Hypocalcemic hyper-CK-emia in hypoparathyroidism

A 15-year-old boy with increased serum creatine kinase (hyper-CK-emia) due to hypocalcemia in turn caused by idiopathic hypoparathyroidism (HP) is presented. Hyper-CK-emia was incidentally noted while managing a patient, aged nine, with mental retardation, epilepsy and mild hypocalcemia. Neurological examination showed normal deep tendon reflexes and no muscle weakness; electromyogram was normal. The hyper-CK-emia normalized during treatment for the hypocalcemia. Previously reported patients with hypocalcemic hyper-CK-emia or myopathy together with HP are discussed, as well as the degree of hypocalcemia and the wide spectrum of the muscle dysfunction.     

Cortical myoclonus due to hypocalcemia 12 years after thyroidectomy

Although seizures have been described in hypocalcemia, myoclonus has been rarely reported. We report the first case of a patient with hypocalcemic cortical myoclonus due to hypoparathyroidism following a previous thyroidectomy. The patient was an 84-year-old woman who presented with multifocal myoclonus, which was predominant in the upper extremities, neck, jaw, and facial muscles. Electrophysiological studies revealed enlarged somatosensory evoked potentials, cortical reflexes evoked by peripheral nerve stimulation, and a cerebral potential preceding myoclonic jerks determined by jerk-locked averaging. All these findings were consistent with cortical myoclonus. The myoclonic state disappeared as serum calcium level became normal. Hypocalcemia should be considered in patients who had had a thyroidectomy, even if it was performed more than 10 years previously.     

Crises épileptiques révélant des anomalies du métabolisme phosphocalcique

Hypocalcemia due to hypoparathyroidism produces a broad spectrum of clinical manifestations, but overt symptoms may be sparse. One unusual presentation is onset or aggravation of epilepsy in adolescence revealing hypoparathyroidism. This situation can lead to delayed diagnosis, with inefficacity of the antiepileptic drugs. We report five cases of adolescence-onset epilepsy with unsuccessful antiepileptic therapy, even with gradually increasing dose. Physical examination revealed signs of hypocalcemia, confirmed biologically. Full testing disclosed the origin of the seizures: hypoparathyroidism in three patients and pseudohypoparathyroidism in the other two. In four of five patients, computed tomography showed calcification of the basal ganglia, defining Fahr's syndrome. The patients were treated with oral calcium and active vitamin D (1-alphahydroxy vitamin D3). Seizure frequency progressively decreased and serum calcium levels returned to normal. These cases illustrate the importance of the physical examination and of routine serum calcium assay in patients with new-onset epileptic seizures in order to detect hypocalcemia secondary to hypoparathyroidism.     

A case with temporal lobe epilepsy associated with hypocalcemia due to primary hypoparathyroidism]

We report a 30-year-old man with temporal lobe epilepsy associated with hypocalcemia due to primary hypoparathyroidism. He had frequent jamais vu since age 14 years, and later developed generalized convulsive seizures. It was initially controlled by phenytoin. The patient also had hypocalcemia due to primary hypoparathyroidism. The presence of jamais vu suggested the seizure focus in the mesial temporal area, being consistent with EEG finding, and it was most likely activated by the associated hypocalcemia. Control of hypoparathyroidism, and furthermore, selection of valproic acid as an antiepileptic drug which did not interfere with calcium metabolism were essential for this particular patient.     

Hypocalcemic focal seizures in a one-month-old infant of a mother with a low circulating level of vitamin D

We present a case of a one-month-old infant with hypocalcemia and rickets, with symptoms of focal seizures. The ictal EEG showed left occipital spikes spreading over all of the left hemisphere. From the laboratory studies, we concluded that a low maternal circulating level of vitamin D would cause infantile hypocalcemia and rickets, while immature renal response to parathyroid hormone and transient hypoparathyroidism in infancy would induce hyperphosphatemia. Hypocalcemia may be an important factor in the cause of focal seizures which start even after the age of one month. Further, investigation of maternal vitamin D levels should be done in infantile hypocalcemia.     

Tonic-clonic seizures in a patient with primary hypoparathyroidism: a case report.

