Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.

SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.

The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.

“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”

Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.

The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.

None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.

“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

A 26-year-old woman presented to a nephrology office in Virginia for a reevaluation and second opinion regarding her history of kidney stones. This condition had led to uremia and acute kidney failure, requiring hemodialysis.

Her history was significant for recurrent kidney stones and infections, beginning at age 12. Over the next six years, she passed at least five stones and underwent three lithotripsy procedures; according to the patient, however, neither she nor her parents were ever informed of any decrease in her kidney function. The patient said she had been told that her stones were composed of calcium oxalate, and she was placed on potassium citrate therapy but did not take the medication on a regular basis.

After high school, she left the area for college and for several years she frequently and spontaneously passed gravel and stones. She was a runner in high school and college and had two children without experiencing any hypertension, proteinuria, or stone problems during her pregnancies. She had been treated for numerous recurrent urinary tract infections in outpatient clinics and private offices during the 10 years leading up to her current presentation. She had a distant history of a cholecystectomy.

In May 2009, the patient was hospitalized for a kidney infection and underwent cystoscopy with a finding of left ureteral obstruction caused by a stone. A stent was placed, followed by lithotripsy. Her serum creatinine level was measured at 2.2 mg/dL at that time (normal range, 0.6 to 1.5 mg/dL). In August 2009, she was treated again for a kidney infection; a right-sided stone obstruction was noted at that time, and again a stent was placed and lithotripsy was performed. Her serum creatinine level was then 3.3 mg/dL. During these episodes, the patient’s calcium level ranged from 8.2 to 10.1 mg/dL (normal, 4.5 to 5.2 mg/dL). Her phosphorus level was noted to range from 2.6 to 9.5 mg/dL (normal, 2.5 to 4.5 mg/dL).  Her intact parathyroid level was 354 pg/mL (normal, 10 to 60 pg/mL). Thus, she had documented secondary hyperparathyroidism, which was treated with paricalcitol and a phosphate binder.

In February 2010, the patient was “feeling poorly” and was taken to a local hospital in South Carolina. She was admitted in acute renal failure and started on dialysis. She did well on hemodialysis with little to no fluid gain and good urine volume. She returned to Virginia temporarily for treatment, to be closer to her family and to prepare for kidney transplantation. She had family members who were willing to donate an organ.

The patient’s family history was negative for gout, kidney disease, or kidney stones. No family member was known to have hypertension, diabetes, or enuresis.

Physical examination showed a thin white woman with a runner’s lean look. She denied laxative use. Her blood pressure was measured at 120/84 mm Hg, and her pulse, 96 beats/min. Findings in the skin/head/eyes/ears/nose/throat exam were within normal limits except for the presence of contact lenses and a subclavicular dialysis indwelling catheter. Neither thyroid enlargement nor supraclavicular adenopathy was noted. Her heart rate was regular without murmurs. The abdomen was soft and nontender without rebound. The extremities showed no edema. Neurologic and vascular findings were intact.

The most recent 24-hour urine study showed a urine creatinine clearance of 4 mL/min (normal, 85 to 125 mL/min), despite a very large urine volume. Renal ultrasonography revealed two small kidneys that were highly echogenic, with evidence of medullary nephrocalcinosis without obstruction bilaterally.

The presentation of a woman with a kidney stone load high enough to cause full kidney failure by age 26 led the nephrologist to suspect the presence of hyperoxaluria type 1 (primary) or type 2 (secondary). The patient’s urine oxalate level was 158 mcmol/L (normal, < 57 mcmol/L), and her plasma oxalate level was 73 mcmol/L (normal, < 10 mcmol/L).

In response to the patient’s high blood and urine oxalate levels and her interest in kidney transplantation, genetic testing was performed to determine whether she had type 1 or type 2 hyperoxaluria. If she was found to have type 1 hyperoxaluria, she would need a liver transplant before her body showered a newly transplanted kidney with stones, causing recurrent kidney failure.

