sign in sign up
<<
Home , Paratonia, Tuberous sclerosis

CME

Neurology and renal disorders renal replacement (RRTs) and may resolve completely after successful renal transplantation.3 Osheik Seidi MBBS ABIM MRCP(UK), Neurological problems Consultant Neurologist, Sunderland Royal associated with renal Osmotic demyelination syndromes Hospital and the Regional Neuroscience replacement therapies Centre, Newcastle upon Tyne The osmotic demyelination syndromes Dialysis dysequilibrium syndrome (ODS) complicate treatment of hypo- Clin Med 2007;7:165–70 natraemia in which serum sodium is The dialysis dysequilibrium syndrome is usually less than 120 mmol/l. The a complication of haemodialysis caused commonly recognised type is central by the creation of an osmotic gradient pontine myelinolysis (CPM), although Following the introduction of haemo- between the brain cells and the plasma. extrapontine myelinolysis (EPM) is dialysis and renal transplantation it Rapid clearance of urea and other solutes increasingly reported; the pathogenesis became particularly clear that renal leads to a shift of water into the brain is the same in both types. ODS should be disease may adversely affect the nervous parenchyma with resultant cerebral considered in patients who deteriorate system. A range of neurological manifes- oedema. It presents with headache, neurologically after an illness associated tations of acute (ARF) and chronic renal nausea, vomiting, restlessness, muscle with hyponatraemia or have received a failure (CRF) have been recognised. cramps and confusion. It usually resolves large volume of intravenous fluids even • There are well-known interactions in a few hours after dialysis and is if the imaging is not supportive initially. when systemic disorders such as prevented by slower dialysis. To prevent this serious complication the diabetes or hypertension affect both sodium should not be corrected by more the and the nervous system. Dialysis than 8 mmol/l/day, particularly in • Systemic erythematosus (SLE), chronic hyponatraemia (serum sodium other vasculitides and Dialysis dementia is now seen in- <136 mmol/l for >48 hours). granulomatous disorders commonly frequently (if at all) compared with the CPM presents with brainstem dys- show neurological and renal early years of haemodialysis. It was function, including flaccid tetraparesis complications. linked to an increased level of and occasionally the locked-in aluminium in the soft water used in the Electrolyte disturbances in patients syndrome. EPM has variable presenta- • dialysate and presented with dysarthria, with renal and systemic disorders tions which depend on the affected area dysphasia and dysgraphia, progressing can manifest with specific and non- to gait apraxia, myoclonic jerks and specific neurological features. These , leading in extreme cases to should be recognised early to avoid immobility and mutism followed by Key Points permanent sequelae which may death. Dialysis dementia is treated with occur if not treated promptly, as in The kidney and the nervous system the chelating agent desferrioxamine.2 the osmotic demyelination have close interactions under both physiological and pathological syndromes following rapid states correction of hypo- or Uraemic encephalopathy hypernatraemia. Systemic disorders like diabetes, Either acute or chronic, uraemic Rare, but potentially treatable, hypertension, vasculitudes and • encephalopathy is usually more severe in genetic disorders can affect both serious neurorenal conditions the context of ARF. The initial symptoms the nervous system and the kidney include thrombotic are fatigue, poor concentration and Awareness and early recognition of (TTP) clumsiness, but as the renal function and cocaine-related .1 conditions such as deteriorates there is progression to thrombocytopenic purpura and • Neurological features may be the asterixis, multifocal mycoclonic jerks, osmotic demyelination syndromes first indication of renal disease, for generalised seizures, confusion and should lead to prompt treatment example peripheral neuropathy with coma. In the chronic form, patients show and prevention of serious sequelae CRF, aneurysmal subarachnoid emotional lability, sluggishness and Neurological features can be the first haemorrhage in polycystic kidney inversion of sleep pattern as well as manifestations of a renal disease or disease (PKD), myoclonus in ARF or frontal lobe features, including impaired complications of renal replacement confusion and coma in ARF or CRF. abstract thinking, palmomental reflex therapies This review summarises some of these and a resistance to passive movement KEY WORDS: brain, dialysis, genetic conditions in which neurological mani- (paratonia). The correlation is poor disorders, kidney, muscle diseases, festations are seen in connection with between the chronic form and the degree neurological manifestations, renal disorders. of uraemia. Both forms improve with neurorenal, renal, vascular disorders

