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Biomedical subjects

Ahmad Beydoun

Publications and source records attributed to Ahmad Beydoun.

At least 19 recordsLinked to original sources
PubMed2024

Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.

PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.

Humans↗
PubMed2005

Diagnostic and localizing value of ictal SPECT in patients with nonconvulsive status epilepticus.

In this study, we evaluate the diagnostic and localizing value of SPECT in three patients with nonconvulsive status epilepticus (NCSE). Our results indicate that ictal/subtraction ictal SPECT is a useful complementary noninvasive diagnostic test in patients with focal NCSE. This is especially the case when the EEG findings are inconclusive and for patients in whom surgical treatment is being considered.

Adolescent↗
PubMed2005

Predictive value of early EEG after epilepsy surgery.

To determine whether EEG performed within few months after epilepsy surgery is predictive of seizure outcome, 58 consecutive patients undergoing surgery for presumptive temporal lobe epilepsy (TLE) who had clinical follow-up of at least 2 years and EEG data available both pre- and postoperatively were analyzed. Patients were classified by preoperative brain magnetic resonance imaging into lesional, cryptogenic, and hippocampal sclerosis groups. Seizure outcome was classified according to Engel's outcome scale. Comparison was made between the presence of interictal epileptiform discharges (IEDs) in the postoperative EEG and seizure outcome. Patients who experienced seizures within 2 months after surgery were considered to have early recurrence. The mean follow-up period was 3 years. Sixty percent of patients achieved a class I seizure outcome. Almost all (95%) postoperative EEGs were obtained within 4 months after surgery. IEDs were present in 26% of postoperative EEGs, but were significantly less frequent in EEGs recorded after the first two postoperative months (P = 0.011). The presence of IEDs on postoperative EEGs was not predictive of seizure outcome either in the whole cohort or in any of the subgroups, regardless of whether it was performed within or after the first two postoperative months. It was also not predictive of outcome in the 44 patients (76%) who did not suffer early recurrence. The authors conclude that EEG performed a few months after epilepsy surgery is not useful as a predictor of long-term seizure outcome.

Adolescent↗
PubMed2004

Full neurologic recovery after fulminant thrombotic thrombocytopenic purpura with status epilepticus.

Thrombotic thrombocytopenic purpura (TTP) is an ischemic vasculopathy frequently associated with neurological dysfunction including seizures. However, status epilepticus (SE) has rarely been reported in this condition. We report on a 70-year-old woman with fulminant TTP who developed convulsive SE despite high therapeutic serum levels of phenytoin and phenobarbital. Her electroencephalogram (EEG) was characterized by bilateral independent periodic lateralizing epileptiform discharges (BIPLEDs) propagating into clinical and electrographic seizures. She recovered completely after intensive plasmapheresis and treatment with pentobarbital induced coma for 5 days. This case illustrates that aggressive treatment with pentobarbital and plasmapheresis may prevent permanent neurologic deficits when TTP is complicated by SE and that periodic lateralizing epileptiform discharges (PLEDs) in this syndrome can be the manifestation of a reversible ischemic insult.

Aged↗
PubMed2004

Sporadic Creutzfeldt-Jakob disease presenting with nonconvulsive status epilepticus.

Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by a spongiform encephalopathy in humans. Although the characteristic triad of myoclonus, dementia, and periodic EEG activity is easy to recognize, unusual manifestations of the disease may be challenging and create a diagnostic dilemma. We report a case of CJD that occurred in a 26-year-old patient who presented with a receptive (Wernicke's) aphasia secondary to nonconvulsive status epilepticus.

Adult↗
PubMed2004

Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 until September 2002, with selected manual searches up to 2003. RESULTS: Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Acetates↗
PubMed2004

Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) [gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS)] in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 to March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. GBP can be effective for the treatment of mixed seizure disorders, and GBP, LTG, OXC, and TPM for the treatment of refractory partial seizures in children. Limited evidence suggests that LTG and TPM also are effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox-Gastaut syndrome. CONCLUSIONS: The choice of AED depends on seizure and/or syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Acetates↗
PubMed2003

Conversion to monotherapy: clinical trials in patients with refractory partial seizures.

