Neurological disorders associated with cassava diet: a review of putative etiological mechanisms.

Tropical ataxic neuropathy (TAN) and epidemic spastic paraparesis (konzo) are two neurological disorders associated with the consumption of cassava (Manihot esculenta) in several African countries. TAN is characterized by sensory polyneuropathy, sensory ataxia, bilateral optic atrophy and bilateral sensori-neural deafness. It occurs in elderly individuals subsisting on a monotonous cassava diet with minimal protein supplementation. Konzo is a syndrome of symmetrical spastic paraparesis with a predilection for children and young women and invariably associated with consumption of inadequately processed bitter cassava roots with minimal protein supplementation. Despite numerous epidemiological, clinical and biochemical studies aimed at elucidating the etiological mechanisms of these disorders, their etiologies remain unknown, and there is no known treatment. The diseases continue to be prevalent in endemic areas, causing significant disability and increased mortality. A fresh appraisal of the putative etiologic mechanisms proposed for these intriguing and enigmatic syndromes is presented in this paper. Evidences against a causal role for cyanide intoxication are discussed, and evidences implicating thiamine deficiency as a unifying etiological mechanism for these neurological syndromes are presented. It is concluded that urgent research is needed to evaluate thiamine status and implement a therapeutic trial of thiamine in these debilitating neurological disorders.

Evolution of the Vagus Nerve Stimulation (VNS) Therapy System Technology for Drug-Resistant Epilepsy.

The vagus nerve stimulation (VNS) Therapy® System is the first FDA-approved medical device therapy for the treatment of drug-resistant epilepsy. Over the past two decades, the technology has evolved through multiple iterations resulting in software-related updates and implantable lead and generator hardware improvements. Healthcare providers today commonly encounter a range of single- and dual-pin generators (models 100, 101, 102, 102R, 103, 104, 105, 106, 1000) and related programming systems (models 250, 3000), all of which have their own subtle, but practical differences. It can therefore be a daunting task to go through the manuals of these implant models for comparison, some of which are not readily available. In this review, we highlight the technological evolution of the VNS Therapy System with respect to device approval milestones and provide a comparison of conventional open-loop vs. the latest closed-loop generator models. Battery longevity projections and an in-depth examination of stimulation mode interactions are also presented to further differentiate amongst generator models.

Post-ictal alpha activity in supplementary motor seizures mimics nonepileptic seizures.

Supplementary motor area seizures may present with bilateral tonic-clonic movements with no loss of consciousness and no postictal confusion, and patients may be erroneously thought to have psychogenic nonepileptic seizures. We describe the rapid emergence of alpha activity in the immediate postictal period in patients with supplementary motor area seizures as an additional confounding factor that may lead to the erroneous diagnosis of nonepileptic seizures in these patients. We present two cases of patients with intractable supplementary motor area seizures investigated with video/EEG monitoring. Their postictal EEG records revealed an immediate postictal recovery of alpha activity, mimicking the pattern seen with psychogenic nonepileptic seizures. Prolonged video/EEG monitoring is mandatory in establishing the diagnosis of supplementary motor area seizures and in distinguishing this condition from nonepileptic seizures.

Cryptogenic gelastic epilepsy originating from the right temporal lobe.

OBJECTIVE: To present a case of intractable cryptogenic gelastic epilepsy with ictal video-EEG to localize the seizure focus. CLINICAL PRESENTATION AND INTERVENTION: A 39-year-old female presented with a 2-year history of intractable gelastic epilepsy characterized by recurrent episodes of stereotyped pathological laughter, transient unresponsiveness, automatisms and brief postictal confusion. The patient failed to respond to multiple antiepileptic drugs. Several interictal EEGs did not show any abnormalities. Magnetic resonance imaging of the head with seizure protocol and diffusion tensor imaging were normal. Ictal video-EEG monitoring showed rhythmic, sharp activity emanating from the right temporal lobe. CONCLUSION: This case suggests that the right temporal lobe may be actively involved in the epileptogenic network generating gelastic epilepsy. Video-EEG monitoring should be considered for patients with gelastic epilepsies to better clarify the nature of events, localize the seizure focus and correlate EEG changes with the clinical manifestations.