Discussion
Primary hyperoxaluria (PHO) type 1 is a very rare recessive hereditary disease with a prevalence of one to three cases per one million persons.¹ Patients typically present with kidney stones at an early age (as did the case patient) or in full kidney failure. It is calculated that PHO is responsible for 1% of all end-stage renal disease among pediatric patients.^2,3

Stones are caused by a deficiency of the liver enzyme alanine-­glyoxylate aminotransferase (AGXT), which ordinarily converts glyoxylate to glycine.^2,4 When AGXT is absent, glyoxylate is converted instead to oxalate, which forms insoluble salts that accumulate in the kidney as oxalate kidney stones. Most patients (ie, 80% to 90%) present in late childhood or early adolescence with systems of recurrent stones and urinary tract infections resulting from blockage.^5,6 The natural history of the disease is progression to kidney failure and death from end-stage renal disease unless dialysis is initiated. 

While testing of oxalate-to-creatinine molar ratio in a random urine sample may be helpful, this measurement does not stabilize until age 14 to 18—often after kidney damage has already occurred.⁷ Liver biopsy can confirm whether the enzyme AGXT is absent. Differentiation between PHO and type 2 hyperoxaluria can only be confirmed by genetic testing in which the AGXT gene is identified.⁸

There is an increased incidence of PHO in Tunisia and Kuwait^9-11 and in the Arab and Druze families of Israel¹² as a result of intermarriages in this population. Since AGXT is a recessive gene, the child of parents who are both carriers has a 25% chance of having the disease. If either parent carries the genetic variant, there is a 50% chance that the recessive gene will be passed on.

Diagnosis
Early diagnosis of PHO is critical. However, because the disease is so rare, more than 40% of affected patients do not receive a diagnosis until three years after symptoms develop, and 30% are diagnosed only upon presentation with end-stage renal disease.^2,13

If PHO is detected early, the key management goal is to minimize renal and skeletal oxalate deposition. Components of medical management are shown in the table.^2,14-17 It is important to note that these strategies are effective only if initiated early, that is, before the patient’s glomerular filtration rate drops below 25 mL/min.¹⁸

Treatment
Organ transplantation remains the only definitive treatment for PHO^14,19—to prevent severe systemic oxalosis or to manage the patient who has progressed to end-stage renal disease. Researchers from the Mayo Clinic in Rochester, Minnesota (where, it should be noted, a National Oxalosis and Hyperoxaluria Registry is maintained under the direction of Dawn S. Milliner, MD), recently published an observational study of outcomes in transplant graft survival among 203 PHO patients. Bergstralh et al²⁰ reported high rates of recurrent oxalosis in patients undergoing kidney transplantation alone, and significantly improved outcomes in patients who underwent both liver and kidney transplantation.

Before 1990, according to a report by the Rare Kidney Stone Consortium,¹⁸ the prognosis for PHO transplant patients in the United States was so poor that a donor kidney was considered wasted on these patients. Since the year 2000, however, survival after transplantation has improved greatly, with rates similar to those of all kidney transplant patients nationwide. The explanation for increased survival rates among PHO patients undergoing transplantation was twofold:

• Increased preoperative stone control

• Use of combined liver-kidney transplants.^21,22

Since the liver is responsible for the cascade of calcium oxalate stones, the native liver must be fully removed prior to transplantation of a new liver and kidney. Postoperatively, stones will also emerge from where they have lodged in the skeletal tissue to shower the new kidney. Thus, medical management of this cascade of new stones is vital if the transplanted grafts are to survive.²³ Calcium oxalate blood levels can remain high for one to two years posttransplantation,^2,24 so long-term medical management of oxalate is essential.

The Case Patient
Clinicians engaged in a discussion with the patient and her family regarding a possible diagnosis of PHO. Blood was drawn and sent to the Mayo Clinic for genetic analysis. It was found that the patient had an abnormality in the AGXT gene; with the diagnosis of type 1 hyperoxaluria confirmed, she was flown to Rochester for a full workup.

The patient was the only member of her family with the defective AGXT gene, and her genetic counselors considered this a single mutation. She was accepted for the liver/kidney transplantation list. 

