epilessia: causa ed effetto
TRANSCRIPT
Epilessia:
causa ed effetto
dell’iponatremia.
Marco Faustini Fustini
PituitaryUnitIRCCS Istituto delle Scienze Neurologiche di BolognaOspedale [email protected]
epilepsy / seizures hyponatraemia
?
?
Glossary
• Epilepsy. A chronic disorder of the brain characterised by an enduring disposition towards recurrent unprovoked seizures. The diagnosis requires at least 2 seizures occurring greater than 24 hours apart or one seizure with a relevant abnormal electroencephalographic pattern or brain scan suggesting a high probability of a second seizures (Fisher et al 2014).
• Seizure. Transient symptoms and/or signs due to abnormal excessive or simultaneous neuronal activity of a population of neuronal cells in the brain.
Epilepsy Seizures
Drugs
Hypotonic hyponatraemia
Structural causes(tumours, SAH, infections…)
Immune causes
SIAD CSW?
Photograph by C. Lloyd
Hypotonic hyponatraemia: definition.Hypotonic hyponatraemia is a hypo-osmolar state in which there is an excess of total water relative to body solute.
Hyponatraemia – first assessment
Hyponatraemia
Iso-osmolalityIsotonic hyponatraemia(pseudo-hyponatraemia):- hyperlipidaemia- paraproteinaemia
HyperosmolalityHypertonic hyponatraemia:- hyperglicaemia- mannitol, glicerol
Hypo-osmolalityHypotonic hyponatraemia
ECF volume
Normal ECFDecreased ECF Increased ECF
Ball SG et al 2016
Patients with SIAD are clinically euvolemic, but ECV status and total body water are slightly increased (impaired water excretion after a water load).
Photographby C. Lloyd
Peters JP et al. (1950)
A salt-wasting syndrome associated with cerebral disease.
Trans Assoc Am Physicians 63: 57-64
In their report, the authors described 3 patients with acute neurological insult who presented with:
-hyponatraemia- renal sodium wasting- clinical evidence of volume depletion- no obvious disturbance in the pituitary-
adrenal axis
CNS disease and the complex journey to hyponatraemia
CNS disease and the complex journey to hyponatraemia
• Cort JH. (1954) Cerebral salt wasting. Lancet 1: 752-754
• Schwartz WB et al (1957) A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretichormone. Am J Med 13: 529-542
• Nelson PB et al. (1981) Hyponatremia in intracranial disease: perhaps not the syndrome of inappropriate secretion of antidiuretic hormone. J Neurosurg 55: 938-941
• Nelson PB et al (1984) Hyponatremia and natriuresis following subarachnoid hemorrhage in a monkey model. J Neurosurg 60: 233-237
• Ganong CA and Kappy MS. (1993) Cerebral salt wasting in children. The need for recognition and treatment. Am J Dis Child 147: 167-169
• Berendes et al. (1997) Secretion of brain natriuretic peptide in patients with aneurismal subarachnoid haemorrhage. Lancet 349: 245-249.
• …to be continued…
CNS disease, hyponatraemia, and natriuresis
A number of neurological and neurosurgical patients
may develop hyponatraemiawith natriuresis
(SIADH? CSW?):
- cerebrovascular disorders
- central nervous system infections
- head injury
- intracranial tumours
- surgery for pituitary tumours (SIADH…)
- surgery for other CNS diseases
Hyponatraemia with natriuresis in CNS diseases
• SIAD (syndrome of inappropriate antidiuresis):- hyponatraemia with plasma osmolality< 275 mOsm/L,- inappropriately concentrated urine (>100 mOsm/L),- natriuresis (UNa> 40 mmol/L),- fluid overload (expansion of the ECF volume with normal or slightly increased intravascular volume).SIAD is a volume-expanded state.
Treatment: fluid restriction (in mild-moderate hyponatraemia); 3% NaCl hypertonic saline (in severe hyponatraemia); vaptans?