The efficacy, tolerability, and safety of a potential antiepileptic drug (AED) are initially evaluated in clinical trials employing add-on designs. When positive, those trials allow us only to conclude that the study drug is efficacious when administered as adjunctive therapy. However, to demonstrate efficacy and safety as monotherapy, the drug must be evaluated using a monotherapy trial design. Such a design needs to take into account important methodologic issues that can affect clinical relevance and/or raise ethical concerns. This review critically assesses two monotherapy trial designs: outpatient conversion to monotherapy and presurgical conversion to monotherapy in patients with medically refractory seizures of partial onset. The efficacy and safety data derived from published studies of AED monotherapy in patients with partial-onset seizures that utilize these trial designs are evaluated and the advantages and disadvantages of each trial design are discussed.

Anticonvulsants↗
PubMed2003

Mechanistic stratification of antineuralgic agents.

Current treatment options in neuropathic pain include antidepressants, antiepileptics, antiarrhythmics, and analgesics. However, stratification of treatments based on their original therapeutic class is inadequate, as drugs belonging to a particular class may have distinct antineuralgic modes of action. It is therefore useful to review the mechanisms of action of these drugs and determine which of these mechanisms is most likely responsible for the drugs' efficacy in the symptomatic treatment of neuropathic pain. Switching from the traditional therapeutic class stratification to one based on putative antineuralgic mechanisms of action will allow more rational selection of therapies, and aid evaluation of the additive or synergistic effects of drugs when used in combination.

Analgesics↗
PubMed2003

Safety and tolerability of oxcarbazepine in elderly patients with epilepsy.

Despite the high incidence of seizures and epilepsy in the elderly, the tolerability and safety of anticonvulsants are rarely evaluated in this patient population. We compared the safety and tolerability of oxcarbazepine in a cohort of 52 patients aged 65 years and older and a group of 1574 adult patients ranging in age between 18 and 64 years. There was no significant difference between the two groups with respect to premature discontinuation due to adverse events. The four most common adverse events experienced by patients in the elderly group, irrespective of their causal relationship to oxcarbazepine, were vomiting (19%), dizziness (17%), nausea (17%), and somnolence (15%). Three patients developed an asymptomatic hyponatremia, with at least one serum sodium level below 125mEq/L. Elderly patients on concomitant natriuretic drugs were significantly more likely to develop serum sodium levels below 135mEq/L. The results indicate that oxcarbazepine is safe to use in elderly patients and that its tolerability in this age group is similar to that of younger adult patients.

Adolescent↗
PubMed2003

Efficacy of topiramate in children with refractory status epilepticus.

PURPOSE: Status epilepticus (SE) is a life-threatening medical condition associated with significant morbidity and mortality that requires urgent medical intervention. Although several agents are available to treat SE, they occasionally fail to abort seizure activity. Topiramate (TPM) was anecdotally reported to be effective in adult patients with refractory SE. In this study, we evaluated the efficacy of TPM administered to children with this condition. METHODS: We retrospectively reviewed the pediatric SE database at the University of Michigan Medical Center and identified three children with refractory SE who were treated with TPM. Those children failed to respond to treatment with benzodiazepines, phenytoin, phenobarbital, midazolam, or pentobarbital. Additional treatment with TPM was administered by nasogastric tube. All patients were continuously monitored by 21-channel digital EEG machines, and the diagnosis of SE was made by a board-certified neurophysiologist. RESULTS: The ages of the three children were 4.5 months, 34 months, and 11 years. TPM was initiated at 2 mg/kg/day in two children and at 3 mg/kg/day in the third. The status was terminated in all three children within 24 h of maintenance therapy with TPM at 5-6 mg/kg/day. CONCLUSIONS: These results support the potential efficacy of TPM for children with refractory SE. Larger prospective series are needed to confirm those results.