Due to the increase in reported survival among patients if they undergo transplantation early in the natural history of stone deposition, the average wait time for PHO patients is only three to four months. The case patient returned to the dialysis unit in Virginia, where she was placed on a dialysis regimen of five-hour treatments, five times per week (nighttime and day); this was determined to be the peak treatment duration for most efficient stone removal, as determined by calcium oxalate measurement during her workup at the Mayo Clinic.

This regimen was continued for three months, at which time the patient was nearing the top of the transplant waiting list. She returned to the Mayo Clinic in September 2010 and underwent transplantation in October; since then, she has regained excellent kidney function and experienced an immediate drop in her calcium oxalate levels. She remained in Rochester until late November, then returned to her home in South Carolina, where she continues to undergo follow-up at a local transplantation center.

The case patient was fortunate that an attending nephrologist at the nephrology office in Virginia developed a high clinical suspicion for her actual condition and started the workup that led to a diagnosis of PHO. She could well have been among the 19% of patients with PHO in whom the correct diagnosis is not reached until after a newly transplanted kidney has been showered with stones again,^18,25 necessitating a second kidney transplant following the essential liver transplantation.

Before her current presentation, the patient had been under the care of another nephrologist and had spent six months on a transplant waiting list. If she had proceeded with her original plan, the scheduled kidney transplant (unaccompanied by the essential liver transplant) would have been ineffective, and her donor would have undergone major surgery to no good result.

Conclusion
Type 1 hyperoxaluria is a rare diagnosis that is frequently missed. According to data from the Rare Kidney Stone Consortium,¹⁸ nearly one-fifth of patients with PHO do not receive a correct diagnosis until after an unsuccessful kidney transplantation, as liver transplantation is initially required.

The author wishes to extend special thanks to Stephen G. Goldberger, MD, “for being such a good detective.” 

References
1. Ajzensztejn MJ, Sebire NJ, Trompeter RS, Marks SD. Primary hyperoxaluria type 1. Arch Dis Child. 2007; 92(3):197.

2. Niaudet P. Primary hyperoxaluria (2010). www.uptodate.com/contents/primary-hyperoxaluria?source=search_result& selectedTitle=1%7E39. Accessed February 17, 2011.

3. Latta K, Brodehl J. Primary hyperoxaluria type I. Eur J Pediatr. 1990;149(8):518-522.

4. Danpure CJ. Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1: prospects for gene therapy. Nephrol Dial Transplant. 1995;10 suppl 8:24-29.

5. Lieske JC, Monico CG, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol. 2005;25(3):290-296.

6. Genetics Home Reference. Primary hyperoxaluria. www.ghr.nlm.nih.gov/condition/primary-hyperoxaluria. Accessed February 17, 2011.

7. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research. Am J Clin Nutr. 2002;75(3):561-569.

8. Danpure CJ. Molecular and clinical heterogeneity in primary hyperoxaluria type 1. Am J Kidney Dis. 1991;17(4):366-369.

9. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol. 1996;10(4):479-482.

10. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc. 2004;36(6):1788-1791.

11. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging! Pediatr Nephrol. 2006;21(8):1075-1081.

12. Rinat C, Wanders RJ, Drukker A, et al. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. J Am Soc Nephrol. 1999;10(11):2352-2358.

13. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;18(10):986-991.

14. Watts RW. Primary hyperoxaluria type I. QJM. 1994;87(10):593-600.

15. Hoppe B, Latta K, von Schnakenburg C, Kemper MJ. Primary hyperoxaluria: the German experience. Am J Nephrol. 2005;25(3):276-281.

16. Milliner DS, Eickholt JT, Bergstralh EJ, et al. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med. 1994;331(23):1553-1558.

17. Danpure CJ. Primary hyperoxaluria: from gene defects to designer drugs? Nephrol Dial Transplant. 2005;20(8):1525-1529.

18. Rare Kidney Stone Consortium. Primary hyperoxaluria. www.rarekidneystones.org/hyperoxaluria. Accessed February 9, 2011.