• CSW (cerebral salt wasting): traditional laboratory criteria for SIAD, butwith decreased ECF and intravascular volume(hypovoloemia).
CSW is a volume-depleted state.Treatment: fluid and salt replacement (saline in mild-moderate
hyponatremia; 3% NaCl hypertonic saline in severesymptomatic hyponatraemia; fludrocortisone?)
Pathophysiology of CSW
The mechanism by which (acute) cerebral disease leads to
renal salt wasting is poor understood.
• Decreased sympathetic input to the kidney?
• Release of one or more natriuretic factors (ANP, BNP,
others)?
Palmer, TrendsEndocrinolMetab2003Palmer, NDT 2003
IMCD: inner medullary collecting duct; EABV: effective arterial blood volume
Pathophysiology of CSW
SIAD
Mild expansion of ECF volume
Decreased proximal Na+ reabsorption Increased GFR and renal plasma flow
Increased urinary Na+ excretion(equal to dietary intake)
Decreased proximal reabsorption of substances (such as uric acid and urea nitrogen) which arereabsorbed proximally in concert with Na+
Decreased uric acid and urea nitrogen in serum
Caratteristiche cliniche e biochimiche SIAD CSW
Stato del volume extracellulare aumentato ridotto
Volemia (volume arterioso efficace) essenzialmente normale ridotta
Cambiamenti posturali di PA e polso assenti presenti
Membrane mucose normali aride
Vene periferiche normali appiattite
Pressione venosa centrale normale o lievemente aumentata ridotta
Uricemia ridotta normale o ridotta
Uremia/creatininemia ridotto aumentato
Ematocrito normale aumentato
Albuminemia normale aumentata
Potassiemia normale normale o aumentata
Sodiuria > 40 mmol/L presente presente
Uosm > 100 mOsm/kg H2O presente presente
Bilancio idrico In equilibrio o lievemente positivo negativo
Bilancio del sodio In equilibrio negativo
Perdita di peso assente presente
Trattamento restrizione idrica (iponatr. lieve)sol. NaCl 3% (iponatr. severa)vaptani (antagonisti V2R)
sol. salina (NaCl 0.9%)sol. NaCl 3% (casi selezionati)fludrocortisone ?
Tratto da: M. Faustini-Fustini. Le iponatremie centrali. In: IPOFISI (Ed. P. Beck-Peccoz), 2009
Approach to the hyponatraemicpatient with CNS disease
EABV: effective arterial bloodvolumeECF: extra-cellular fluid
Patient with extracellular fluid volume depletion:- orthostatic- dry skin- light-headed
Hypovolaemichyponatraemia- Clinical signs of volume depletion- Plasma urea tends to be high rather than low- Urine sodium <30 mmol/l (extra-renal salt wasting), but may be >30 if intravenous saline has already been administered or if renal salt wasting is working.
Euvolaemichyponatraemia- Clinical state of ECV may not help diagnostically- Plasma urea tends to be low rather than high- Urine sodium >30 mmol/l, but may be <30 if dietary access to salt restricted
BMJ 2006; 332: 702
Epilepsy Seizures
Drugs
Hypotonic hyponatraemia
Structural causes(tumours, SAH, infections…)
Immune causes
SIAD CSW?