Hypoparathyroidism, a life threatening disorder, occurs when insufficient parathyroid hormone is produced to maintain extracellular calcium levels within the normal range. The acute clinical signs and symptoms of hypoparathyroidism are the same as those of hypocalcemia, ranging from tingling to intractable generalized tonic-clonic seizures; therefore, it can be mistaken for epilepsy. We report the case of a 36-year-old man who presented two tonic-clonic seizures, characterized by sudden loss of consciousness with a fall and diffuse tonic contractions and clonic jerks. At first diagnosis of epilepsy was established and therapy with valproate was commenced. In the following days, the patient presented typical signs of hypocalcemia and the diagnosis of hypoparathyroidism was made. In the 4 months follow up, antiepileptic drug therapy was reduced until suspension and calcium supplementation was initiated. We briefly review the most recent reports in the literature.     

Hypocalcemic generalised seizures as a manifestation of iatrogenic hypoparathyroidism months to years after thyroid surgery.

Hypoparathyroidism is a relatively common side effect of a thyroidectomy and leads to hypocalcemia. Carpopedal spasm and tetany are typical manifestations and usually occur within weeks after surgery. The first signs can be less typical and include movement disorders such as chorea, as well as symptoms of increased intracranial pressure or epileptic seizures. We describe two cases with generalised tonic-clonic seizures as the first manifestation of postoperative hypoparathyroidism, appearing months and years after thyroidectomy. Iatrogenic hypoparathyroidism needs to be considered in the differential diagnosis of adult-onset, generalised, tonic-clonic seizures even if the thyroidectomy was performed years earlier.     

Marcus Gunn Jaw-Winking synkinesis in a neonate.

This report describes a 9-day-old female infant admitted for hypocalcemic seizures. The hypocalcemia was treated, but the infant was noted to have vesico-ureteral reflux and a mild ptosis of her left eye with rhythmic blinking during bottle feeding. The eye findings were subsequently diagnosed as Marcus Gunn jaw-winking Synkinesis.     

Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association

We report a patient with chronic, untreated idiopathic hypoparathyroidism who presented with papilledema and progressive deterioration of visual function. The papilledema resolved with treatment of the hypocalcemia. Visual acuity progressively improved as the serum calcium rose during treatment with vitamin D and calcium supplements. Lumbar puncture may also have contributed to the normalization of cerebrospinal fluid pressure and recovery of vision in this patient. The association of hypoparathyroidism and pseudotumor cerebri is rare, and a retrospective review of 41 patients with hypoparathyroidism admitted to two local general hospitals revealed no other cases.     

Topiramate blocks perinatal hypoxia-induced seizures in rat pups

Neonatal seizures caused by hypoxia can be refractory to conventional anticonvulsants. Currently, there is no effective postnatal intervention for newborn infants with hypoxic encephalopathy to prevent brain injury and long-term neurologic sequelae. We previously developed a rat model of perinatal hypoxia-induced seizures with subsequent long-term increases in seizure susceptibility and showed that these epileptogenic effects are selectively blocked by the alpha-amino-3-hydoxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione. Using this model of perinatal seizures, we evaluated the efficacy of topiramate, a structurally novel anticonvulsant drug recently shown to attenuate AMPA/kainate currents. Topiramate effectively suppressed acute seizures induced by perinatal hypoxia in a dose-related manner with a calculated ED50 of 2.1 mg/kg, i.p. Furthermore, in animals that had seizures suppressed by topiramate during acute hypoxia, there were no long-term increases in susceptibility to kainate-induced seizures and seizure-induced neuronal injury. Our results suggest that topiramate may have clinical potential as a therapeutic agent for refractory seizures in human neonates.     

Pseudohypoparathyroidism and Epilepsy: Diagnostic Value of Computerized Cranial Tomography

Computerized cranial tomograms (CCTs) unexpectedly showed bilateral symmetrical calcifications in the basal ganglia and frontal areas in two unrelated epileptic patients 12 and 13 years of age. The patients presented with a variety of seizures, some with focal features; these seizures were resistant to medication in the first case. Subsequent testing revealed hypocalcemia and other biochemical and radiologic features of pseudohypoparathyroidism, despite absence of the usual phenotypic features, tetanic symptoms, and positive family history. The CCT scan may provide the first clue to an underlying hypocalcemic disorder in an epileptic patient even when the skull X-ray is normal. Early detection of this metabolic condition by CCT scanning allows specific treatment to restore serum calcium levels to normal, which usually eliminates seizures and favors optimal cerebral functioning. Serial CCT scanning also provides a useful means for following the intracerebral calcifications, which remained unchanged after 1 and 2 years of normocalcemia in our 2 patients.     