19. Brinkert F, Ganschow R, Helmke, K, et al. Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth. Transplantation. 2009;87(9):1415:1421.

20. Bergstralh EJ, Monico CG, Lieske JC, et al; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010;10(11):2493-2501.

21. Millan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience. Transplantation. 2003;76(10):1458-1463.

22. Watts RWE, Danpure CJ, De Pauw L, Toussaint C; European Study Group on Transplantation in Hyperoxaluria Type 1. Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. Nephrol Dial Transplant. 1991;6(7):502-511.

23. Broyer M, Jouvet P, Niaudet P, et al. Management of oxalosis. Kidney Int Suppl. 1996;53:S93-S98.

24. de Pauw L, Gelin M, Danpure CJ, et al. Combined liver-kidney transplantation in primary hyperoxaluria type 1. Transplantation. 1990;50(5):886-887.

25. Broyer M, Brunner FP, Brynger H, et al. Kidney transplantation in primary oxalosis: data from the EDTA Registry. Nephrol Dial Transplant. 1990;5(5):332-336.

CASE: Disruptive and withdrawn

Police bring Ms. D, age 33, to our psychiatric facility because of violent behavior at her group home. When confronted for allegedly stealing, she became upset, fought with a housemate, and spat. Six months before coming to our facility she was admitted to a private hospital for psychotic disorder, not otherwise specified (NOS) where she was mute, refused all food and medications, lay in her room, and covered her face with a sheet when someone tried to talk to her.

Ms. D denies having depressive symptoms, sleep disturbance, racing thoughts, thoughts of hurting herself or others, or auditory or visual hallucinations. She complains of poor appetite. Ms. D denies a history of mental illness and says she is not taking any medication. She is upset about being hospitalized and says she will not cooperate with treatment. We cannot obtain her complete psychiatric history but available records indicate that she has 1 previous psychiatric hospitalization for psychotic disorder NOS, and has received trials of haloperidol, lorazepam, diphenhydramine, escitalopram, ziprasidone, and benztropine. Her records do not indicate the dosages of these medications or how she responded to pharmacotherapy.

During her mental status exam, Ms. D is well dressed, covers her hair with a scarf, has no unusual body movements, and responds to questions appropriately. She describes her mood as “okay” but appears upset and anxious about being in the hospital. She exhibits no overt psychotic symptoms and does not appear to be responding to auditory hallucinations or having delusional thoughts. Her cognitive function is intact and her intelligence is judged to be average with impaired insight and judgment. However, she speaks with a distinct accent that sounds Jamaican; otherwise, her speech is articulate with normal rate and tone. When we ask about her accent, Ms. D, who is African American, does not disclose her ethnicity and seems to be unaware of her accent. We did not question the authenticity of her accent until after we obtained collateral information from her family.

The authors’ observations

Based on the available information, we make a provisional diagnosis of psychotic disorder NOS and Ms. D is admitted involuntarily because of concerns about her safety. She is reluctant to accept any treatment and receives an involuntary probate commitment for 90 days. At admission, Ms. D is evasive, guarded, secretive, and at times hostile. Her physical examination reveals no signs or symptoms of focal neurologic deficits. Laboratory testing, including urine toxicology, is unremarkable. She refuses an MRI. Later testing reveals a critical ammonia level of 143 μg/dL, warranting an axis III diagnosis of asymptomatic hyperammonemia.

HISTORY: Paranoia and delusions

Ms. D says she was born and raised in a southern state. She reports that she was born to an Egyptian mother who died during childbirth; her father, who is white, was an ambassador stationed abroad. Ms. D attended school until the 11^thgrade and was married at age 19 to a Secret Service agent. She says she has a son who was kidnapped by her husband’s enemies, rescued by paying ransom, and currently lives with his grandfather. Ms. D is paranoid and fears that her life is in danger. She also believes that she has gluten sensitivity that could discolor and damage her hair, which is why she always keeps a scarf on her head for protection.