Antiepileptic drugs
Drug-induced hyponatraemia1. Drugs affecting sodium and water homeostasis
1.1 Diuretics
- Thiazides(act solely in the distal tubules and do not interfere with urine concentration) -Amiloride
- Indapamide
- Loop diuretics (impair both concentrating and diluting mechanisms)
2. Drugs affecting water homeostasis
2.1 Increased hypothalamic production of ADH (SIAD)
- Trycyclic antidepressants ( amitryptiline, protriptyline, desipramine, venlafaxine)
- Selective serotonin reuptake inhibitors
- Monoamine oxidase inhibitors
- Phenothiazines (thioridazine, trifluoperazine)
- Butyrophenones (haloperidol)
- Carbamazepine, oxcarbazepine
- Sodium valproate, lamotrigine
- Anticancer agents
- Vinca alkaloids (vincristine, vinblastine)
- Platinum compounds (cisplatin, carboplatin)
- Alkilating agents (intravenous cyclophosphamide, melphalan, ifosfamide)
- Monoclonl antibodies
- Miscellaneous (methotrexate, interferon a and g, levamisole, pentostatin)
- Opiates (included tramadol)
- Antidiabetic drugs (chlorpropamide, tolbutamide)
- Nonsteroidal anti-inflammatory drugs
Rare causes of drug-induced hyponatraemiaAntihypertensive agents
- ACE-inhibitors
- Amlodipine
Immune globulin (intravenous)
Ecstasy (3,4 Methylenedioxymethylamphetamine)
Antibiotics
- trimethoprim-sulfamethoxazole
- ciprofloxacin
- cefoperazone/sulbactam
- rifabutin
Antiarrhytmic drugs (amiodarone, lorcainide, propafenone
Theophylline
Proton pump inhibitors
Bromocriptine
Terlipressin
Duloxetine
Fluorescin angiography
Bupropion
Odd ratio (OR) for hospitalization due to hyponatraemia in patients with ongoing (white) and newly initiated antiepileptic drug treatment (black).
Hyponatraemia: 29.9% in OXC vs. 13.5% in CBZ
Hyponatraemia: 46% in OXC vs. 26% in CBZ
CBZ/OXC - Impaired water excretion after a water load (SIAD)
Hyponatraemia: 7/253 (2.8%)
Hyponatremiawas the most frequent (10.2%) reported adversereaction, with more than half of these cases occurring at daily doses of 1200 mg.
Epilepsy Seizures
Drugs
Hypotonic hyponatraemia
Structural causes(tumours, SAH, infections…)
Immune causes
SIAD CSW?
Immune causes of epilepsy
Hyponatremia: 60%.Seizures: common. Faciobrachialdystonic seizures: 50%.Tumour screening: positive in 0-11%. Abnormal findings on MRI: 65% (medial temporallobe, basal ganglia, hippocampus, insula). Limbic encephalitis (subacute disturbance of memory, behavior and spatial orientation).
LGI1 positive
The challenge of hyponatraemia –
Choosing the right treatment !
Signs and symptoms of hyponatraemia
• Anorexia/nausea• Muscle cramps• Headache• Central nervous system symptoms and signs
- Letargy/apathy- Disorientation, confusion, ataxia, gait disorder, falls- Tremulousness, agitation/delirium- Abnormal sensorium
- Vomiting (urgent treatment with hypertonic saline!)- Seizure- Depressed deep tendon reflexes- Pathologic reflexes- Focal neurologic deficits- Pseudobulbar palsy- Cheyne-Stokes respiration
Multiple factors interact to determine signs and symptoms of hyponatraemiaAbsolute sodium concentration, rate of change in serum sodium and inherent adaptivecapacity to osmolar stress combine to determine the clinical picture in patients presentingwith hyponatraemia. Co-morbidities will also impact on presentation.
Best PractResEndocrinolMetab2016; 30: 161
Sterns RH. N Engl J Med 2015;372:55-65.
Astrocytes and the Neurovascular Unit.
Sodium readily crosses systemiccapillary membranes through cleftsbetween endothelial cells. As aconsequence, in most tissues, thesodium concentrations of plasmaand interstitial fluid are nearly thesame, with a small differencecreated by intravascular albumin.
Brain capillaries have tightendothelial junctions and arelined by astrocytic footprocesses, creating a blood-brainbarrier that sodium cannot cross.Consequently, an abnormal plasmasodium concentration causes waterto enter or leave brain tissue.Because of the confines of the skull,only a small degree of brain swelling or shrinkage is compatiblewith life.
Sterns RH. N Engl J Med 2015;372:55-65.
Consequences of Rapid Changes in the Plasma Sodium Concentration.
