to 10% of patients on HD. It is more c ommon in African-Americans. Patients develop hyperkeratotic papules or nodules 1 \200\22310 mm diameter, often umbilicated with central crust- \201 lled crater. There is a linear o r serpiginous distribution on trunk and extensor surfaces. The face and scalp are rarely af fected. Spontaneous resolution can occur along with development of new lesions. most commonly in the great toe; affected joint; warm, swollen, erythematous and very painfu l. Tophaceous gout: \200 \201 rm asymptomatic dermal or subcutaneous nodules or fusiform swelling; painful ulcerat ion may occur; commonly affects helix or antihelix of ear, along ulnar surface of forearm a nd index \201 ngers and olecranon bursa (other tissues in <10% cases). \200 There is male predominance. Prevalence increases with obesity, diabetes mellitus and alcoho l consumption. Etiology It is associated with ESRD and diabetes mellitus. Proposed mechanisms include: \200 diabetic microangiopathy; \200 dysregulation of vitamin A or D metabolism; \200 a bnormality of collagen or elastic \201 bers; \200 in \202 ammation and connective tiss ue degradation caused by dermal deposition of substances such as uric acid and calcium pyro phosphate. Etiology Decreased excretion of uric acid occurs secondary to diu- retic therapy and CKD. I n some renal disorders, e.g. medullary cystic disease and chronic lead nephropathy, hyperur icemia may occur with minimal renal insuf \201 ciency. Investigations Serum uric acid levels are raised during an acute attack. Joint aspiration m ay be diagnostic in acute gout; sodium urate crystals show positive birefringence under pol arized light. Joint X-ray: subcortical cysts, calci \201 cation in pseudogout. Histologica l examination of tophi if diagnosis in doubt. Investigations Skin biopsy shows transepidermal elimination of both col- lagen and elastic \201 bers. Treatment Potent topical or intralesional steroids. Cryotherapy. Phototherapy. Systemic ret inoids. Treatment for chronic gout Low purine diet: avoid meat, poultry, \201 sh, seafood, alcoho l, beans and peas. CHAPTER 11.13 Dermatologic disorders in chronic kidney disease 453 Nephrogenic \201 brosing dermopathy (NFD) This is a progressive \201 brosing condition associated with the use of gadolinium-containing contrast used in MRI. It is rare. It has m ainly been described in patients with ESRD, mostly on long-term HD, but has been reported i n AKI. Red indurated plaques develop over weeks leading to extensive thickened skin with a \200\230woody texture \200\231. It starts at extremities with progressive involvement of t he trunk. The face and neck are usually spared. Flexion of adjacent joints is inhibited. Pr uritus is common. Systemic involvement of lung, myocardium, striated muscle have been repor ted. It may be seen in patients with advanced CKD not on dialysis. The reported prevalence is 1 \200\22318% in patients on HD. Etiology This is unclear. Possible mechanisms include: \200 phototoxic reaction or inadequate excretion of porphyrins; HD patients may produce or be ex posed to compounds altering normal heme synthesis; drugs including tetracyclines, nabumeton e, nalidixic acid, naproxen, frusemide and phenytoin. Investigations Serum, urine and stool porphyrins normal (unlike PCT). Skin biopsy shows sub epidermal separation. Treatment Sun-protection advice. Phlebotomy and IV erythropoetin (patients likely to have c oncurrent anemia and may not tolerate phlebotomy). Renal transplantation leads to complete resolution. Etiology This is unknown. Recombinant erythropoetin has \201 brogenic properties and it h as been suggested may play a role. Investigations Skin biopsy shows: \200 Further reading Abdelbaqi-Salhab M, et al. A current review of cutaneous manifesta- proliferation of \201 broblasts in dermis and subcutaneous septae; increased dermal and s eptal collagen and mucin detected by Alcian Blue stain; absence of in \202 ammatory cell i n \201 ltrate. tions of renal disease. J Cutan Pathol 2003; 30: 527 \200\223538. Avermaete A, et al. Skin changes in dialysis patients: a review. Nephrol Dial Transplant 2001; 16: 2293 \200\2232296. Johnston GA, Graham-Brown RAC. The skin and disorders of the alimentary tract, the hepatobi liary, kidney and cardiopulmonary systems. In: Wolff K, Goldsmith L, Katz S, Gilchrest B, P aller A, Leffel D (eds), Fitzpatrick \200\231s dermatology in general medicine, 7th edn. Ne w York: McGraw-Hill. pp. 1445 \200\2231460. Treatment Improvements have been reported with correction of renal failure following renal transplantation. Decreasing erythropoetin dose may ameliorate (but not cure) the