Through an Internet search, we find articles about Ms. D’s son’s kidnapping. The 7-year-old had been missing for weeks when police found him with his mother in safe condition in another state, after Ms. D called her mother to ask for money and a place to stay. The child was taken from Ms. D’s custody because of concerns for his safety. We also find Ms. D’s mother. Although Ms. D insists her mother is deceased, after some persuasion, she signs a release allowing us to talk to her.

Ms. D’s mother reports that her daughter’s psychiatric problems began when she was pregnant. At the time Ms. D did not have a foreign accent. She had started to “talk funny” when her psychiatric symptoms emerged after she married and became pregnant.

Foreign accent syndrome

A foreign accent can be acquired by normal phenomena, such as being immersed in a foreign language, or a pathological process,¹ which can include psychiatric (functional) or neurologic illness (organic causes). Foreign accent syndrome (FAS) is a rare speech disorder characterized by the appearance of a new accent, different from the speaker’s native language, that is perceived as foreign by the listener and in most cases also by the speaker.² Usually an FAS patient has had no exposure to the accent, although in some cases an old accent has re-emerged.^3,4

FAS can result from lesions in brain areas involved in speech production, including precentral gyrus, premotor mid-frontal gyrus, left subcortical prerolandic gyrus, postrolandic gyri, and left parietal area.⁴ Most FAS cases are secondary to a structural lesion in the brain caused by stroke, traumatic brain injury, cerebral hemorrhage, or multiple sclerosis.² There are a few cases in the literature of acquired foreign accent with psychogenic etiology in patients with schizophrenia and bipolar disorder with psychotic features.⁵

TREATMENT: Combination therapy

Based on Ms. D’s unstable mood, irritability, delusional beliefs, and paranoid ideas, we start divalproex, 500 mg/d titrated to 1, 750 mg/d, and risperidone, 3 mg in the morning and 4 mg at bedtime.

The unit psychologist evaluates Ms. D and provides individual psychotherapy, which is mainly supportive and psychoeducational. Ms. D gradually becomes cooperative and friendly. She is not willing to talk about her accent or its origin; however, as her psychiatric symptoms improve, her accent gradually diminishes. The accent never completely resolves, but reduces until it is barely noticeable.

The authors’ observations

Ms. D’s foreign accent was more prominent when she displayed positive psychotic symptoms, such as delusions and disorganized thinking, and gradually disappeared as her psychotic symptoms improved. Ms. D’s case was peculiar because her accent was 1 of the first symptoms before her psychosis fully manifested.

How are FAS and psychosis linked?

Language dysfunction in schizophrenia is common and characterized by derailment and disorganization. Severity of language dysfunction in schizophrenia is directly proportional to overall disease severity.^6,7 Various hypotheses have suggested the origin of FAS. In patients with FAS secondary to a neurologic disorder, a lesion usually is found in the dominant brain hemisphere, but the cause is not clear in patients with psychosis who have normal MRI findings. One hypothesis by Reeves et al links development of FAS to the functional disconnection between the left dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus (STG) during active psychosis.⁵ In normal speech production, electric impulses originate in the DLPFC and are transmitted to STG in Wernicke’s area. From there, information goes to Broca’s area, which activates the primary motor cortex to pronounce words. In healthy individuals, word generation activates the DLPFC and causes deactivation of the bilateral STG.⁸ In schizophrenia, the left STG fails to deactivate in the presence of activation of the left DLPFC.⁹ Interestingly, STG dysfunction is seen only during active phase of psychosis. Its absence in asymptomatic patients with schizophrenia and bipolar disorder^10,11 suggest that a foreign accent-like syndrome may be linked to the functional disconnection between the left DLPFC and left STG dysfunction in patients with active psychosis.⁵

Performing functional neuroimaging, including positron-emission tomography, functional MRI, and single-photon emission computed tomography, of patients with FAS could shed more light on the possible link between FAS and psychosis. In a case report of a patient with bipolar disorder who developed FAS, MRI initially showed no structural lesion but a later functional imaging scan revealed a cerebral infarct in the left insular and anterior temporal cortex.²

One of the limitations in Ms. D’s case is the lack of neuroimaging studies. For the first few weeks of her hospitalization, it was difficult to communicate with Ms. D. She did not acknowledge her illness and would not cooperate with treatment. She was withdrawn and seemed to experience hysterical mutism, which she perceived as caused by extreme food allergies. Later, as her symptoms continued to improve with pharmacologic and psychotherapeutic interventions, neuroimaging was no longer clinically necessary.