Electroconvulsive treatment for nonepileptic seizure disorders.

Because of its striking prevalence among females, the paroxysmal disorder presenting with nonepileptic seizures was termed hysteria in premodern times. In our time, the disorder has remained widely misunderstood and mistreated. The diagnostic early history of painful traumatic events as the source of the nonepileptic seizures is hidden by the shame of the victim and remains ignored. Early effective psychotherapeutic intervention is rarely carried out. Antiepileptic treatment is commonly initiated, and tends to worsen the seizure condition, which commonly becomes chronic. Key evidence from our treatment of patients with both epileptic and nonepileptic seizures had shown that low doses of antiepileptic drugs were required, because the patients markedly improved as some epileptic seizures were allowed to occur. This prompted our use of electroconvulsive treatment for a select series of 18 patients with the most severe chronic nonepileptic seizure condition. This treatment proved remarkably effective for 11 of the 15 patients who tolerated the treatment. Together with their seizures, the patients had had bodily pains, depressive moods, and often anxiety. Their disorder can be clearly distinguished from ordinary depression, and the remarkable effect of electroconvulsive treatment in its treatment seems to be in accordance with premodern views of a polarity between the two paroxysmal disorders epilepsy and hysteria. Further studies of our topic are called for.

A case of ictal burst-suppression.

"Burst-suppression" pattern consists of complete attenuation of background between bursts of mixed frequencies, variable morphology and waveforms. It is a subgroup of periodic patterns seen in severe cerebral damage, anesthesia or prematurity. Here, we present a 46-year-old woman with post-anoxic encephalopathy on cooling protocol with two electrographically similar patterns of burst-suppression (one with a clinical ictal correlate of isolated eye movements), as well as three electroclinical seizures. The literature on rare clinical phenomenon of isolated eye movements associated with burst-suppression is reviewed, with the conclusion that the presented case suggests an ictal origin.

Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs.

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on staple crops with low thiamine content, or food preparation practices, such as milling grains and washing milled rice. Clinical manifestations of thiamine deficiency are variable; this, along with the lack of a readily accessible and widely agreed upon biomarker of thiamine status, complicates efforts to diagnose thiamine deficiency and assess its global prevalence. Strategies to identify regions at risk of thiamine deficiency through proxy measures, such as analysis of food balance sheet data and month-specific infant mortality rates, may be valuable for understanding the scope of thiamine deficiency. Urgent public health responses are warranted in high-risk regions, considering the contribution of thiamine deficiency to infant mortality and research suggesting that even subclinical thiamine deficiency in childhood may have lifelong neurodevelopmental consequences. Food fortification and maternal and/or infant thiamine supplementation have proven effective in raising thiamine status and reducing the incidence of infantile beriberi in regions where thiamine deficiency is prevalent, but trial data are limited. Efforts to determine culturally and environmentally appropriate food vehicles for thiamine fortification are ongoing.

A diagnosis and treatment gap for thiamine deficiency disorders in sub-Saharan Africa?

Staple diets that are deficient in thiamine can result in low body thiamine levels, which may be subclinical or may manifest as a thiamine-deficiency syndrome. In many communities in the developing countries of Africa, the staple diets of polished rice or processed cassava are deficient in thiamine, and thus the communities are at high risk for marginal or frank thiamine deficiency unless their diets are supplemented by other sources of thiamine, such as protein meals and vegetables. African communities with large numbers of individuals in low socioeconomic strata are more likely to subsist on a monotonous diet of rice or cassava with minimal or no protein supplementation and are therefore particularly at risk of thiamine-deficiency disorders. Indeed, there is evidence of widespread biochemical thiamine deficiency from community-based studies in Africa. The protean manifestations of thiamine deficiency disorders in the developing countries of Africa are presented in this paper. We present evidence supporting the contention that there is a diagnosis and treatment gap for thiamine-deficiency disorders in Africa. We discuss research and clinical options for bridging the putative diagnosis and treatment gap for thiamine-deficiency disorders in the developing countries of Africa.

