Epilessia:

causa ed effetto

dell’iponatremia.

Marco Faustini Fustini

PituitaryUnitIRCCS Istituto delle Scienze Neurologiche di BolognaOspedale Bellariamarco.faustini@isnb.it

epilepsy / seizures hyponatraemia

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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 Bolognamarco.faustini@isnb.it