Clinical Vol 7 No 2 April 2007 165 CME Neurology

and may cause parkinsonism, confusion, Neurological complications of renal may be more liable to pressure palsies. hemiparesis and hemianaesthesia.4 The transplantation Carpal tunnel syndrome is particularly clinical picture can evolve over several These are summarised in Table 1. common in patients with CRF, even if days. Magnetic resonance imaging is they do not have a dialysis fistula in a usually diagnostic in CPM, showing focal forearm,7 and in some cases there is demyelination in the basis pontis (Fig 1). Peripheral nerve problems in renal coexistence of dialysis amyloid which Treatment is supportive and the disease affects both wrists.8 prognosis is variable but has greatly There is a wide range of peripheral nerve 5 complications in renal disease but senso- improved with early intervention. Systemic disorders with rimotor neuropathy or pressure palsies Careful management of hyponatraemia neurorenal manifestations is vital in prevention. ODS has also been are the most common. A frequent reported with rapid correction of hyper- presenting symptom is distal pain due to Hypertension and diabetes are beyond natraemia, but this is less well defined. In small fibre sensory neuropathy; this can the scope of this article. a few cases ODS has been attributed to be the first manifestation of CRF. On 6 the background of neuropathy the nerves severe hypophosphataemia. Thrombotic thrombocytopenic purpura (a) (b) The first description of TTP was in Russia in 1924 in a young woman with an abrupt onset of haemolytic anaemia, thrombocytopenia, neurological mani- festations, renal dysfunction and fever.9 Deficiency of the metalloprotease ADAMTS-13 (A Disintegrin-like and Metalloprotease with Thrombospondin Motifs) is the major risk factor. Endothelial cells secrete adhesive and unusually large von Willebrand factor multimers which are normally cleaved by ADAMTS-13. Deficiency of the protease causes platelet microthrombi showers into any vascular bed and the occlusive 10 Fig 1. T2-weighted magnetic resonance image showing (a) central pontine microangiopathy characteristic of TTP. myelinolysis (CPM) (white arrow) and (b) a myelin stained cross-section of the pons The clinical and neurological features are showing CPM in the basis pontis (black arrow) in a different patient.4 Reproduced by shown in Tables 2 and 3. kind permission of BMJ Publishing Group Ltd.

Vasculitides and granulomatous Table 1. Neurological complications of renal transplantation. disorders Complications The primary vasculitides (polyarteritis nodosa, SLE and Churg-Strauss disease) Surgical procedure • Peripheral nerve injury: mostly neuropraxia of femoral or lateral cutaneous nerve of thigh have protean neurological and renal • Conus medullaris syndrome/spinal cord ischaemia secondary manifestations, the former including to diversion of blood in the iliac vessels to the grafted kidney encephalopathy, seizures, mononeuritis Immunosuppression • Acute hypertension (ciclosporin or tacrolimus) multiplex, peripheral neuropathy and • Reversible posterior leukoencephalopathy stroke. • CNS infections: Secondary vasculitides involving the – viral (eg CMV, Herpes zoster, EBV (rarely JCV), leading to progressive multifocal leukoencephalopathy kidney and the nervous system are associ- – Mycobacterium : meningitis ated with infections (eg infective endo- – Listeria monocytogenes: meningitis, rhombencephalitis carditis), toxins and illicit drug use, and – cryptococcal or nocardia meningitis in association with lymphoproliferative • Post-transplant lymphoproliferative disorder: disorders. Granulomatous disorders, – ranges from mild B cell proliferation to malignant primary CNS lymphoma particularly Wegener’s granulomatosis, can manifest with renal involvement in CMV = cytomegalovirus; CNS = central nervous system; EBV = Epstein-Barr virus; JCV = Jamestown- Canyon virus. association with cranial nerve and peripheral neuropathies as well as

