Case Of Quadriparesis With Renal Failure Biology

A young male presented with easy fatigability, anorexia, nausea of 06 weeks duration with small bowel diarrhea of four days duration. After resuscitation with IV fluids he had a seizure, altered sensorium, acute onset quadriparesis, dysphagia and mutism. He was found to have advanced renal failure with shrunk kidneys and managed with haemodialysis with good improvement in level of sensorium, however other neurological symptoms had persisted. Further neurological evaluation revealed an interesting iatrogenic cause for the quadriparesis. Patient made gradual recovery from the neurological syndrome over the ensuing weeks but continued to be dialysis dependant.

An eighteen year old male presented with anorexia, vomiting, malaise and easy fatigability of 6 weeks duration. He gave history of loose watery stools of 4 days duration. He had been oliguric and had been in altered sensorium for 1 day prior to presentation. No h/o fever, hematuria, dysuria, pyuria, swelling of face or feet, yellowing of eyes or urine / hemetemesis, pain abdomen or distension of abdomen, chest pain / dyspnea on exertion/ orthopnea, use of any drugs or TB in the past.

What is your analysis of symptoms so far ?

This young man has an underlying chronic disorder, the nature of which is unclear due to nonspecific symptoms. The possible differential diagnosis could be - chronic hepatitis, endocrine disorders like Addison's, HIV infection, uraemic symptoms. The present problem is an episode of small bowel diarrhoea that has resulted in volume depletion and oliguria suggestive of acute kidney injury. The cause of altered sensorium could be hypovolemic or septic shock, dyselectrolytemia or uremic encephalopathy. Tropical infections like severe malaria should also be kept in mind in a young patient with short history of diarrhoea, altered sensorium and renal failure, however, absence of fever would be an odd point.

He was managed with 12 bottles of IV fluids as per the attendant's history. He had an episode of GTCS and continued to be in altered sensorium. He started having difficulty in breathing and inability to produce sound. He was noticed not to be moving all 4 limbs and hence was shifted to a referral hospital.

What could be the cause of difficulty in breathing, altered sensorium and inability to move all four limbs in this patient?

Difficulty in breathing could be due to fluid overload, aspiration in a patient with altered sensorium or ARDS. The altered sensorium in this clinical scenario could be due to a

* MD, DNB, DM (Nephro), Reader in Medicine, Dept of Medicine, AFMC.

E mail: [email protected] Tele: 020-26306012(O), 9545081656(M)

metabolic cause like hyponatremia, hypoxia, sepsis, uraemia or CNS infection. The reason he is not moving his limbs could be postictal drowsiness, basilar artery thrombosis, osmotic demyelination, or post-para infectious demyelination.

What are the causes of acute onset quadriparesis?

Spastic

Cervical cord - Acute Compressive

Myelopathy and Non compressive myelopathy

Basilar artery thrombosis

Central pontine myelinolysis

Flaccid

Poliomyelitis

AIDP

Diphtheria

Porphyria

Arsenic poisoning

Tick paralysis

Botulism

Elapid Snake bite

Hypokalemic Periodic paralysis

Myasthenis gravis - crisis

He was shifted to a referral hospital in view of his deteriorating condition. Evaluation revealed anemia ( Hb-5 gm%), azotemia (Urea-171 mg% , Cr- 15 mg%)and bilateral shrunken kidneys on ultrasound( RK-6.8cm, LK-5.5cm). He was managed with twice weekly hemodialysis through subclavian catheter. Diarrhoea subsided within two days of admission.

What could be the cause of renal failure in this patient?

In view of the bilateral shrunk kidneys, he has chronic kidney disease that account for the uraemic symptoms of 6 weeks duration. A prerenal component due to the volume depletion from acute gastroenteritis would have resulted in acute on chronic renal failure. The differential diagnosis of acute renal failure after diarrhoea should also include haemolytic uraemic syndrome, however bilateral shrunk kidneys would rule out the possibility.

What are the causes of chronic renal failure in childhood?

Inherited cystic kidneys

ARPKD, ADPKD

Congenitally maldeveloped kidney

"CAKUT"

Reflux nephropathy

Posterior urethral valves

Obstructive uropathy

PUJ obstruction, UVJ obstr

Inherited Glomerular disease

Alport's, Inherited podocytopathies

Metabolic disease

Primary Hyperoxaluria, Fabry's

CGN

Lupus, Primary and secondary glomerulopathies

The patient continued to have weakness of all 4 limbs with no improvement in power. Weakness of limbs was symmetrical, involving both proximal and distal musculature. He remained dependent for activities of daily living. However, the level of sensorium improved with dialytic support over 2 weeks . He started to respond to verbal commands but remained bed bound. Patient was unable to swallow both solid and fluids. He was unable to speak or phonate although comprehension was intact. There was no history of regurgitation or choking. He was on ryle's tube feeding. He was on foley's catheter for urinary drainage and his urine output was adequate. No h/o fever, hematuria, dysuria, swelling of face/feet, any episodes of weakness in past, jaundice, use of any drugs in the past, joint pain or rashes, dogbite or vaccination, exposure to insecticides.