Therapy with IV sodium chloride compared with fluid restriction in elderly women with chronic symptomatic
hyponatremia (JAMA 281:2299, 1999)
A total of 53 postmenopausal women with chronicsymptomatic hyponatremia(central nervous system manifestations) were consecutively evaluated.
• Group 1 (n.17): IV sodium chloridebefore the onset of respiratory insufficiency.
• Group 2 (n.22): IV sodium chlorideafter respiratory insufficiency (patients intubated with assisted vent.)
• Group 3 (n.14): fluid restriction only.• Mean (SD) age: 63 (11) years (45-89).• Duration (SD) of the hyponatremia: 5.2 (4.5) days.• Etiologies for the hyponatremia were similar among
the groups (SIADH, diuretics, postoperative…).
Effects of therapy on outcome in 53 postmenopausal women
with chronic hyponatremic encephalopathy
Effects of hyponatraemia on the brain and adaptive responses (NEJM 2000)
The biphasic adaptive response of brain cells to a fall in extracellular osmolality.Influx of water along a concentration gradient triggers an efflux of osmolytes. This serves to reduce the osmotic gradient for water entry and reduce cell swelling.
Best PractResEndocrinolMetab2016; 30: 161
MRI findings in central pontine myelinolysisT2-weighted axial scan, showing the
characteristic “bat-wing” appearance of CPM
(Clin Radiol 57: 800, 2002)
MRI findinds in extrapontine myelinolysisAxial T2-weighted image showing bilateral symmetrical high
intensity in the caudate heads, basal ganglia, and thalami. Clin
Radiol 57:800, 2002
(2) Central pontine and extrapontinemyelinolysis (osmotic
demyelinationsyndromes)
• The patient has usually gone through a biphasic clinical course, initiallyencephalopathic or presenting with seizures from hyponatraemia, then recovering rapidly as normonatraemia is restored, only to deteriorate several days later.
(2) Osmotic demyelinationsyndromes
• Central pontinemyelinolysis (CPM).
The initial signs include dysarthria and dysphagia, a flaccid quadriparesis which later becomes spastic, all from the involvement of the basis pons. Oculomotor abnormalities may occur with the extension to the tegmentum of the pons.
• Extrapontinemyelinolysis (EPM).
A variety of sites may be involved (cerebellum, thalamus, putamen, caudate nucleus…).
Signs and symptoms:mutism, movement disorders (parkinsonism, dystonia), catatonia.
Photograph by Mike Yamashita
Adrogue, Madias NEJM, 2000
Formulas for estimating the effect of any infusate on serum sodium
Hypertonic saline
• The primary shortcoming of the formula is its failure to assess ongoing renal and extrarenal losses. This is particularly critical in hypovolemic patients, when the nonosmotic release of vasopressin is no longer operant (because of the restoration of volume over 24-48 hrs) and a water diuresis ensues.
• The formula does not allow for the increase in serum sodium concentration that accompanies the administration of potassium in the potassium-depleted group (e.g., role of potassium in hypokalemia-induced hyponatremia).
Clin J Am Soc Nephrol 3: 331, 2008
Treatment of hypotonic hyponatraemiawith severe symptoms(vomiting, seizures, coma, respiratory distress)
Hypertonic saline 3% NaCl(0.5-2 ml/Kg/hr or 100-150 ml as i.v. bolus in 20’-30’)
Outline plan for emergency treatment of hyponatraemia with hypertonic fluid
Best PractResEndocrinolMetab2016; 30: 161
Treatment of SIAD with mild/moderate symptoms (nausea, disorientation, unsteady gait)
Fluid restrictionUrea (osmotic diuretic)Tolvaptan (15-30 mg daily; maximum recommended dose: 60 mg daily) Others (demeclocycline, lithium carbonate)
Ten common pitfalls in the evaluation of patients with hyponatraemia
Grazie dell’attenzione
PituitaryUnit- Ospedale BellariaIRCCS Istituto delle Scienze Neurologiche di [email protected]