166 Clinical Medicine Vol 7 No 2 April 2007 CME Neurology

Table 2. Clinical features of thrombotic thrombocytopenic purpura (TTP). Table 3. Neurological manifestations of thrombotic thrombocytopenic purpura (TTP). Characteristic • Thrombocytopenia: petechia features include: • Fever (60%) • Altered mental status (36%): • Microscopic haematuria (gross in 18%) – agitation (very common) • Neurological deficit – confusion • Microangiopathic haemolytic anaemia – coma (the level may fluctuate secondary to Other • TTP can affect any organ system the microhaemorrhagic and microocclusive important facts: • TTP is a potentially treatable life-threatening vascular changes in the brain) multisystem disease • Generalised headache • Non-specific flu-like symptoms are prodromal • Focal defects: • It is unusual for all features to be present from the outset – hemiplegia (12%) • A high index of suspicion is necessary Visual disturbance Coomb’s test is negative, clotting screen is normal, • • Seizures (16%) lactate dehydrogenase is high • • Treatment is plasma exchange (usually 5–10 • Paraesthesia (4%) sessions) with adequate general support • Cerebral bleeding (an ominous feature)

focal central nervous system (CNS) is mapped to chromosome 3p25-p26 lesions of adenoma sebaceum. Renal ischaemia.3 and causes dysfunction in a tumour involvement is seen in 40–80% of cases, suppressor leading to an increased with the development of epithelial Genetic disorders involving the risk of developing various tumours. CNS leading to haematuria and recurrent nervous system and the kidney haemangioblastomas are important, upper urinary tract infections. There is a predominantly in the cerebellum (Fig 2), tendency to develop angiomyolipomata. Polycystic kidney disease less commonly in the spinal cord. Renal TS is autosomal dominant, with almost cell carcinomas are the major cause of complete but a wide range of PKD is due to a defect in polycystin, a death. Ocular presentations are common clinical severity and new are membrane glycoprotein. Renal and since retinal capillary haemangioma is a also seen. It is mapped to chromosomes cysts may be associated with intracranial frequent manifestation of VHL disease.14 9 (TSC1 gene at 9q34) and 16 (TSC2 at aneurysm, hypertension and cardiac 16p13.3). valvular defects. This genetically hetero- geneous group of disorders is usually Fabry’s disease (angiokeratoma autosomal dominant (ADPKD) and the corporis diffusum) defect in most Europeans is mapped to Deficiency of the lysosomal enzyme chromosome 16p13.3 (ADPKD-1). α-galactosidase A (ceramide trihexo- Intracranial aneurysm is seen in sidase) leads to the accumulation of 11 5–15%, but the pathological link glycosphingolipids in the small blood between PKD and intracranial aneurysm vessels in the brain, peripheral nerves, is as yet unknown. There is no correla- myocardium, kidney, cornea and the tion between the presence of intracranial skin. This results in hypertension, renal aneurysm and hypertension. It is recom- and failure, as well as lancinating mended to screen patients with adult acral pains, cerebral vasculopathy, PKD and a family history of intracranial dysautonomia and characteristic skin aneurysm by means of magnetic lesions (angiokeratomas).15 Fabry’s 12 resonance angiography, which is non- disease is X linked and multiple muta- invasive and has a sensitivity of 85% and tions are identified, the commonest 13 specificity of 90%. being Xq22. Recently, enzyme replace- PKD is also associated with an ment has been introduced with increased incidence of mitral and aortic good results,16 and experimental gene valve regurgitation as well as mitral valve transfer therapy is under investigation.17 prolapse, leading to increased risk of embolic strokes in young patients. Tuberous sclerosis Fig 2. T1-weighted gadolinium enhanced brain magnetic resonance The most common neurocutaneous syn- image. Axial section, through the von Hippel-Lindau disease posterior fossa showing a cerebellar drome after , tuberous haemangioblastoma. Courtesy of Dr Jay The defect in the autosomal dominant dis- sclerosis (TS), causes , mental Krishnan, Department of Neuroradiology, order von Hippel-Lindau (VHL) disease retardation, and the characteristic skin Newcastle General Hospital.