OUTCOME: Accent disappears

As Ms. D improves, psychotherapy evolves to gently and carefully challenging her delusions and providing insight-oriented interventions and trauma therapy. As her delusions gradually start to loosen, Ms. D reveals she had been physically and emotionally abused by her husband.

At discharge after 90 days in the hospital, Ms. D’s symptoms are well managed and she no longer shows signs of a thought disorder. Her thinking is clear, rational, and logical. She demonstrates incredible insight and appreciation that she needs to stay in treatment and continue to take divalproex and risperidone. Her delusions appear to be completely resolved and she is focused on reuniting with her son. Many of her previous delusions appear to be related to trauma and partly dissociative.

Ms. D contacts the psychologist several months later to report she is doing well in the community, staying in treatment, and working on legal means to reunite with her son. No trace of any foreign accent is detectable in her voice.

Related Resources

• Miller N, Lowit A, O’Sullivan H. What makes acquired foreign accent syndrome foreign? Journal of Neurolinguistics. 2006; 19: 385-409.
• Tsuruga K, Kobayashi T, Hirai N, et al. Foreign accent syndrome in a case of dissociative (conversion) disorder. Seishin Shinkeigaku Zasshi. 2008; 110(2): 79-87.

Drug Brand Names

• Benztropine • Cogentin
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Lorazepam • Ativan
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Disruptive and withdrawn

Police bring Ms. D, age 33, to our psychiatric facility because of violent behavior at her group home. When confronted for allegedly stealing, she became upset, fought with a housemate, and spat. Six months before coming to our facility she was admitted to a private hospital for psychotic disorder, not otherwise specified (NOS) where she was mute, refused all food and medications, lay in her room, and covered her face with a sheet when someone tried to talk to her.

Ms. D denies having depressive symptoms, sleep disturbance, racing thoughts, thoughts of hurting herself or others, or auditory or visual hallucinations. She complains of poor appetite. Ms. D denies a history of mental illness and says she is not taking any medication. She is upset about being hospitalized and says she will not cooperate with treatment. We cannot obtain her complete psychiatric history but available records indicate that she has 1 previous psychiatric hospitalization for psychotic disorder NOS, and has received trials of haloperidol, lorazepam, diphenhydramine, escitalopram, ziprasidone, and benztropine. Her records do not indicate the dosages of these medications or how she responded to pharmacotherapy.

During her mental status exam, Ms. D is well dressed, covers her hair with a scarf, has no unusual body movements, and responds to questions appropriately. She describes her mood as “okay” but appears upset and anxious about being in the hospital. She exhibits no overt psychotic symptoms and does not appear to be responding to auditory hallucinations or having delusional thoughts. Her cognitive function is intact and her intelligence is judged to be average with impaired insight and judgment. However, she speaks with a distinct accent that sounds Jamaican; otherwise, her speech is articulate with normal rate and tone. When we ask about her accent, Ms. D, who is African American, does not disclose her ethnicity and seems to be unaware of her accent. We did not question the authenticity of her accent until after we obtained collateral information from her family.

The authors’ observations

Based on the available information, we make a provisional diagnosis of psychotic disorder NOS and Ms. D is admitted involuntarily because of concerns about her safety. She is reluctant to accept any treatment and receives an involuntary probate commitment for 90 days. At admission, Ms. D is evasive, guarded, secretive, and at times hostile. Her physical examination reveals no signs or symptoms of focal neurologic deficits. Laboratory testing, including urine toxicology, is unremarkable. She refuses an MRI. Later testing reveals a critical ammonia level of 143 μg/dL, warranting an axis III diagnosis of asymptomatic hyperammonemia.