Thiamine content of F-75 therapeutic milk for complicated severe acute malnutrition: time for a change?

Since community-based management of severe acute malnutrition has become the standard of care, the clinical profile of severe acutely malnourished patients admitted to hospitals or inpatient therapeutic feeding centers has changed significantly. These patients are usually very ill and often present with several comorbidities, such as shock, sepsis, and pneumonia. Complicated severe acute malnutrition patients are at risk of thiamine insufficiency, and critically ill patients have higher thiamine requirements. The thiamine content of F-75, the therapeutic milk formula used in the early stabilization phase of refeeding in patients with severe acute malnutrition, seems insufficient. Here, we discuss the need and rationale for a substantial increase in the thiamine content of F-75.

The effect of vagus nerve stimulation on migraines.

Vagus nerve stimulation (VNS) inhibits nociceptive behavior in animals. VNS might reduce pain in patients with VNS device implanted for intractable seizures. One case report described possible benefits on migraines. We contacted all patients who received VNS therapy for intractable epilepsy between 1993 and 1999 at Southern Illinois University, Springfield, Illinois. Patients who had concomitant chronic pain were subsequently interviewed. Pain intensity before and after VNS implantation was rated by the patient as average, worst, and least and on numeric rating scale from 1 to 10. Current pain measurements were compared to preimplantation by using Global Pain Relief Rating Scale. Of 62 patients who received VNS, 27 patients were interviewed; 4 patients had common migraine, and no other chronic pain syndromes were identified. All patients with migraine reported reductions in headache frequency and numeric rating scale score for average and least headache intensity. One patient reported complete relief of headaches. Improvement was reported to start 1 to 3 months after initiation of therapy. On Global Pain Relief Rating Scale, 1 patient reported complete pain relief, 2 reported a lot of pain relief, and 1 reported slight pain relief. Concomitant antiepileptic drugs were decreased in 3 patients and slightly increased in 1. VNS might be beneficial for prophylactic therapy of migraine.

Update on once-daily zonisamide monotherapy in partial seizures.

Zonisamide is an antiepileptic drug that is structurally different from other antiepileptic agents. Its long half-life, once-daily dosing, lack of induction of hepatic enzymes, and broad spectrum of action makes it a suitable candidate for monotherapy. It has been approved as monotherapy for partial onset epilepsy in Japan and South Korea for more than a decade, and was recently approved as monotherapy in Europe. In the USA, it is only approved by the US Food and Drug Administration for adjunctive treatment of partial onset epilepsy. In this paper, we briefly review the literature on zonisamide monotherapy in partial onset epilepsy with regard to its efficacy, safety, tolerability, and long-term side effects, including a recent noninferiority trial in comparison with extended-release carbamazepine. While European regulatory agencies use noninferiority trials for approval of monotherapy, such a trial design does not meet the current regulatory requirements for approval as monotherapy in the USA.

Lacosamide treatment of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy is the most common form of idiopathic generalized epilepsy with onset at puberty or late teenage years. About 80-90% of patients with juvenile myoclonic epilepsy respond to appropriate antiepileptic treatment and achieve seizure freedom, and about 15% of patients become intractable. Valproic acid, levetiracetam, lamotrigine, topiramate and zonisamide are used as first line or adjunctive therapy of this disorder. Lacosamide is approved for adjunctive treatment of partial onset epilepsies. The role of lacosamide in treatment of idiopathic generalized epilepsy including juvenile myoclonic epilepsy is unknown. We present three patients with classic clinical and electrographic features of juvenile myoclonic epilepsy that were maintained on lacosamide (one on monotherapy and two as adjuvant therapy). There were no special pharmacodynamic actions causing exacerbation or worsening of myoclonic jerks or generalized seizures in these three patients. In conclusion, although, the data from our three patients' suggest that lacosamide may be effective in the treatment of juvenile myoclonic epilepsy, larger studies are needed to explore efficacy and role of lacosamide in the treatment of this disorder.