Clinical Medicine Vol 7 No 2 April 2007 167 CME Neurology

(a) (b) (e)

(c) (d)

Fig 3. A 26-year-old man with Ehlers-Danlos syndrome who presented with repeated renal infarction and an episode of subarachnoid haemorrhage (SAH). (a) SAH shown in plain CT scan. He has large cerebral (b), bilateral renal (c) and multiple iliac arterial (d) aneurysms. He has very elastic skin with hyperextensible joints (e). Courtesy of Dr V Jayakrishnan, Department of Neuroradiology, Newcastle General Hospital.

Disorders of walls FMD and 10% have vertebral artery the presence of a ‘string of beads’ appear- affecting the central nervous involvement. FMD may also affect ance due to the presence of luminal system and the kidney lumbar, mesenteric, coeliac, hepatic and stenosis alternating with aneurysmal iliac arteries. There is a weak association outpouchings. Percutaneous trans- Ehlers-Danlos syndrome with α-1 antitrypsin deficiency and luminal renal angioplasty may resolve The Ehlers-Danlos syndrome encom- suspicion of hormonal involvement in renovascular hypertension and reduce 19 passes a heterogeneous group of disorders this predominantly female disease. the risk of stroke. of the , usually Renal arteriography may help in recessively inherited and involving confirming the diagnosis. FMD has three Muscle and the kidney different components of collagen. It can distinct histological types: intimal, Rhabdomyolysis cause cerebral and renal artery medial and subadventitial (perimedial) aneurysms, leading to subarachnoid fibroplasia of the arterial wall. The Because of disruption of the muscle haemorrhage (Fig 3) and renal medial type is the most common, sarcolemma with fibre necrosis (Fig 4), infarction.18 classically diagnosed on angiography by leading to the spillage of muscle contents

Fibromuscular dysplasia Fig 4. A muscle photomicrograph Of unknown aetiology, fibromuscular (x 300) stained with dysplasia (FMD) affects the renal arteries haematoxylin/eosin, showing fibre in 85% of patients and often presents necrosis (thin arrow) with renovascular hypertension. The and widespread internal carotid arteries are the second disruption of the most commonly affected and are sarcolemma (thick involved bilaterally in about 65% leading arrow) typical of rhabdomyolysis. to transient ischaemic attack (29%) or Courtesy of Dr J thromboembolic stroke (6%). FMD has Miller, Newcastle been associated with intracranial General Hospital. aneurysm in as many as 30% of patients and spontaneous carotid artery dissec- tion in 10–20%. About 30% of those with carotid FMD also have renal artery

168 Clinical Medicine Vol 7 No 2 April 2007 CME Neurology

(a) (b) Table 5. Causes of rhabdomyolysis. Muscle diseases Genetic • and oxidation pathway defects (eg McArdle disease and carnitine palmitoyl transferase I & II, respectively) • Malignant hyperpyrexia Secondary • Drugs: – eg statins • Neuroleptic malignant syndrome: – chlorpromazine and other phenothiazines, rapid withdrawal of dopamine agonists • Heat stroke • Mechanical: – crush injuries (compartment syndromes) – • Venoms: – snake bites • Inflammatory: – autoimmune (polymyositis) – infections (legionella, influenza A, B) Fig 5. Urine sample showing (a) myo- • Endocrine and metabolic: globinuria in contrast to (b) normal – thyroid disease urine. – severe hypophosphataemia