What are the clinical possibilities at the end of history?

The patient has an acute on pre-existing CKD. The acute factor is enteritis with maybe sepsis. The euderlying cause of CKD is possibly chronic interstitial nephritis. He probably had uremic or metabolic encephalopathy that improved improved with haemodialysis. The neurological diagnosis at the functional level would be acute onset flaccid quadriparesis, mutism and dysphagia. The anatomical localisation would be pons with involvement of corticospinal and bulbar tracts. The cause could be osmotic demyelination due to rapid correction of hyponatremia in the setting of hypovolemic hyponatremia. Alternatively, the patient could have suffered from a pontine infarction due to severe dehydration.

On examination, he was averagely built and nourished with a weight 48Kg, height 156cm and BMI19.6 kg/m2. He was Afebrile with pulse 110/min, BP 110/60 mm Hg and respiratory rate18/min. He had pallor but no edema, icterus, clubbing or lymphadenopathy. Nervous system evaluation revealed a conscious with GCS 11/15 (E4V1M6). He was mute but obeying verbal commands. Pupils were equal size and reacting to light. The horizontal conjugate eye movements were restricted with normal vertical movements. There was no nystagmus or facial asymmetry and jaw jerk was not elicitable. He had decreased palatal movements, diminished gag reflex with normal tongue movements. Motor system examination revealed normal bulk, hypertonia in all limbs, with power 2/5 in both upper limbs with handgrip 60-70%. The power in hips and knees was 3/5. All the deep tendon jerks were brisk with bilateral ankle clonus and extensor plantars and no sensory deficit. The examination of lungs, abdomen and CVS revealed no abnormalty.

What is the difference between coma, Locked in syndrome, vegetative state and akinetic mutism? Which of these conditions is our patient have?

Coma means a depressed level of alertness to complete unresponsiveness and is grading as per Glasgow coma scale. "Locked in syndrome" refers to a mute and motionless but remains awake, alert, aware of self, and capable of perceiving sensory stimuli. A patient with akinetic mutism - although seemingly awake, remains silent and motionless. Persistent vegetative state is a lack of awareness of self and external stimuli, accompanied by sleep and wake cycles, with preservation of vital vegetative functions. Our patient is in a "locked in state" because he is conscious and is responding to verbal stimuli, but remains mute, quadriplegic with intact vertical movements.

What are the causes of Locked in syndrome?

The causes of a locked in syndrome would be - Basilar artery thrombosis with ventral pontine infarction, pontine haemorrhage, pontine tumor,osmotic demyelination syndrome and rarely - bilateral ventral midbrain lesions and tentorial herniation.

Investigations revealed Hb 6.2g/dl, TLC 30400/mm3, DLC P82% L15%, platelet 2.64 lakh/ , Bl sugar 99mg/dl, Serum bilirubin 0.9mg/dl, normal transaminases, Bl urea 180mg/dl, serum creatinine 8.0 mg/dl, Serum sodium 134 mol/L, Serum potassium 3.4 mmmol/L. Peripheral blood smear showed toxic granules, Blood culture and urine culture revealed no growth, Viral markers HbsAg and anti-HCV were Neg and HIV was Non reactor. CT brain showed diffuse hypodensities involving pons, midbrain, extending into middle and superior cerebellar peduncle, cerebral peduncle and bilateral post limb of internal capsule. MRI brain showed large areas of altered signal intensity within pons as well as midbrain extending to posterior limbs of internal capsule suggestive of osmotic demyelination. The patient was managed as a case of ESRD with Biweekly MHD and supportive care. His neurological status improved gradually over 2 -3 weeks and was able to swallow, phonate and ambulate with support.

What are the clinical settings associated with osmotic demyelination?

Multiple clinical scenarios involving rapid correction of hyponatremia results in osmotic demyelination. These are as shown in the table below.

Common associations

Chronic hepatocellular dysfunction

Malnutrition

Chronic alcoholism

Liver transplantation

Chemotherapy

Hypothyroidism

Addison's

Chronic renal failure

Uncommon associations

Dialysis dysequilibrium

Normonatremic dehydration

Correction of hyponatremia with normal saline

Correction of hyponatremia with water

restriction alone

Hypernatremia

Hyponatremia with associated hypokalemia

Hypophosphatemia

What is the pathogenesis of osmotic demyelination syndrome?