condition. Phototherapy and plasma exchange have been reported in the literature but there is insuf \201 cient evidence to recom- mend these at present. Internet resources British Association of Dermatologists has a number of use- ful patient i nformation lea \202 ets: www.bad.org.uk International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR): Bullous disease of HD (pseudoporphyria) This resembles porphyria cutanea tarda (PCT) with m echanical skin fragility and crops of delicate blisters or crusted erosions on sun-exposed areas (hands and face). Incidental trauma may precede lesions. Atrophic scarring, milia and hyperpigmentation may also be seen. http://www.pathmax.com/dermweb/ See also Medical management of dialysis patients, p. 528 T. FRIEDMAN AND P. RAO 454 Neuropsychiatric disorders in chronic kidney disease In this chapter the common neuropsychiatric manifesta- tions of renal failure, and related issues, are discussed. Electrophysiology studies show reduced conduction velocities. Histology reveals axonal dege neration in distal nerve trunks. Myelin sheaths may appear normal on transverse electron mi croscopy but splitting of myelin lamella may be noted. Peripheral neuropathy Renal failure results in neurological dysfunction due to uremia. Peri pheral neuropathy is a common complication of ESRD and is usually a uremic neuropathy, alth ough other causes of neuropathy such as ethanol-related neuropathy, chronic in \202 ammato ry demyelinating polyradiculoneuropathy, and diabetic neuropathy should be borne in mind. Management Management is essentially focused on ensuring adequate dialysis. Vitamin supplem ents have been used but have not been shown to be consistently bene \201 cial. Tricyclic a ntidepressants (amitryptiline, nortriptyline) and anticonvulsants such as gabapentin can be used for symp- tomatic relief of neuropathic pain. Care must be taken if prescribing high doses due to the underlying renal insuf \201 - ciency as well as cardiac adverse effects o f the medications themselves. Local anesthetics such as lidocaine may be bene \201 cial by stabilizing neuronal membranes and thus decreasing pain intensity. The use of high \202 ux dialyser membranes and alteration of hemodialysis schedules have been studied but have n ot been shown to be consistently bene \201 cial. Renal transplantation, especially if perf ormed early in the course of the neuropathy, has been shown to be effective. All but the mo st severe cases are usually reversed. Epidemiology There is a widely variable prevalence ranging from 10 to 100% (commonly accept ed \201 gure of 60 \200\22365%). It is more common in females. It can occur at any age bu t is uncommon in children. It usually develops below GFR of 12 mL/min, and the severity is moderately correlated with the severity of renal insuf \201 ciency. Pathogenesis Uremia is the common denominator and pathological changes are similar to other neuropathies. The exact mechanism is unknown although there are many theories. The search for a speci \201 c uremic neurotoxin remains elu- sive. Urea, creatinine, guanidine, methy lguanidine, guanidi- nosuccinic acid, uric acid, oxalic acid and a host of other substances have been proposed. The \200\230middle molecule hypothesis \200\231 postulates that there may be accumulation of slowly dialyzable neurotoxic mol- ecules of molecular weight 300 \200\2232000 Da. Newer research attributes an important role to K+ (chronic hyperkalemic de polarization) necessitating the need to maintain the serum K+ within normal limits. Clinica l features Uremic neuropathy presents as a symmetric distal sensori- motor polyneuropathy w ith greater lower limb involve- ment. It is usually of insidious onset, with progression ov er months. Clinical features include: \200 \200 \200 \200 \200 Myopathy Most patients with ESRD have muscle weakness and fatigue. Uremic myopathy refers t o the cluster of functional and occasionally structural muscle abnormalities in patients wi th CKD that may be attributed to the uremic state itself. Epidemiology The incidence of myopathy in CKD is unknown due to the lack of well-conducted studies. Increasing age and female sex are risk factors. The estimated prevalence is 50%. Pathogenesis The pathogenesis is inadequately understood. The \200\230middle molecule hypo thesis \200\231 (toxins incompletely dia- lysed and harmful to muscle) has been postulated. In many cases uremic myopathy is related to secondary hyperparathyroidism and is superimpo sed on osteomala- cia-associated myopathy. tingling and prickling in the lower limbs; paresthesia (commonest and earliest symptom); we akness, muscle wasting; impaired