into the circulation, there is a triad of quate RRT. There is frequently associated 9 Lammle B, Kremer Hovinga JA, Alberio L. myalgia, muscle weakness and the dark bone pain and muscle tenderness and a Thrombotic thrombocytopenic purpura. urine of myoglobinuria (Fig 5). The most suspected link with osteomalacia and Review. J Thromb Haemost 2005;3:1663–75. 10 Mayer SA, Aledort LM. Thrombotic 21 serious complication is ARF. Despite the hyperparathyroidism. microangiopathy: differential diagnosis, dark brown or red discolouration of the pathophysiology and therapeutic strategies. urine, microscopy does not show red cells References Mt Sinai J Med 2005;72:166–75. (Table 4). Numerous disorders may cause 11 Lespinasse J, Fourcade J, Schir F. [Polycystic rhabdomyolysis leading to myoglobinuria 1 Gertner E, Hamlar D. Necrotizing kidney diseases: molecular genetics and granulomatous vasculitis associated with counselling.] Nephrol Ther 2006;2:120–6. (Table 5).20 cocaine use. J Rheumatol 2002;29:1795–7. In French. 2 McCarthy JT, Milliner DS, Johnson WJ. 12 Graf S, Schischma A, Eberhardt KE et al. Uraemic myopathy Clinical experience with desferrioxamine in Intracranial aneurysms and dolichoectasia dialysis patients with aluminium toxicity. in autosomal dominant polycystic kidney Uraemic myopathy is a controversial dis- QJ Med1990;74:257–76. disease. Nephrol Dial Transplant 2002;17: 3 Burn DJ, Bates D. Neurology and the 819–23. order reputed to cause wasting of prox- kidney. J Neurol Neurosurg 13 Broderick JP, Sauerbeck LR, Foroud T et al. imal muscles with normal creatinine 1998;65:810–21. The Familial Intracranial Aneurysm (FIA) . Muscle biopsy reveals loss of type 4 Martin RJ. Central pontine and study protocol. BMC Med Genet 2005;6:17. 2 fibres. Most cases improve with ade- extrapontine myelinolysis: the osmotic 14 Kreusel KM, Bechrakis NE, Krause L, demyelination syndromes. J Neurol Neumann HP, Foerster MH. Retinal Neurosurg Psychiatry 2004;75(Suppl 3): in von Hippel-Lindau disease: a longitudinal ophthalmologic Table 4. Action in patients with dark red iii22–8. study. 2006;113:1418–24. urine. 5 Kumar S, Fowler M, Gonzalez-Toledo E, Jaffe SL. Central pontine myelinolysis, an 15 Fellgiebel A, Muller MJ, Ginsberg L. CNS • A positive urine dipstick for blood update. Review. Neurol Res 2006;28: manifestations of Fabry’s disease. Lancet (haem) should be followed by 360–6. Neurol 2006;5:791–5. microscopy without delay 6 Michell AW, Burn DJ, Reading PJ. Central 16 Eng CM, Guffon N, Wilcox WR et al. • If no red cells are seen, consider pontine myelinolysis temporally related to Safety and efficacy of recombinant human myoglobinuria and haemoglobinuria* hypophosphataemia. J Neurol Neurosurg alpha-galactosidase A–replacement therapy • Myoglobinuria is serious and can lead Psychiatry 2003;74:820. in Fabry’s disease. N Engl J Med 2001;345: to acute renal failure 7 Staub F, Dombert T, Assmus H. [Carpal 9–16. • There are many causes of tunnel syndrome in haemodialysis patients: 17 Seino Y, Takahashi H, Fukumoto H, rhabdomyolysis and a careful analysis of clinical and electrophysiological Utsumi K, Hirai Y. Cardiovascular differential needs early consideration findings in 268 patients (395 hands).] manifestations of Fabry disease and the • A muscle biopsy may help in the Handchir Mikrochir Plast Chir novel therapeutic strategies. J Nippon Med diagnosis** 2005;37:150–7. In German. Sch 2005;72:254–61. 8 Dember LM, Jaber BL. Dialysis-related 18 Proske S, Hartschuh W, Enk A, Hausser I. * Fig 5; ** Fig 4. amyloidosis: late finding or hidden [Ehlers-Danlos syndrome – 20 years’ epidemic? Semin Dial 2006;19:105–9. experience with diagnosis and classification