Child↗
PubMed2003

Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy.

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy. METHODS: This study is the open-label extension phase that followed a multicenter, randomized, double-blind, dose-response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open-label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double-blind phase of the core study by an intent-to-treat and completer analysis. Safety and tolerability were evaluated by using an intent-to-treat analysis. RESULTS: Of the 87 patients enrolled in the double-blind study, 76 patients participated in the open-label extension phase. Fifty-five (72%) patients completed 48 weeks of open-label treatment on a median OXC dose of 2,400 mg/day. Based on an intent-to-treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient. CONCLUSIONS: The efficacy of OXC is sustained with good safety and tolerability profiles during long-term treatment of patients with medically refractory partial epilepsy.

Adolescent↗
PubMed2003

Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy.

PURPOSE: Epilepsy surgery can result in complete seizure remission rates of upto 80% in patients with mesial temporal sclerosis and unilateral seizures. The seizure-free rate after surgery for patients with extratemporal nonlesional epilepsy has ranged between 30% and 40%. Some patients with medically refractory localization-related epilepsy cannot be offered surgical resection because of inadequate localization of the epileptogenic zone, documentation of bilateral ictal onsets, or functionally important areas of cortex that prohibit resection. The short-term rate of complete remission with medications in temporal lobe epilepsy is poor. Less is known about remission rates in patients who are not surgical candidates. In this study, we evaluated the outcome of medical treatment in patients with medically refractory partial epilepsy who were evaluated for possible epilepsy surgery but deemed to be inadequate surgical candidates. METHODS: A retrospective chart review and telephone survey with a self-rating questionnaire were completed for all patients who underwent epilepsy surgery evaluation but were not ultimately offered surgical treatment at the University of Michigan from 1990 through 1998. We assessed changes in seizure frequency and type, imaging characteristics, ictal recordings, interim medication history, and subjective changes in quality of life. RESULTS: Thirty-four subjects were available for follow-up study, at an average of >4 years after surgical evaluation. A significant reduction in seizure frequency was noted at the time of follow-up compared with that at the time of surgical evaluation. Of patients, 21% achieved seizure remission and remained seizure free for an average of 2.5 years. Four of the seven seizure-free patients attributed their remission to new antiepileptic drugs (AEDs). On a global self-rating item, 15 of 34, or 44%, felt more or much more satisfied with their lives, and 41% felt their quality of life was stable. CONCLUSIONS: A surprisingly large number of patients we surveyed, with refractory partial epilepsy not eligible for surgical management, reported reduced seizure frequency at follow-up, and 21% were seizure free. Our findings suggest that the long-term prognosis in patients with refractory partial epilepsy who are not surgical candidates may be more positive than might be generally expected.

Adult↗
PubMed2002

Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4.

We evaluated a kindred with X-linked mental retardation and epilepsy. Seven affected males with mild to moderate mental retardation developed seizures (primarily generalized, tonic-clonic, and atonic) that began on average at 6.8 months of age (range, 4 to 14 months). These patients did not have a history of infantile spasms. There were no dysmorphic features. Other than mental retardation, the neurological examination was unremarkable, with exception of 2 affected subjects who had mild generalized rigidity and ataxia. We identified tight linkage to a group of markers on Xp21.1-p11.4. A maximum two-point LOD score of +3.83 at straight theta = 0 was obtained for markers DXS8090, DXS1069, DXS8102, and DXS8085. This locus spans 7.7cM between DXS1049 and DXS8054 and does not overlap the locus for X-linked West syndrome. The tetraspanin gene, implicated in nonspecific mental retardation, is mapped to this region. We sequenced the tetraspanin coding sequence in subjects with X-linked mental retardation and epilepsy and did not identify disease-specific mutations. The syndrome we describe, designated X-linked mental retardation and epilepsy, is clinically and genetically distinct from X-linked West syndrome and other X-linked mental retardation-epilepsy syndromes.

Adolescent↗