vibration sense; pain that is partly relieved by movement. The clinical features re \202 ect large \201 ber involvement. Mononeuropathies can occur at compression points: median nerve (carpal tunnel syndrome), ulnar nerve or peroneal nerv e. A positive Tinel sign may be present. The vestibulocochlear nerve is the most common cra nial nerve affected and can manifest with variable loss of hear- ing that tends to improve with dialysis. Clinical features Proximal limb weakness and wasting. Easy fatiguability and poor endurance . Functioning is worsened by bone pain and tenderness. Re \202 exes may be impaired due to concomitant neuropathy. Muscle strength is usually impaired (<50% of normal). Investigations These mainly focus on ruling out other causes of neuropathy. Use of imaging has not been shown to be bene \201 cial. Investigations Electromyography (EMG) and serum creatine kinase are normal. CHAPTER 11.14 Neuropsychiatric disorders in chronic kidney disease 455 Muscle biopsy \201 ndings are often nonspeci \201 c but can show \201 ber necrosis. Symptoms include: \200 \200 \200 low mood; easy fatiguability; inability to derive pleasure from activities that were pre- v iously enjoyed; decreased sleep and early morning awakening; decreased appetite and weight loss; diurnal variation of mood; decreased motivation, concentration and self-esteem; ideas of helplessness, hopelessness and worthlessness and suicidal ideations. Management High doses of vitamin D3 have been recommended but have not been shown to be con sistently effective. The condition is less common among well-dialysed patients, suggesting a role for optimization of dialysis adequacy. Successful renal transplantation has been ass ociated with improvement although may not restore full physical work- ing capacity. \200 \200 \200 \200 Autonomic dysfunction Autonomic dysfunction may present as postural hypotension, sweating a nd diarrhea. Sometimes the symptoms may be \200\230understandable \200\231 in the context of the physic al illness but they still deserve assess- ment and treatment. Use of screening questionnair es such as the Beck \200\231s Depression Inventory or General Hospital Questionnaire may be helpful but there is no better screening tool than a good clinical enquiry of symptoms. De pression may worsen at certain stages of the illness, such as at times of diagnosis, clinic al worsening of the con- dition, awareness of poor prognosis or transplant failure. It is i mportant to be more vigilant at these times. Management includes use of antidepressants and psycho- logical therapies such as cognitive behavior therapy (CBT). There is no evidence f or the use of \200\230counseling \200\231 and unfo- cussed therapies have the potential fo r harm. SSRIs are the drugs of choice although dose adjustments may be necessary. Tricyclic antidepressants usually do not require dosage adjustments in renal dysfunction but they ha ve other adverse effects (anticholinergic, sedation) and are not drugs of \201 rst choice . CBT focusses on the \200\230here and now \200\231 and uses techniques such as Socratic q uestioning and behavioral exercises to bring about change. Epidemiology It is more commonly seen in diabetic and elderly patients. It is found in 50% of patients with advanced CKD. Investigations Sympathetic skin responses (SSR) can be assessed with routine EMG equipment. They reveal a delayed or absent sympathetic skin response. Other tests include: \200 \200 \200 plasma noradrenaline levels in response to posture; Thermoregulatory Sweat Test (TST); Quan titative Sensory Testing (QST). Esophageal manometry can also be useful in patients with possible autonomic neuropathy and dysphagia. Management Supportive management includes advice regarding reduc- ing sudden changes in pos ture and recumbent dialysis. Anemia should be avoided. Pharmacologic treatment is attempted when conservative treatment is unsuccessful although results are variable: \200 \200 \200 Midodrine, a selective A1-adrenoreceptor agonist which is metabolized to desglymidodr ine, may be used. It acts by arterioconstriction and venoconstriction. Erythropoetin therap y will not only correct renal anemia but may also increase norepinephrine levels and can be effective. \202 udrocortisone; SSRIs (serotonin reuptake inhibitors); NSAIDs. Bipolar disorder This disorder is characterized by episodes of depression and/or mania. The main issue is usually the safe and effective manage- ment of bipolar illness considering t hat patients may be prescribed lithium and this has the potential to worsen uremia. The dos e of lithium is dif \201 cult to manage in CKD and therefore other mood