EEG findings in an adult with severe case of alobar holoprosencephaly.

Holoprosencephaly is a category of congenital brain malformation that is frequently associated with epilepsy. Epileptic spasms and partial seizures are reported with a variety of electrographic ictal and interictal EEG findings. We report a case of severe alobar holoprosencephaly with cortical tissue limited to inferior-anterior-frontal areas and a thin mantle over the posterior areas, and no appreciable connective fibers to the subcortical structures. Interictal EEG consisted mainly of 2-3 Hz irregular delta activity during wakefulness and sleep. Clinical seizures had two different semiologies: (1) epileptic spasms lasting 0.5s during state change and (2) prolonged tonic spasms lasting 5-8s followed by appendicular clonic activity, abnormal nystagmoid eye movements and eye flutter lasting 5-8s. Preceding the epileptic spasms, there was 1-2s of electrodecrement in the EEG. During prolonged tonic spasms there was also electrodecrement in the EEG. No other electrographic activity was seen. Due to lack of any appreciable connecting fibers between cortical and subcortical structures, these findings suggest an increase in brain stem excitability with inefficient (or lack of) cortical modulation as a possible underlying mechanism for epileptic spasms in this patient.

False lateralization of seizure onset by scalp EEG in neocortical temporal lobe epilepsy.

False lateralization of ictal onset by scalp EEG has been reported in patients with severe hippocampal sclerosis associated with hemispheric lesions or atrophy. There has been no report of cases of false lateralization by scalp EEG in patients without detectable structural abnormalities on MRI, or in patients with neocortical temporal lobe epilepsy. We report a case of false lateralization of ictal onset by scalp EEG in a patient with neocortical temporal lobe epilepsy and a normal MRI examination, investigated by intracranial EEG recordings. The ictal activity failed to propagate in the ipsilateral temporal lobe, but was strongly propagated to the contralateral temporal lobe resulting in a false lateralization of seizure onset by scalp EEG. It is possible that the poor homolateral propagation and evolution of ictal activity in this patient may be due to a functional rather than structural abnormality of the ipsilateral hippocampus, causing reduced synchrony and amplitude in the ipsilateral temporal cortex.

Etiology of Konzo, epidemic spastic paraparesis associated with cyanogenic glycosides in cassava: role of thiamine deficiency?

Konzo is a syndrome of symmetrical, non-progressive, non-remitting spastic paraparesis occurring in epidemic and endemic forms in several countries in Africa, invariably associated with monotonous consumption of inadequately processed bitter cassava roots (Manihot esculenta) with very minimal protein supplementation. Despite numerous epidemiological, clinical and biochemical studies by authors in several countries aimed at elucidating the etiological mechanisms of Konzo, the etiology remains unknown. High cyanide consumption with low dietary sulfur intake due to almost exclusive consumption of insufficiently processed bitter cassava roots was proposed as the cause of Konzo, but there has been no evidence of a causal association between cyanide consumption and Konzo. In this paper a new etiological mechanism of thiamine deficiency is presented, based on detailed review of the epidemiological, clinical and biochemical features of Konzo. It is postulated that in Konzo patients, a severe exacerbation of thiamine deficiency results from the inactivation of thiamine that occurs when, in the absence of dietary sulfur-containing amino acids; the sulfur in thiamine is utilized for the detoxification of cyanide consumed in improperly processed bitter cassava. Thiamine is known to be rendered inactive when the sulfur in its thiazole moiety is combined with hydrogen cyanide. This hypothesis may stimulate studies examining the role of thiamine in the etiology of Konzo, and may lead to the formulation of strategies for the prevention and treatment of this debilitating disease.