HISTORY: Paranoia and delusions

Ms. D says she was born and raised in a southern state. She reports that she was born to an Egyptian mother who died during childbirth; her father, who is white, was an ambassador stationed abroad. Ms. D attended school until the 11^thgrade and was married at age 19 to a Secret Service agent. She says she has a son who was kidnapped by her husband’s enemies, rescued by paying ransom, and currently lives with his grandfather. Ms. D is paranoid and fears that her life is in danger. She also believes that she has gluten sensitivity that could discolor and damage her hair, which is why she always keeps a scarf on her head for protection.

Through an Internet search, we find articles about Ms. D’s son’s kidnapping. The 7-year-old had been missing for weeks when police found him with his mother in safe condition in another state, after Ms. D called her mother to ask for money and a place to stay. The child was taken from Ms. D’s custody because of concerns for his safety. We also find Ms. D’s mother. Although Ms. D insists her mother is deceased, after some persuasion, she signs a release allowing us to talk to her.

Ms. D’s mother reports that her daughter’s psychiatric problems began when she was pregnant. At the time Ms. D did not have a foreign accent. She had started to “talk funny” when her psychiatric symptoms emerged after she married and became pregnant.

Foreign accent syndrome

A foreign accent can be acquired by normal phenomena, such as being immersed in a foreign language, or a pathological process,¹ which can include psychiatric (functional) or neurologic illness (organic causes). Foreign accent syndrome (FAS) is a rare speech disorder characterized by the appearance of a new accent, different from the speaker’s native language, that is perceived as foreign by the listener and in most cases also by the speaker.² Usually an FAS patient has had no exposure to the accent, although in some cases an old accent has re-emerged.^3,4

FAS can result from lesions in brain areas involved in speech production, including precentral gyrus, premotor mid-frontal gyrus, left subcortical prerolandic gyrus, postrolandic gyri, and left parietal area.⁴ Most FAS cases are secondary to a structural lesion in the brain caused by stroke, traumatic brain injury, cerebral hemorrhage, or multiple sclerosis.² There are a few cases in the literature of acquired foreign accent with psychogenic etiology in patients with schizophrenia and bipolar disorder with psychotic features.⁵

TREATMENT: Combination therapy

Based on Ms. D’s unstable mood, irritability, delusional beliefs, and paranoid ideas, we start divalproex, 500 mg/d titrated to 1, 750 mg/d, and risperidone, 3 mg in the morning and 4 mg at bedtime.

The unit psychologist evaluates Ms. D and provides individual psychotherapy, which is mainly supportive and psychoeducational. Ms. D gradually becomes cooperative and friendly. She is not willing to talk about her accent or its origin; however, as her psychiatric symptoms improve, her accent gradually diminishes. The accent never completely resolves, but reduces until it is barely noticeable.

The authors’ observations

Ms. D’s foreign accent was more prominent when she displayed positive psychotic symptoms, such as delusions and disorganized thinking, and gradually disappeared as her psychotic symptoms improved. Ms. D’s case was peculiar because her accent was 1 of the first symptoms before her psychosis fully manifested.

How are FAS and psychosis linked?

Language dysfunction in schizophrenia is common and characterized by derailment and disorganization. Severity of language dysfunction in schizophrenia is directly proportional to overall disease severity.^6,7 Various hypotheses have suggested the origin of FAS. In patients with FAS secondary to a neurologic disorder, a lesion usually is found in the dominant brain hemisphere, but the cause is not clear in patients with psychosis who have normal MRI findings. One hypothesis by Reeves et al links development of FAS to the functional disconnection between the left dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus (STG) during active psychosis.⁵ In normal speech production, electric impulses originate in the DLPFC and are transmitted to STG in Wernicke’s area. From there, information goes to Broca’s area, which activates the primary motor cortex to pronounce words. In healthy individuals, word generation activates the DLPFC and causes deactivation of the bilateral STG.⁸ In schizophrenia, the left STG fails to deactivate in the presence of activation of the left DLPFC.⁹ Interestingly, STG dysfunction is seen only during active phase of psychosis. Its absence in asymptomatic patients with schizophrenia and bipolar disorder^10,11 suggest that a foreign accent-like syndrome may be linked to the functional disconnection between the left DLPFC and left STG dysfunction in patients with active psychosis.⁵

