Quadriparesis in diabetes due to dyselectrolytemia.

A tendency for magnesium deficiency in patients with diabetes mellitus is well established. Hypomagnesemia is commonly associated with hypokalemia and hypocalcemia. Here, we report a case of a 55 yr old woman with diabetes mellitus, presenting with acute onset quadriparesis, paresthesia and muscle cramps, associated with hypokalemia, hypomagnesemia and hypocalcemia, with total recovery on correction of electrolytes for which no other secondary cause could be ascertained.

Introduction

Glycosuria and hyperinsulinemia related hyper-magnesuria and nutritional factors can all contribute to hypomagnesemia in diabetics (1). Potassium channels are inhibited by magnesium. Hypomagnesemia results in increased efflux of intracellular potassium. The cell loses potassium which is then excreted by the kidneys, resulting in hypokalemia. Hypomagnesemia alters the normal heteroionic exchange of calcium and magnesium at the bone surface, leading to an increased bone release of magnesium ions in exchange for an increased skeletal uptake of calcium from the serum. Lack of magnesium also inhibits the release of parathyroid hormone due to impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP), which can result in hypoparathyroidism and hypocalcemia (2). Hypomagnesemia also causes end organ resistance to parathyroid hormone.

Case report

The patient, a 55 yr old female with Type 2 diabetes mellitus for the last 14 years, on insulin for 2 years, pre-sented with the complaint of sudden onset weakness of all four limbs for five days. She had a preceding history of severe muscle cramps and paraesthesia for about a month. History revealed that the patient had severe generalised weakness twenty days back, for which she had been admitted in a local hospital and had improved symptomatically (though some amount of muscle pain persisted) with intravenous fluid and injectable medications, the details of which could not be gathered. The onset of quadriparesis was acute, noticed on getting up in the morning, five days prior to admission in our institute. There was no history of unusually high carbohy-drate intake, cold exposure, excessive exertion or alcohol intake the previous night. She denied unexplained sweating, tremors, heat intolerance, prolonged vomiting, or any drug intake over a prolonged period of time. General examination revealed carpopedal spasm, hypertension(160/100 mm Hg) and mild pallor. Neurological examination revealed bilater-ally symmetrical weakness (Gr 1/5) of all four limbs and generalized hyporeflexia. Muscles of the eyes, face, tongue, pharynx, larynx, diaphragm and sphincters were not involved. Higher functions, cranial nerves and sensory system were intact. Plantar was bilaterally flexor. Apart from mild hepatomegaly, systemic examination was normal.

Investigations revealed hypokalemia(1.3 mEq/l), hypocalcemia (corrected 5.8 mg/dl) and hypomagnesemia (1.1 mg/dl) with normal sodium and chloride levels. Routine blood examination was normal. Fasting and post prandial plasma glucose was 171mg/dl and 309mg/dl respectively with an HBA1c of 9.5%. Serum osmolality was normal.

Urinary ketones were negative. Liver function tests were slightly deranged with AST of 71 mg/dl and ALT of 186 mg/dl. Serum protein was 7.09mg/dl, albumin - 3.2 mg/dl, globulin - 3.8mg/dl, serum bilirubin -0.5mg/dl. Serum creatinine was 1.l mg/dl and microalbuminuria was present. CPK and LDH were within normal limits. Thyroid profile was normal. Serum phosphorus was normal and PTH was 50.3 pg/ml(normal–10 to 55 pg/ml). 24 hour urinary calcium was 61mg (normal - 100 to 300mg/24hrs). Urinary potas-sium excretion was 53 mEq/L /day (normal-25-120 mEq/L/day). Blood gas analysis revealed metabolic alkalosis. Electrocardiogram, ultrasound abdomen, plain picture abdomen, X-ray cervical spine and chest X-ray were normal. MRI of brain, spine and abdomen were also normal.

Initially, the patient was treated with injectable potas-sium, magnesium and calcium preparations. Normalization of serum potassium and calcium was achieved only after total correction of magnesium level. There was gradual improve-ment in muscle power after 24 hours of therapy. Complete recovery was achieved after five days of treatment, following which she was shifted to oral preparations. Glycemic control was achieved using insulin and hypertension was controlled with Amlodepin 5 mg. She was discharged after two weeks on oral calcium(l gm daily) and advised to take diet rich in potassium and magnesium. On subsequent follow up at one and three months, she was asymptomatic with normal electrolyte levels and good glycemic control.

Discussion

Episodic weakness beginning after age 25 is almost never due to primary periodic paralysis (3). Moreover, absence of a similar family history should raise strong suspicion of a secondary disorder (4). Thyrotoxicosis which can mimic periodic paralysis, especially in Asians, had to be ruled out in this case (5).

Secondary hypokalaemic periodic paralysis with normotension, alkaline urine, hypercalcuria and metabolic alkalosis is seen in hyperplasia of the juxtaglomerular apparatus with severe hyperaldosteronism and moderate to marked increase in renin activity. Also known as Bartter′s syndrome, this condition is caused by a mutation in the renal Na-K-2 Cl cotransporter gene and begins in childhood presenting with short stature, polyuria, polydipsia, and a tendency to dehydration during infancy or before school age. Classic Bartter′s syndrome is a severe congenital disease that is inevitably recognized before the age of 6 years (6).