Clinical Medicine Vol 7 No 2 April 2007 169 CME Neurology

at the university skin clinic of Heidelberg.] J Dtsch Dermatol Ges 2006;4:308–18. In Drug-induced disorders of the German. 19 Mahmud E, Brocato M, Palakodeti V, nervous system Tsimikas S. Fibromuscular dysplasia of renal arteries: percutaneous revascularization based on hemodynamic assessment with a pressure measurement Mark R Baker MA MB BChir PhD MRCP, single agents; these are well documented guidewire. Catheter Cardiovasc Interv Specialist Registrar, Department of elsewhere.1 2006;67:434–7. Neurology, Royal Victoria Infirmary, 20 Laforet P, Eymard B. [Exercise-intolerance DINDs can occur at initiation, during Newcastle upon Tyne and exercise-induced rhabdomyolysis: sudden withdrawal of therapy (eg tram- etiology and diagnosis.] Review. Rev Don J Mahad MB ChB PhD MRCP, Specialist adol withdrawal seizures) and after many Neurol (Paris) 2004;160:217–23. In French. Registrar and Wellcome Trust Intermediate months or years of therapy (eg valproate 21 Mora Palma FJ, Ellis HA, Cook DB et al. Fellow, Mitochondrial Research Group, encephalopathy). Treatment is primarily Osteomalacia in patients with chronic School of Neurology, Neurobiology and concerned with controlled withdrawal, renal failure before dialysis or Psychiatry, , Newcastle upon but toxic levels may necessitate haemo- transplantation. QJ Med1983;52:332–48. Tyne dialysis or haemofiltration (eg lithium), specific neutralising therapies (eg Fab Clin Med 2007;7:170–6 fragments in digoxin toxicity) or sympto- matic treatments. Recent detailed and comprehensive Drug-induced neurological disorders reviews of DINDs can be found (DINDs) are important because early elsewhere.2,3 recognition and drug withdrawal can prevent irreversible damage. This review Seizures deals specifically with the recognised neurological complications of prescrip- Seizures may be caused by antipsychotics, tion-only, single-agent therapy, either at antidepressants, antineoplastic agents recommended doses or in excess (alkylators, antimetabolites, vinca alka- (including overdose and abuse of pre- loids, ifosfamide and cisplatin), peni- scription drugs), and summarises the cillins, cephalosporins, quinolones, more important DINDs. Some of the antimalarials, aminophylline and allop- drugs described may also exacerbate neu- urinol. They are frequently observed in rological disorders that are often drug-induced encephalopathy (see subclinical and undiagnosed. Drug below). Other less frequently reported interactions can increase the toxicity of drugs which may induce seizures include

Key Points

Prescription drugs are an important reversible cause of common neurological disorders

Mitochondrial toxicity is an important mechanism in a number of drug-induced neurological disorders (DINDs)

Early recognition of DINDs and drug withdrawal can prevent irreversible damage

Some DINDs require urgent symptomatic treatment to avoid serious complications

Vitamins and essential trace elements may help to reverse some DINDs

Statin-induced neurological disorders are likely to become more prevalent

Increasing use of novel humanised monoclonal antibodies may cause previously unrecognised DINDs

KEY WORDS: antiretrovirals, drug-induced disorders, mitochondrion, monoclonal antibodies, nervous system, statins

170 Clinical Medicine Vol 7 No 2 April 2007