stabilizers such a s sodium valproate may be used. Close liaison with the treating psychiatrist is essential. Case reports of mania being associated with uremia and improved with dialysis have been pub lished. Psychological dysfunction There is a higher prevalence of psychiatric illnesses in peo- ple suffering from physical disorders when compared to the general population. Studies have co nsistently shown higher rates for admission in patients with comorbid depression, anxiety d isorders, dementia, substance misuse psychoses and personality dis- orders. One has also to be mindful of the stigma that mental ill- nesses continue to have in society. This may res ult in patients hiding their diagnoses or symptoms, resulting in inadequate psychological t reatment, which may in turn in \202 uence the treatment of the physical disorder. Anxiety disorders Anxiety may be related to diagnosis, prognosis or treat- ments such as di alysis and renal transplantation. Patients may also suffer anxiety due to the intimidating environment of a sophisticated renal unit and the complex- ity of treatments required for p rogressive CKD. Some patients may develop a phobia for the unit or the treatment. Others ma y have pre-existing speci \201 c phobic disorders such as needle phobias which may interfe re with treatment. Post-traumatic stress disorder may pre-exist or may develop with the str ess of the illness. Affective disorders Depression Depression is the commonest of the affective disorders assoc iated with CKD. T. FRIEDMAN AND P. RAO 456 The sleep \200\223wake cycle is disrupted in the later stages. The course is \202 uctuati ng and can change over days or even hours. In the later stages delirium may be prominent wi th disorientation, perceptual abnormalities and agitation lead- ing to dif \201 culty in m anagement on the ward. The \201 nal stages are marked by torpor, a semicomatose state and generalized tonic \200\223clonic seizures. Neurological examination reveals increased tone and hyperre \202 exia with tremors (leading to asterixis), ankle clonus and an extensor p lantar response. Deterioration in renal function is associated with increased severity. Oth er contributing factors include electrolyte imbalance and drug toxicity. The pathophysiolog y is not well-de \201 ned although electro- lyte imbalances are a postulated cause. Most c hanges are nonspeci \201 c. Abnormalities of sodium, calcium and magne- sium levels are co mmon. There seems to be little correlation between the level of uraemia and the clinical pr esentation. Imaging is not usually helpful except to rule out other sus- pected causes of a n acute confusional state. Lumbar puncture may reveal aseptic meningitis. EEG shows a gener alized slowing, most prominent in the frontal region. Spike and wave discharges may be pres ent. Treatment is with the careful institution of dialysis to avoid dialysis disequilibrium syndrome. Symptoms such as sluggishness and sleep \200\223wake cycle abnormalities may per sist. Clinical features include physical symptoms such as: \200 \200 \200 \200 palpitations; dizziness; sweating; tremulousness. Psychological symptoms include a sense of impending doom. A careful enquiry must be made of these symptoms as it is easy to subsume them (especially the physical symptoms) under the symptoms of renal failure. Treatment includes both pharmacological measures (such as SSRIs) and psychological measures (such as CBT). Psychoses These are unlikely to be caused by uremia. The important issue is to distinguish \200\230functional \200\231 psychotic symptoms from the symptoms of encephalopathy. It is useful to recognize that visual hallucinations and diso- rientation usually indicate an \200\230organic \200\231 cause. Auditory hallucinations and persistent delusions in clear c onsciousness are indicative of primary psychotic illnesses. It is also important to be awar e that schizoaffective disor- der may be treated by lithium. Antipsychotics such as sulpiri de and amisulpiride are excreted by the kidneys and their dose must be adjusted or they mus t be discontinued altogether depending on the renal function. Cognitive dysfunction Cognitive functioning can be affected by many medical conditions incl uding encephalopathy and cerebrovascular disease. Aluminum accumulation may be a contributi ng factor and other factors suggested include trace metal ions found in the dialyzate inclu ding manganese, cadmium, boron and tin. Uremia can also depress cognitive function and this is partly improved with dialysis. Rapid dialysis may also con- tribute to cognitive dysfun ction. The Mini-Mental State Examination is a good tool to screen