As an adaptation to chronic hyponatremia there is a loss of intracellular osmolytes(sodium, potassium, chloride, and organic osmolytes such as myoinositol, glutamate,taurine, glutamine) from the brain cells to prevent cerebral edema. Rapid correction of chronic hyponatremia corrects the tonicity of blood but the brain cells are hypotonic; this leads to sudden shrinking of cells and loss of myelin. Gray matter- white matter interface is maximum in the ventral pons and hence rapid shifts in osmolarity result in myelinolysis especially in the region of pons, hence the old term- "Central pontine myelinolysis". Today it is well known that loss of myelin may occur from extrapontine sites too, hence the enitity has been termed "Osmotic demyelination syndrome".

What are the guiding principles in the correction of hyponatremia in order to prevent osmotic demyelination?

Rapid correction of even mild hyponatremia carries the risk of osmotic demyelination. Na should be corrected no faster than 0.5 meq/l/hour and not more than 10 meq/l/24 hours. Hypertonic saline should be used only if clinically warranted. The treatment of mild asymptomatic hyponatremia (plasma sodium> 120 meq/l) needs just stopping hypotonic fluid therapy and withholding diuretics. In hypovolemic patients correction with isotonic saline will usually correct hyponatremia if adrenal function is normal. In hypervolemic patients, in whom dilutional hyponatremia is due to renal Na retention, water restriction combined with treatment of the underlying disorder (heart failure, cirrhosis, nephrotic syndrome) is often successful. In euvolemic patients, treatment is directed at the cause (e.g. adrenal insufficiency, hypothyroidism). If SIADH is present, severe water restriction (250-500ml/24hrs) is required.

The risk of osmotic demyelination syndrome is increased in chronic hyponatremia due to the cerebral adaptation to the chronic hypo-osmolar state. In chronic asymptomatic hyponatremia, the plasma Na should be raised not more than 5 - 8 meq/L/d to avoid osmotic demyelination syndrome. Severe asymptomatic hyponatremia can usually be treated with stringent restriction of water intake.

All symptomatic patients with acute hyponatremia, for hyponatremia associated with underlying neurologic or neurosurgical conditions, exercise induced hyponatremia and for all hyponatremic patients with seizures or coma regardless of the duration of the electrolyte disturbance should be treated with a bolus infusion of 100 mL of 3% NaCl to acutely reduce brain edema with up to 2 additional 100 mL 3% NaCl bolus infusions that should be given at 10-minute intervals if there is no clinical improvement. Hypertonic saline (3% saline) should be used only with frequent electrolyte determinations (every 2-4 hour). Once the bolus therapy has been completed, further treatment with hypertonic saline may be unnecessary. This regimen translates to a maximum of 6 mL/kg of 3% saline in a 50-kg woman, enough to increase the serum sodium concentration by 5 to 6 mmol/L.

What are the safe rates of correction of severe symptomatic hyponatremia?

The limits of rate of correction laid out are : 10 mmol/L in 24 hours, 18 mmol/L in 48 hours, and 20 mmol/L in 72 hours. These should be regarded as limits not to be exceeded rather than therapeutic goals. The goal of therapy should be adequate to keep patients safe from serious complications of hyponatremia while staying well clear of correction rates that risk iatrogenic injury. Accordingly, the suggested goals are : 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours. For the first 2-3 hours of treatment, rate not exceeding 1mmol/l/h has been suggested, but for patients with seizures rates upto 2mmol/L/h has been suggested. The slower rate of correction is much less critical in acute (<2 days in development) symptomatic hyponatremia, though immediate attainment of normonatremia is not suggested.

In a given case how is the amount of sodium to be infused calculated?

The amount of Na in meq may be calculated by using the formula :

Na deficit = (Desired change in Na) x TBW, where TBW is 0.6 x body weight in kg in men and 0.5 x body weight in kg in women. An alternative method of calculating the requirement is by use of the Adrogue Madias formula that predicts the increase in Na level.

Expected increase in serum Na with 1L infusate = Infusate Na-Serum Na

TBW +1

The use of prediction formulae tends to result in inadvertent overcorrection. Once the impairment resolves, excretion of dilute urine increases the serum sodium concentration by much more than would be predicted by calculations that ignore this factor.

Final diagnosis - Osmotic demyelination syndrome in end stage renal diseaseCommentary

Osmotic demyelination syndrome is an iatrogenic complication of inappropriate correction of hyponatremia. Previously described as central pontine myelinolysis, it has been well described in other extra pontine sites too. With the widespread availability of MRI the condition has been recognized as not an uncommon condition. Osmotic demyelination due to correction of hyponatremia in the setting of renal disease has been described, but is relative;ly uncommon. Appropriate correction of hyponatremia, sticking to the laid down principles can go a long way in preventing this disorder.

Take Home Message

1. A high index of suspicion in typical clinical settings can pick up instances of osmotic demyelination syndrome early.

2. One needs to exercise due caution in correcting hyponatremia to prevent osmotic demyelination syndrome.