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Case Report

Insulinoma presenting as refractory seizure disorder

[version 1; peer review: 2 approved]
PUBLISHED 21 Sep 2012
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Abstract

Hypoglycaemia can lead to acute disorders of cognition, consciousness, epilepsy, transient ischemia, psychosis and chronic disorders of dementia and neuropathy. Misdiagnosis and delay in treatment are common and prolonged hypoglycemia can lead to permanent neurological deficit or fatal coma. Hypoglycemia caused by an insulinoma is a readily treatable condition that should be considered in the differential diagnosis of intractable seizures. The following case report highlights the need for careful reassessment of all seizures that are atypical and refractory to medication.

Keywords

Hypoglycemia, seizures, insulinoma

Case report

A 29 year old man had a one year history of multiple seizure episodes, which were as frequent as 3–4 episodes in a week despite being on regular antiepileptic medication of 3 drugs including carbamazepine, sodium valproate and clobazam. All the episodes were uncannily similar in that they always occurred on awakening and in the early hours of morning, between 5.00 to 7.00 am. The attacks were episodic stereotyped confusional spells characterized by abnormal posturing, perioral and eyelid twitching and unresponsiveness. The attacks would usually last from a few minutes to about half an hour. Upon initial OPD visits, compliance was checked and metabolic causes were ruled out. MRI Brain was done which was normal. No interracial epileptic activity was observed during prolonged video EEG monitoring.

Five months later, seizures started occurring at increased frequency. On presentation to our hospital he was brought early morning in an unconscious state and was found to have hypoglycemia (48 mg/dl) which recovered immediately after treatment. On further questioning, it was apparent that his previous seizures tended to occur in early morning or several hours after the meal and that the post seizure confusion state could be shortened if he ate something during the confusion period. The patient had gained 10 kg weight over the period of last 6 months. The subsequent endocrine evaluation suggested insulinoma. Contrast enhanced CT revealed a solitary insulinoma in the head of pancreas. (Figure 1 and Figure 2) The patient underwent a surgical removal of the insulinoma with a Whipple’s resection procedure. A benign insulinoma was confirmed on histopathological examination. Following the procedure he has been totally seizure free and asymptomatic for last 6 months.

56d73c01-6c08-4eb5-b6e2-7e04e6e9c549_figure1.gif

Figure 1. Contrast enhanced CT revealed a solitary insulinoma in the head of pancreas.

56d73c01-6c08-4eb5-b6e2-7e04e6e9c549_figure2.gif

Figure 2. Contrast enhanced CT (transverse section) revealed a solitary insulinoma in the head of pancreas.

Discussion

Insulinomas are the commonest hormone-secreting tumor of the gastrointestinal tract; the incidence is 4 cases/million/year. Tumors may occur as a unifocal sporadic event or in 5–10% of patients with MEN-1. 10% are metastatic, and a further 10% are multiple but behave as benign tumors. Insulinomas are found throughout the pancreas and are small (usually 10–20 mm). The median interval from onset of symptoms to the diagnosis of insulinoma is 2 years with a wide range of one month to 30 years as reported by Service F. and collegues1. Presentation is usually insidious with neuroglycopenia and fasting hypoglycemia.

Diagnosis relies on key neuroglycopenic and sympathetic symptoms together with biochemical confirmation by documenting blood glucose levels below 50 mg/dl during monitored symptomatic episodes (that improve with oral intake), elevated C-peptide levels (>200 pmol/L), increased serum insulin levels (>5 µmol/mL), and absence of plasma sulfonylurea.

Many patients with an insulinoma do not report the adrenergic symptoms of hypoglycemia and present with neurological or psychiatric manifestations that often lead to misdiagnosis. The delay in diagnosis is due to several factors. Firstly, the symptoms of insulinoma lack specificity, including various seizure disorders, personality change, bizarre behavior, amnesia, convulsions, and incidentally dystonia and polyneuropathy; these symptoms are similar with many common neurological and psychiatric disorders. Secondly, fasting blood glucose level can be normal in some patients. Thirdly, hypoglycemia itself induces neuroglycopenic and autonomic unawareness.

