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Star fruit has been reported as containing neurotoxins that often cause severe neurological complications in patients with chronic renal disease. We report two patients with chronic renal failure at a pre-dialyzed stage who developed refractory status epilepticus after ingestion of star fruit. In addition, we review 51 cases in the literature. Among 53 patients, 16 patients presented with epileptic seizures (30%). The mortality rate was as high as 75% in patients with seizures. On the other hand, in patients without seizures, the mortality rate was only 0.03%. There is a poor correlation with the degree of underling renal function and mortality due to intoxication. We propose that epileptic seizure is significantly associated with poor prognosis, and that status epilepticus is an unpredictable and potentially fatal complication in star fruit intoxication. We advise consultant neurologists that star fruit intoxication must be considered when patients with chronic renal disease present with seizures or other unexplained neurological or psychiatric symptoms. Since no effective treatment has been established, star fruit consumption should be avoided in patients with chronic renal disease, especially in the elderly.
Star fruit (Averrhoa carambola), which originated in Southeast Asia in prehistoric times, has been cultivated in many tropical and warm subtropical areas including Taiwan, Brazil, Thailand, Malaysia, Indonesia, India and Southern China. This fruit was introduced into the American tropics 150 years ago. Becoming increasingly popular in Western markets, Taiwanese and Brazilian star fruits are also available in many European countries and Canada. In Taiwan, this fruit is usually consumed fresh or as pickled juice. Star fruit is also recommended as a diuretic or as an expectorant and cough suppressant. However, outbreaks of star fruit intoxication have been reported in patients with chronic renal disease.
The most common symptoms in star fruit intoxication include persistent and intractable hiccups, vomiting, variable degrees of disturbed consciousness, psychiatric symptoms, decreased muscle power, paresthesia, paresis, insomnia, epileptic seizures and death.
conscious disturbance is suggested as being associated with poor prognosis. Nevertheless, the role of epileptic seizures in star fruit intoxication is infrequently mentioned in the literature, particularly regarding neurologic issues.
Herein, we report two patients with chronic renal failure at a pre-dialyzed stage who developed refractory status epilepticus after ingestion of star fruit. In addition, we review reported cases of star fruit intoxication in the literature. This study aims to elucidate the relationship of seizures and the neurotoxicity of star fruit and to ascertain whether the high mortality rate in such patients is associated with the occurrence of seizures.
Methods
Two patients with chronic renal disease who had acute neurological complications and status epilepticus after consumption of star fruit were reported. A Medline research was conducted to identify published papers regarding star fruit intoxication between 1967 and February 2005. In addition, other relevant articles that had been published in Taiwanese journals were searched through a prominent reference database in Taiwan, “Index to Chinese Periodical Literature”. Our attention focused on the epileptic seizures occurring during the course of star fruit intoxication.
Results
Patient 1
An 84-year-old female had been diagnosed with chronic renal insufficiency, but hemodialysis was not clinically required yet. She had nausea, incoherent speech, echolalia and bizarre behavior after consuming three fresh star fruits over three days. Thus, the patient was admitted to our hospital. On initial examination, her blood pressure was 175/103 mmHg, and her body temperature was 36.4 °C. The initial laboratory investigation revealed that glucose was 9.1 mmol/L, blood urea nitrogen (BUN) was 18.56 mmol/L, creatinine (Cr) was 671.84 μmol/L, sodium was 143 mmol/L, potassium was 5.4 mmol/L, ammonia was 36.98 μmol/L, and white blood cell count was 8.6 × 109/L. The brain computed tomography scans showed negative findings, and the cerebrospinal fluid (CSF) study revealed normal results. There was no history of alcoholic or drug addition, other systemic diseases, psychiatric disorders or use of medication.