for cognitive problems. B edside examination of cortical lobes is also useful. Specialized psychometric tests are ind i- cated for prolonged or severe dif \201 culties. EEG shows bursts of high voltage slowin g and frontal spik- ing in relation to excess aluminum. In dementia, the EEG shows slow wav es. Treatment depends upon the etiology. Commencing dialy- sis or increasing the dialysis d ose has been suggested and there is evidence that correction of anemia with erythro- poieti n therapy may improve cognitive dysfunction. Dialysis disequilibrium syndrome This was \201 rst described when patients were dialysed infre- quently and rapidly, and refers to the development of acute neurological symptoms oc curring during or after intermit- tent dialysis. The incidence is unknown. Risk factors inc lude: \200 \200 \200 \200 severe uremia; \201 rst dialysis; young or old age; pre-existing neurological disease (he ad injury, stroke, malignant hypertension). Symptoms usually occur at the end of or after dialysis. Mild symptoms include: \200 \200 \200 \200 nausea; severe headaches; restlessness; muscle cramps. These can rarely progress to: \200 confusion and delirium; \200 myoclonus; \200 gener alized tonic clonic seizures; \200 cardiac arrhythmias; \200 blurring of vision (due to papilloedema and raised intraocular pressure). Uremic encephalopathy Uremic encephalopathy is an organic brain syndrome seen in advanced C KD. The symptoms are nonspeci \201 c and are seen in a wide range of encephalopathies. Cog nitive symptoms include dif \201 culty with attention and memory. Patients \201 nd it di f \201 cult to perform tasks that require mentation or those that require multiple ideas a t once. Frontal lobe signs and myoclonic jerks may be present. Hallucinosis, paranoid ideat ions, emotional lability can be seen. Autonomic (e.g. dizziness) and neuromuscular disturba nces (e.g. fatigue) are also present. Disequilibrium syndrome is linked to: Rapid changes in the osmotic gradient between the pla sma and the brain. This is especially so with rapid dialysis or in people with severe uremi a. Removal of urea during dialysis occurs slower across the blood \200\223brain barrier tha n from plasma. This generates a \200\230reverse osmotic gradient \200\231 causing CHAPTER 11.14 Neuropsychiatric disorders in chronic kidney disease 457 water movement into the brain leading to cerebral edema. A decrease in cerebral intracellul ar pH by mechanisms that are not completely understood has been proposed as an alternative hypothesis: intracellular acidosis is associated with an increase in unmeasured organic aci ds which increase cerebral osmolality thus leading to cerebral edema. Management is mainly focussed on prevention. Frequent dialysis (every 1 \200\2232 days) of short duration (2 h) using a smaller dialyser will facilitate slow removal of urea. patient starts dialysis) may occur. Clinical manifestations are not speci \201 c and can \202 uctuate. Cognitive impairment can be present. Wernicke \200\231s encephalopathy resul ting from thiamine de \201 - ciency (which may be made worse when the patient starts dialy sis due to thiamine egress during dialysis) can occur. An underlying genetic predisposition , chronic malnutrition with anorexia, and the administration of glucose containing IV \202 uids are contributory factors. The classic triad (oph- thalmoplegia, ataxia and confus ion) is rarely present. Treatment is by thiamine replacement. Early treatment prevents prog ression to Korsakoff \200\231s psychosis which is not amenable to thiamine replacement. Sle ep disorders. The commonest sleep problems reported with CKD are insomnia, restless leg syn drome and exces- sive daytime sleepiness. Other reported syndromes include obstructive slee p apnea syndrome, sleepwalking and nar- colepsy. Uremia is postulated as the common denomin ator and commencement of dialysis may improve symptoms but rarely results in complete resol ution. Dialysis dementia Dialysis dementia, also known as dialysis encephalopathy, is a progressiv e, often diffuse encephalopathy which occurs in some patients on chronic HD. Prevalence is estimated to be 1%. It is equally prevalent among the sexes and different age groups. Comm unication dif \201 culties are often the presenting fea- ture with dysarthria, dysphasia a nd slurred, stuttering speech. This may initially be present only during or after dialysis. Other cognitive signs such as dyslexia, dyspraxia and dys- calculia may be seen. Impairmen t of memory, depression and paranoid ideation may occur. Progression to myoclonus, asterixi s, seizures and personal- ity change may be seen. In the later