Thiamine deficiency and the etiology of tropical ataxic neuropathy.

Tropical ataxic neuropathy (TAN) is a syndrome characterized by sensory polyneuropathy, sensory ataxia, bilateral optic atrophy and bilateral sensorineural deafness. The syndrome has occurred in endemic form in several African countries, and in epidemic form in Cuba. In endemic communities, the syndrome has a high prevalence and a demonstrated risk for high mortality. Despite several studies aimed at elucidating the etiological mechanisms of TAN, the etiology has remained unknown more than five decades after its original description. Chronic cyanide intoxication from a monotonous diet of cassava was long thought to be the major etiological factor, but there has been no evidence of a causal association. Vitamin deficiencies were thought to play little or no role in the pathogenesis of TAN. Evidence from the literature implicating chronic thiamine deficiency in the etiology of TAN is presented in this communication. This includes evidence of abnormal pyruvate metabolism reversed by thiamine in patients with TAN, evidence from erythrocyte transketolase activity indicating significant thiamine deficiency in patients with TAN compared to controls, and a placebo-controlled trial of therapeutic doses of thiamine which showed a clinically dramatic and statistically significant improvement in ataxia. A long-term thiamine supplementation program for susceptible individuals in endemic areas may be effective in the control and eventual eradication of the disease.

Partial epilepsy presenting as focal atonic seizure: a case report.

A case of atonic seizures localized to the frontal lobe by video-EEG monitoring is reported. The patient is a 38-year-old female with intractable atonic seizures characterized by abrupt onset of facial grimacing and a slow head drop. The onset of atonic seizures was about 6 years before presentation. Video-EEG monitoring showed that her atonic seizures were emanating from the right frontal head region. A high voltage spike and slow wave discharge invariably coincided with the onset of atonic seizures in the patient, similar to the interruption of tonic muscular activity time-locked to a spike on the EEG described in epileptic negative myoclonus; a syndrome associated with epileptic activity in the premotor cortex. Since routine MRI imaging in this patient was normal, diffusion tensor imaging (DTI) was applied to analyze the white matter integrity of the normal-appearing white matter in the frontal lobes of the patient. We compared the fractional anisotropy, parallel diffusivity and perpendicular diffusivity of normal-appearing white matter in the right versus left frontal lobe. Our results showed no significant difference between the two sides. Possible reasons for the normal DTI findings are discussed.

Intrinsic ictal dynamics at the seizure focus: effects of secondary generalization revealed by complexity measures.

PURPOSE: Partial seizures (PSs) may be self-limited regional events or propagate further and secondarily generalize. The mechanisms and dynamics of secondarily generalized tonic-clonic seizures (GTCSs) are not well understood. Methods with which to assess the dynamic of those events are also limited. METHODS: Seizures were analyzed from patients with intractable partial seizures undergoing monitoring with intracranial electrodes. Inclusion in this study required patients to have at least one PS and one GTCS. From >120 patients, seven patients fulfilled these criteria, three with mesial temporal (MTLE) onset seizures and four with neocortical lesional (NCLE) onset seizures. In total, 50 seizures were analyzed by using the matching pursuit (MP) method and the Gabor atom density (GAD), a measure of signal complexity derived from the MP method. RESULTS: The GAD complexity pattern at the seizure focus for the initial ictal period is remarkably consistent in a given patient, regardless of whether secondary generalization occurs. Secondary generalization produces greater modification of seizure activity at the focus in patients with NCLE than in patients with MTLE. In seizures from four patients with NCLE, secondary generalization resulted in an average increase of 115% in complexity at the focus compared to PSs. CONCLUSIONS: GAD shows that seizure dynamics of PSs are often very stereotyped from seizure to seizure in a given patient, particularly during early ictal evolution. Secondary generalization is more likely to produce changes in the duration and dynamics at the seizure focus in NCLE patients compared with MTLE patients. These observations suggest distinct mechanisms (e.g., feedback) that are operational during secondary generalization.