On the secondary day of admission, she later experienced conscious disturbance, rapidly progressing into a coma. Moreover, epileptic seizures with focal motor onset developed, which evolved into status epilepticus. The seizures began from the left side and were initially clonic in nature, later becoming secondary generalized tonic–clonic seizures. She received intravenous phenytoin, phenobarbital, and valproic acid treatment, but epilepsia partialis continua over the left part of the face and shoulder still persisted for three days. The epilepsia partialis continua was finally controlled by propofol use. Although under propofol therapy, an electroencephalogram (EEG) showed bilateral periodic lateralized epileptiform discharges. Brain magnetic resonance imaging (MRI) revealed regional hyperintensities over the bilateral parietoocciptital gray matter with right-side predominance on T2-weighted images and diffusion-weighted images (Fig. 1). Despite performing hemodialysis, the patient died on day 23.
Figure 1Axial view of diffusion weighted image (10000/112/1; b = 1000 s/mm2) shows restrictive diffusion at the bilateral parietooccipital cortex with right-side predominance in Patient 1.
A 74-year-old male with chronic renal insufficiency presented with persistent hiccups and vomiting after ingestion of two fresh star fruits. On day 3, he presented with mental confusion, disorientation and agitation. He was later brought into our emergency room. Initial laboratory data showed that glucose was 5.83 mmol/L, BUN was 18.2 mmol/L, Cr was 415.48 μmol/L, sodium was 133 mmol/L, potassium was 5.1 mmol/L and ammonia was 26.42 μmol/L. There was no fever or infectious signs, and the white blood cell count was slightly elevated to 12.2 × 109/L. The CSF study revealed negative results. Brain MRI revealed old left cerebellar infarction and age matched brain atrophy.
After admission, the patient's consciousness progressively deteriorated, and hiccups and vomiting persisted. Moreover, clonic seizures and facial twitching developed, evolving to status epilepticus. The status epilepticus was refractory to phenytoin and valproic acid therapy. Although emergency hemodialysis was performed, he died on day 7.
Data analysis
A total of 53 patients were included in this study. There were 16 patients who had seizures after star fruit intoxication and 37 patients without seizures occurring during intoxication. Clinical features of the 16 patients with seizures are summarized in Table 1.
Table 1Clinical features of 16 patients with epileptic seizures induced by star fruit intoxication.
The patients were aged between 39 and 84 years. All of the patients had variable degrees of chronic renal disease. In the patients with seizures, 10 patients (62%) had end-stage renal disease on regular dialysis and 6 (38%) were in a pre-dialyzed condition. On the other hand, in the patients without seizures, 27 (73%) patients had received regular dialysis and 10 (27%) were in a pre-dialyzed condition. Among the 16 patients with seizures, 15 patients
had non-convulsive status epilepticus. The overall mortality rate was 24.5%. However, the mortality rate among the 16 patients with seizures was 75%. On the other hand, in patients without seizures, only one patient died, and the mortality rate was 0.03%.
Discussion
Patients with chronic renal disease are vulnerable to developing intoxication through drugs or toxins, and star fruit is probably the only natural fruit that is associated with neurotoxicity in such patients with renal insufficiency.
with star fruit extract injected intraperitoneally into normal mice, resulting in convulsions. Moreover, intracerebroventricular injection of the fruit extract in rats or mice induces immediate and persistent tonic–clonic convulsions.
It has been postulated that an excitatory neurotoxin of an unknown nature exists in star fruit, which could be responsible for the neurological complications in patients with chronic renal disease.
status epilepticus. The mortality rate of patients with seizures occurring after star fruit intoxication is significantly higher than of patients without seizures. Obviously, this result implies that epileptic seizures are a poor prognostic factor in star fruit intoxication.
There is a poor correlation with the degree of underlying renal function and the mortality of intoxication, while more severe symptoms may develop in those patients with pre-dialyzed condition as opposed to those with end-stage renal disease. In this study, we found epileptic seizures progressing to status epilepticus and death in patients with various renal function status. It is clinically important to know that status epilepticus may be a fatal neurological complication following star fruit intoxication, not only in end stage renal disease but also in patients with pre-dialyzed renal disease.