Gitelman's syndrome is an autosomal recessive trait characterized by renal salt wasting and as a result, as in Bartters syndrome, activation of the renin –aldosterone-angiotensin system. As a consequence, affected individuals have low blood pressure, low serum potassium, high serum bicarbonate and permanently decreased serum magnesium. In contrast to Bartters syndrome, urinary calcium excretion is reduced. Chondrocalcinosis is often a feature (7). High doses of magnesium supplementation are required to maintain normal levels in this condition (8). IDH(Isolated dominant hypomagnesemia with hypocalciuria is an autosomal-dominant condition caused by a mutation in the gene FXYD2, which codes for the gamma subunit of the basolateral Na+/K+-ATPase in the distal convulated tubule, associated with few symptoms other than chondrocalcinosis. Patients always have hypocalciuria and variable (but usually mild) hypomagnesemic symptoms (9).

A tendency for magnesium deficiency in patients with diabetes mellitus is well-established. Hypomagnesemia has been reported in 63.3% of hospitalized diabetic hypokalemic patients (10). The mechanism responsible for magnesium deficiency in patients with diabetes is not completely known. Osmotic diuresis clearly accounts for a portion of the magnesium loss. The renal glycosuria that accompanies the diabetic state is believed to impair renal tubular reabsorption of magnesium from the glomerular filtrate (11). Other factors, however, including diarrhea, vomiting, and diuretics use may play a role in hypomagnesemia in diabetes mellitus. Insulin has been reported to enhance the transport of magnesium into cells. Therefore, impaired insulin action or insulin resistance may result in an intracellular magnesium deficit (12). Deficiency of magnesium causes weakness, muscle cramps, cardiac arrhythmia, increased irritability of the nervous system with tremors, athetosis, jerking. In addition, there may be confusion, disorientation, hallucina-tions, depression and epileptic fits. Papaioannou A et al has reported a female diabetic patient with laryngospasm associated with hypomagnesemia, probably due to hypomagnesemia induced hypocalcemia (13). The most classical sign of severe hypomagnesemia (<1.0 mEq/L, 0.5 mmol/L, or 1.2 mg/dl) is hypocalcemia. Immunoreactive PTH levels in most hypomagnesemic-hypocalcemic patients have been either normal or low (and in some cases undetect-able), indicating inappropriately low PTH secretion. Further evidence for a suppressive effect of hypomagnesemia on PTH secretion is the observation that, in the majority of these patients, parenteral magnesium supplementation leads to a rapid rise in plasma PTH levels. Several other factors like parathyroid hormone resistance also plays a role (14). Clinical features of hypocalcemia include neuromuscular irritability, paresthesia, tetany, Chvosteks sign, Trosseaus sign, seizure, fatigue and muscle cramps.

There is a considerable relationship between the levels of magnesium and potassium in serum (15). Whang et al showed that 42% of hospitalized patients who had hypokalemia also had hypomagnesemia (16) . The cause of this association has been studied widely with many plausible theories put forward. One possible explanation is put forth in a 2007 JASN article by Huang and Kuo (17). ROMK, the renal outer medullary potassium channel, provides a rationale as to how low magnesium levels lead to low potassium levels. ROMK is the inwardly rectifying K channel on the apical surface of the distal nephron, which is required for the backleak of K+. When there is high intracellular Mg2 +, it will block the ROMK channel pore and prevent K+ from effluxing. Conversely, a low intracellular Mg2+ would allow for high ROMK efflux activity and therefore result in K+ wasting. Moderate-severe hypokalemia can produce generalized lassitude, muscle weakness and fasciculations, restless legs, paresthesias, depressed deep tendon reflexes whereas profound or rapid onset hypokalemia can produce muscle paralysis (serum potassium < 2 mEq/L). Patients can also present with palpitations, weakness, syncope or sudden death due to cardiac arrhythmias. Hypokalemic quadriparesis as a presenting manifestation of DKA was reported by Patel AN et al (18). Manzano F et al reported a case of acute quadriplegia in diabetic hyperosmotic coma associated with hypokalemia (19)

Our patient was a long standing diabetic, with clinical features encompassing all three forms of dyselectrolytemias described. Though molecular genetic studies were not done, Gitelman's syndrome as the cause of hypomagnesemia was ruled out due to presence of hypertension and normalization of serum magnesium on repeated follow up without magnesium supplementation. Bartters syndrome was ruled out due to older age of presentation, absence of typical clinical features and hypocalcuria. IDH with hypocalciuria was ruled out due to lack of family history and absence of chondrocalcinosis. Other causes of dyselectrolytemia like starvation, diarrhoea or vomiting, parenteral nutrition, diuretic or specific antimicrobial use, ethanol intake and features of hyperthyroidism were absent in our patient. After initial intravenous and subsequent oral supplementation along with stabilization of glycemic status, our patient had a complete recovery and did not require long term potassium and magnesium supplementation. Therefore, we concluded that the cause of dyselectrolytemia and quadriparesis was probably diabetes per se. To the best of our knowledge, there have been no similar reports of diabetes with quadriparesis due to dyselectrolytemia, in the absence of ketoacidosis or hyperosmolar coma.

conclusion, dyselectrolytemia as a cause of acute muscle weakness, (in the absence of other commonly ascribed neurological causes) primarily due to uncontrolled diabetes should be kept in mind. Correction of magnesium levels is critical for normalization of potassium and calcium levels and complete clinical recovery.