stages the patient may becom e mute. Death usually occurs within 15 months. EEG abnormalities of bilateral spike and wav e complexes and frontal slow waves are seen, usually about 6 months prior to the onset of s ymptoms. There is a marked slowing of background rhythm. Neuroimaging has not been shown to be diagnostically helpful. Histopathological changes at postmortem are nonspeci \201 c. H istochemically there is significant elevation of brain aluminum content especially in those cases that are geographically clustered. Cerebrospinal \202 uid aluminum concentrations are of no diagnostic bene \201 t, the disorder occurring at widely varying concentrations. Management must focus on prevention by use of alumin- ium-free dialyzates, puri \201 cati on of water, and avoiding die- tary intake of aluminum. Benzodiazepines such as clonazepam and diazepam are effective in controlling myoclonus. Desferroxamine can be used to chelate aluminum and is used in the treatment of established cases. The chelated complex is removed by dialysis. Improvement is slow and treatment may need to be continued for a year. Chelat ion can lead to an initial deterioration that may be progressive and occasionally fatal. Sp oradic dementia not related to aluminum excess is not amenable to chelation treatment. Psychotropic drug use in the patient with failing renal function The common drugs and the i mplications for prescribing in patients with CKD and ESRD are reviewed in Table 11.14.1. Issues of capacity and consent The law (in England and Wales) assumes that all adults have the capacity to make decisions unless otherwise proven. Different laws may apply in other c ountries and the follow- ing are only general principles. Dif \201 culties and ethical dil emmas arise when issues regard- ing extent of capacity arise. Some important concepts to no te are: \200 \200 Capacity is speci \201 c to the planned treatment. Different suggested treatments may requ ire different levels of capacity. Generally more invasive treatments require a greater unde rstanding of risks and bene \201 ts. Capacity may be present to consent for one treatment but not for another even at the same time. Informed consent is the heart of clinical ethics and it is the duty of the treating physici an to satisfy the criteria required and to make an assessment of capacity. The principles o f assessment of capacity can be summa- rized in the following questions: \200 Does my patient understand the information provided regarding the treatment in question? Do es my patient believe the information provided? Does my patient understand the pros and con s of having this treatment versus any other treatment or even no treatment at all? Can my p atient retain the information provided long enough for him/her to make a decision? Can my p atient communicate (not necessarily by verbal means) the decision made? \200 If the answer to any of the above questions is \200\230No \200\231, it usu- ally signi \201 es a lack of capacity. Common law has supported the principles of Best Interests, Nece ssity and Duty of Care in managing patients without capacity. Other disorders Subdural hematomas, either due to an intrinsic coagulopa- thy in uremia (or due to administration of heparin when the T. FRIEDMAN AND P. RAO 458 The above principles hold true for any individual aged >18 years. For those aged <18 years, the law (in England and Wales) is different. Some important principles are: Young people ( <18 years) CAN CONSENT to treatment if they satisfy the requirements of capacity assessment . However, in practice an adult with parental responsibility is usually involved in the dec ision-making process. Young people (<18 years) CANNOT REFUSE to have any treatment if an ad ult with parental responsibility consents, even if the young person ful \201 lls the crite ria for capacity assessment. The decision of the adult with parental respon- sibility usual ly overrides any decision made by the young person. If in doubt, it is appropriate to consu lt with per- sons with experience in the legal aspects as they apply to young persons. If t he patient is deemed not to have capacity, The Mental Capacity Act (2005) (in England and W ales) provides a legal framework for decision-making. The Act also allows adults with capac ity to make decisions in the event of future incapacity in some areas (including refusal of speci \201 c treatments). When a patient is unable to make an autonomous choice, the heal th professional must act in the best interests of the patient. Second opinions are usually appropriate. The Act lays down some principles for acting in the patient \200\231s best interests: \200 