Seizure is a common neurological complication in patients with renal failure, which may be caused by uremic encephalopathy, disequilibrium dialysis syndrome, hypertensive encephalopathy, fluid and electrolyte disturbances, drug intoxication, intracranial hemorrhage, and central nervous system infections.
However, our patients were not in a serious uremic stage, and they had not previously undergone hemodialysis before. The status epilepticus occurred immediately after ingestion of star fruit, suggesting the convulsant effect of neurotoxin in star fruit. Based on the results of brain MRI scans, CSF studies, clinical information and biochemistry data, other medical causes for the seizure could be excluded in our patients.
Although star fruit has enriched potassium content, hyperkalemia has not been suggested as causing death in reported cases.
Our results were consistent with this notion. Our two patients also presented with no severe hyperkalemia. Furthermore, we found that the amount of ingestion was not related to the symptoms or mortality. Even a small amount of star fruit can cause severe neurological complications and death. The degree of severity of intoxication is variable. We supposed that ethnic and genetic factors might participate in the clinical presentations within the neurotoxicity of star fruit.
Some researchers suspect that there are different toxins in different star fruit subspecies, as well as a powerful neurotoxin that can accumulate in blood and cross the blood–brain barrier in patients with chronic renal disease, eventually causing refractory status epilepticus.
Single voxel proton and 31phosphorous MR spectroscopic studies revealed elevation of lactate, elevation of inorganic phosphate, and reduced phosphocreatine and nucleoside triphosphates in the cerebral cortex in an intoxicated patient.
The metabolic changes indicated the neurotoxin could interfere with oxidative phosphorylation and cause energy deprivation. Although the exact nature of star fruit neurotoxin remains obscure, oxalate, being abundant in star fruit, has been proposed as a possible candidate for acute nephropathy and neurotoxicity.
The definite neurotoxin responsible for star fruit intoxication has not yet been identified. Further studies are needed to elucidate the exact molecule that causes the neurotoxicity.
The unknown neurotoxin in star fruit has been suggested as dialyzable, and intensified dialysis should be tried as a means of therapy in intoxicated patients.
In our two patients, the status epilepticus was characterized by focal convulsion and myoclonus, which is refractory to intravenous administration of phenytoin, phenobarbital and valproic acid. Even though convulsions could be controlled by propofol therapy in Patient 1, EEG studies still showed epileptiform discharges, and a brain MRI showed regional hyperintensities over the gray matter on T2-weighted images and diffusion-weighted images, suggesting this patient was still in the ictal period. Consistent with other reported cases with seizures,
treatment with antiepileptic drugs and hemodialysis were unsuccessful. Plasma exchange has been suggested as an effective treatment of status epilepticus caused by star fruit intoxication.
This suggestion requires further confirmation, particularly in the timing, frequency and dosage of plasma exchange. Although status epilepticus in star fruit intoxication is associated with high mortality, further studies are necessary in the future to develop a more effective antiepileptic drug regimen and novel neuroprotective strategies to reduce brain damage caused by neurotoxin-induced energy deprivation.
In conclusion, neurological and psychiatric symptoms are common presentations, but are often ignored in star fruit intoxication. Epileptic seizure is significantly associated with poor prognosis, and status epilepticus is an unpredictable and potentially fatal complication of intoxication. We warn consultant neurologists that star fruit intoxication must be considered when patients with chronic renal disease present with seizures or other unexplained neurological or psychiatric symptoms. Because no effective treatment has been established, star fruit consumption should be avoided in patients with chronic renal disease, especially in the elderly.
References
Chang J.M.
Hwang S.J.
Kuo H.T.
Tsai J.C.
Guh J.Y.
Chen H.C.
et al.
Fatal outcome after ingestion of star fruit (Averrhoa carambola) in uremic patients.
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