Seizure disorder has been described in few contemporary cases of persistent hypoglycemia later on diagnosed as insulinoma two of them reported by Akanji A. and colleagues in 1992 followed by Basil C. and Pack A. in 20012,3. Of late Wang S. and his colleagues described recurrent episodes of automatism, confusion and convulsion with electroencephalography (EEG) findings resembling the pattern in complex partial seizures in a case of insulinoma4. Jaladyan V. and Darbiyan V. described a case of a girl presenting with drug-refractory myoclonia and generalized tonic-clonic seizure (GTCS) initially misdiagnosed as having juvenile myoclonus epilepsy (JME) before insulinoma was detected5. O’sullivan S. and Redmond J. also presented a case of insulinoma misdiagnosed as late onset refractory epilepsy6.

As in our case, the interpretation of clinical symptoms and normal EEG with seizures refractory to treatment was indicative of any toxic or metabolic cause or poor compliance to treatment. The possibility of hypoglycemia was excluded by three normal blood glucose measurements. Furthermore hypoglycemia due to an insulinoma especially in a young age group comes little lower in the list of other possible causes. Insulinoma, responsible for profound hypoglycemia usually has its onset in middle or older age. Symptoms are usually prominent following prolonged fasting states, especially in the morning as in our patient, but also in late afternoon.

Insulinoma can also mimic other neurological diagnoses apart from seizures. In Daggett and Nabarro's review of 252 reported cases the most common neurological symptoms were confusion, coma, and seizures7. Non-specific headache, generalized weakness, paraesthesia, and stroke-like paralysis were less frequent and dizziness and dysarthria were uncommon. Newman and Kinkel reported a diabetic woman who developed two episodes of limb choreoathetosis and opisthotonus associated with hypoglycemia8. Winer et al. described a woman with an insulinoma who, when recovering from hypoglycemic attacks developed abnormal posturing of her body9. Chronic neuropathic and dementing syndromes due to hypoglycemia have also been described by Danta G. and Snook J. and his colleagues10,11. In a prospective survey done by Harrington M., two of 25 patients referred to neurologists with "funny turns" were found to have an insulinoma12.

This case highlights the importance of considering hypoglycemia in atypical neurological or psychiatric episodes and emphasizes the role of inpatient evaluation of refractory epilepsy. Neuroglycopenia should be considered in all patients with seizures, and other neuropsychiatric symptoms, especially if they do not conform to diagnostic criteria or respond to standard treatment. Taking a full history (including relationship of attacks to food, non-stereotyped or atypical attacks, and poor response to treatment) and clinical suspicion are the key to making a diagnosis of insulinoma. Once suspected, confirming the diagnosis with a 72 h fast is relatively simple.

Benign insulin secreting adenomas are a potentially curable cause of seizures but may be fatal if unrecognized. Our case reiterates the importance of evaluating the metabolic cause of refractory seizure disorders. Although sometimes insulinoma shares some common semiological and EEG features, the possibility of atypical causes like insulinoma associated seizures should be considered in patients with some clues to diagnosis like close relationship to food intake, history of weight gain atypical attacks, seizures refractory to treatment. Seizures that present with such a particular prototypical pattern should arouse a strong clinical suspicion. Hence, early diagnosis and treatment can free many a patient from burdensome multiple antiepileptic treatments.

Consent

Written informed consent was obtained for publication of their clinical details and images was obtained from the patient.

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Correia P, Panchani R, Ranjan R and Agrawal C. Insulinoma presenting as refractory seizure disorder [version 1; peer review: 2 approved]. F1000Research 2012, 1:15 (https://doi.org/10.12688/f1000research.1-15.v1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 21 Sep 2012
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Reviewer Report 02 Oct 2012
Niki Karavitaki, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK 
Approved
VIEWS 10
I confirm that I have read this submission and believe that I have an ... Continue reading
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Karavitaki N. Reviewer Report For: Insulinoma presenting as refractory seizure disorder [version 1; peer review: 2 approved]. F1000Research 2012, 1:15 (https://doi.org/10.5256/f1000research.117.r456)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 29 Sep 2012
Francesco Minuto, Department of Endocrinology and Metabolism, University of Genova, Genova, Italy 
Approved
VIEWS 9
On viewing this seems like properly done research. The work itself ... Continue reading
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CITE
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Minuto F. Reviewer Report For: Insulinoma presenting as refractory seizure disorder [version 1; peer review: 2 approved]. F1000Research 2012, 1:15 (https://doi.org/10.5256/f1000research.117.r455)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 21 Sep 2012
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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