Effect of topiramate following recurrent and prolonged seizures during early development

Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium-pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual-spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.     

Effect of topiramate on cognitive function and activity level following neonatal seizures

Topiramate, an antiepileptic drug with a number of mechanisms of action including blockade of AMPA/KA receptor subtypes, was assessed as a neuroprotective agent following seizures. We administered topiramate or saline chronically during and following a series of 25 neonatal seizures. After completion of the topiramate treatment, animals were tested in the water maze for spatial learning and the open field for activity level. Brains were then examined for cell loss and sprouting of mossy fibers. Rats treated with topiramate performed significantly better in the water maze than rats treated with saline. Topiramate treatment also reduced the amount of seizure-induced sprouting in the supragranular region. There were no differences between topiramate- and saline-treated rats in activity level in the open field, swimming speed, or weight gain. These findings show that long-term treatment with topiramate after neonatal seizures changes the long-term consequences of seizures and improves cognitive function.     

A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group.

OBJECTIVE: To evaluate the efficacy and safety of topiramate as adjunctive therapy for Lennox-Gastaut syndrome in a multicenter, double-blind, placebo-controlled trial. BACKGROUND: Conventional antiepileptic drugs are frequently ineffective against multiple-seizure types of Lennox-Gastaut syndrome. METHODS: Ninety-eight patients >1 year to <30 years of age, with slow spike-and-wave patterns on EEG, seizure types including drop attacks, and either a history of or active atypical absence seizures, were assigned to an 11-week, double-blind treatment phase with either topiramate or placebo. Topiramate was titrated to target doses of approximately 6 mg/kg/d. RESULTS: For drop attacks, the most severe seizures associated with this syndrome, the median percentage reduction from baseline in average monthly seizure rate was 14.8% for the topiramate group and -5.1% (an increase) for the placebo group (p = 0.041). Topiramate-treated patients demonstrated greater improvement in seizure severity than did placebo-treated patients based on parental global evaluations (p = 0.037). The percentage of patients with a > or = 50% reduction from baseline in major seizures (drop attacks and tonic-clonic seizures) was greater in the topiramate group (15/46 or 33%) than in the control group (4/50 or 8%; p = 0.002). The most common adverse events in both groups were CNS related; there were no discontinuations from topiramate therapy due to adverse events. CONCLUSIONS: Topiramate adjunctive therapy was effective in reducing the number of drop attacks and major motor seizures and in improving seizure severity as determined by parental global evaluation.     

Use of topiramate in childhood generalized seizure disorders

Topiramate is a sulfamate derivative of the naturally occurring monosaccharide D-fructose. It was initially approved in the United States as adjunctive therapy for partial seizures in 1997. However, there is increasing evidence that it is effective in the treatment of generalized seizures and epilepsy syndromes. Initially, open-label studies using topiramate as add-on therapy in children with refractory generalized seizure types were performed. These showed improvement in patients with the following generalized seizure types: typical and atypical absence, atonic, myoclonic, generalized tonic-clonic, and juvenile myoclonic epilepsy. Double-blind, placebo-controlled multicentered studies in patients with refractory primary generalized tonic-clonic seizures and epilepsy syndromes were performed. The median reduction in seizure frequency for primary generalized tonic-clonic seizures was 56.7% for topiramate and 9% for placebo. Additionally, 13.6% of topiramate-treated patients were primary generalized tonic-clonic seizure free for the study period. In the topiramate-treated juvenile myoclonic epilepsy patients, primary generalized tonic-clonic seizures were reduced > 50% in 73% of patients. Open-label extension showed that primary generalized tonic-clonic seizures were reduced >50% in 63% of topiramate-treated patients for > or = 6 months, and 16% were primary generalized tonic-clonic seizure free > or = 6 months. Accumulating evidence suggests that topiramate has a broad spectrum of antiepileptic effect. Moreover, life-threatening organ toxicity has not been attributed to topiramate. Topiramate is an effective treatment for refractory generalized seizure types and epilepsy syndromes encountered in children.     

Topiramate for the treatment of neonatal seizures

Therapeutic options for treating neonatal seizures, such as phenobarbital and phenytoin, lack efficacy and are potentially harmful to the developing brain. Topiramate appears effective as both an antiseizure and neuroprotective agent in animal models of newborn brain injury. Although topiramate is a common add-on agent in newborns, its use in this population has not yet been reported. We performed a retrospective cohort study of clinical topiramate use in newborns with acute symptomatic seizures that were refractory to standard agents. In four of six newborns, apparent reduction or no further seizures occurred. None of the children experienced side effects resulting in discontinuation of the drug, either during the hospital admission or after discharge. Prospective studies evaluating the safety and efficacy of topiramate for both seizures and neuroprotection will be important in determining whether it deserves widespread use in clinical practice.     

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group

BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.     

Clinical experience with open-label topiramate use in infants younger than 2 years of age

To assess the efficacy, safety, and tolerability of topiramate in infants younger than 24 months of age, we conducted an open-label, multicenter chart review study of infants who received topiramate. Twenty-eight patients were evaluated. All had refractory epilepsy. The mean age of seizure onset was 3.8 months (range 0-10 months). Refractory infantile spasms were the most common epilepsy syndrome. Among infants without infantile spasms, complex partial seizures were the prominent seizure type in eight, followed by simple partial seizures in six. Topiramate was prescribed as add-on therapy in 25 cases and a s monotherapy in 3 cases. Seven of the eight infantile spasms cases improved on topiramate therapy, attaining topiramate monotherapy in three infants. Half of the infants with other seizure types responded to topiramate. The average treatment duration among topiramate responders was 11 months. Topiramate was prescribed after a mean of 3.3 antiepilepsy drugs had been used in these infants. In no case was topiramate the first prescribed antiepilepsy drug. Adverse effects occurred only in five patients, leading to topiramate discontinuation in two patients. Topiramate was efficacious and well tolerated in infants younger than 24 months of age with refractory epilepsy. Prospective data are needed to corroborate this observation.     

Neonatal Hypocalcemic Seizures Due to Excessive Maternal Calcium Ingestion

Hypocalcemia is a common, treatable cause of neonatal seizures. A term girl neonate with no apparent risk factors developed seizures on day 5 of life, consisting of rhythmic twitching of all extremities in a migrating pattern. Physical examination was normal except for jitteriness. Laboratory evaluation was unremarkable except for decreased total and ionized serum calcium levels and an elevated serum phosphorus level. The mother had ingested 3-6 g of calcium carbonate daily during the final 4 months of pregnancy to control morning sickness. The baby's electroencephalogram showed multifocal interictal sharp waves and intermittent electrographic seizures consisting of focal spikes in the left hemisphere accompanied by rhythmic jerking of the right arm and leg. Treatment with intravenous calcium gluconate over several days resulted in cessation of seizures and normalization of serum calcium. The child has remained seizure free and is normal developmentally at 9 years of age. Hypocalcemic seizures in this newborn were likely secondary to excessive maternal calcium ingestion, which led to transient neonatal hypoparathyroidism and hypocalcemia. Inquiry about perinatal maternal medication use should include a search for over-the-counter agents that might not be thought of as “drugs,” as in this case, antacids.     

Hypoparathyroidism and facial dysmorphism as main symptoms of 22q.11 deletion syndrome

A 12-year-old Japanese boy with mental retardation and facial dysmorphism developed frequent convulsions, and hypocalcemia due to hypoparathyroidism was recognized. Chromosomal analysis involving the fluorescence in situ hybridization method revealed a microdeletion of 22q11.2. However, other laboratory examinations revealed no cardiac anomaly, thymic hypoplasia, or cleft palate. It is well known that typical cases of 22q11 deletion syndrome have a cardiac anomaly, thymic hypoplasia and a cleft palate. However, the phenotype of 22q11 deletion syndrome is diverse, and hypoparathyroidism and facial dysmorphism have been reported in nine cases, including this case, associated with 22q11 deletion. This combination of clinical manifestations could be given another term, such as hypoparathyroidism-facial syndrome. Some hypoparathyroidism patients due to 22q11.2 deletion may be misdiagnosed as having idiopathic hypoparathyroidism, and a child diagnosed as having hypoparathyroidism should be examined for chromosomal 22q.11.2. deletion.