Performing functional neuroimaging, including positron-emission tomography, functional MRI, and single-photon emission computed tomography, of patients with FAS could shed more light on the possible link between FAS and psychosis. In a case report of a patient with bipolar disorder who developed FAS, MRI initially showed no structural lesion but a later functional imaging scan revealed a cerebral infarct in the left insular and anterior temporal cortex.²

One of the limitations in Ms. D’s case is the lack of neuroimaging studies. For the first few weeks of her hospitalization, it was difficult to communicate with Ms. D. She did not acknowledge her illness and would not cooperate with treatment. She was withdrawn and seemed to experience hysterical mutism, which she perceived as caused by extreme food allergies. Later, as her symptoms continued to improve with pharmacologic and psychotherapeutic interventions, neuroimaging was no longer clinically necessary.

OUTCOME: Accent disappears

As Ms. D improves, psychotherapy evolves to gently and carefully challenging her delusions and providing insight-oriented interventions and trauma therapy. As her delusions gradually start to loosen, Ms. D reveals she had been physically and emotionally abused by her husband.

At discharge after 90 days in the hospital, Ms. D’s symptoms are well managed and she no longer shows signs of a thought disorder. Her thinking is clear, rational, and logical. She demonstrates incredible insight and appreciation that she needs to stay in treatment and continue to take divalproex and risperidone. Her delusions appear to be completely resolved and she is focused on reuniting with her son. Many of her previous delusions appear to be related to trauma and partly dissociative.

Ms. D contacts the psychologist several months later to report she is doing well in the community, staying in treatment, and working on legal means to reunite with her son. No trace of any foreign accent is detectable in her voice.

Related Resources

• Miller N, Lowit A, O’Sullivan H. What makes acquired foreign accent syndrome foreign? Journal of Neurolinguistics. 2006; 19: 385-409.
• Tsuruga K, Kobayashi T, Hirai N, et al. Foreign accent syndrome in a case of dissociative (conversion) disorder. Seishin Shinkeigaku Zasshi. 2008; 110(2): 79-87.

Drug Brand Names

• Benztropine • Cogentin
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Lorazepam • Ativan
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Disruptive and withdrawn

Police bring Ms. D, age 33, to our psychiatric facility because of violent behavior at her group home. When confronted for allegedly stealing, she became upset, fought with a housemate, and spat. Six months before coming to our facility she was admitted to a private hospital for psychotic disorder, not otherwise specified (NOS) where she was mute, refused all food and medications, lay in her room, and covered her face with a sheet when someone tried to talk to her.

Ms. D denies having depressive symptoms, sleep disturbance, racing thoughts, thoughts of hurting herself or others, or auditory or visual hallucinations. She complains of poor appetite. Ms. D denies a history of mental illness and says she is not taking any medication. She is upset about being hospitalized and says she will not cooperate with treatment. We cannot obtain her complete psychiatric history but available records indicate that she has 1 previous psychiatric hospitalization for psychotic disorder NOS, and has received trials of haloperidol, lorazepam, diphenhydramine, escitalopram, ziprasidone, and benztropine. Her records do not indicate the dosages of these medications or how she responded to pharmacotherapy.

During her mental status exam, Ms. D is well dressed, covers her hair with a scarf, has no unusual body movements, and responds to questions appropriately. She describes her mood as “okay” but appears upset and anxious about being in the hospital. She exhibits no overt psychotic symptoms and does not appear to be responding to auditory hallucinations or having delusional thoughts. Her cognitive function is intact and her intelligence is judged to be average with impaired insight and judgment. However, she speaks with a distinct accent that sounds Jamaican; otherwise, her speech is articulate with normal rate and tone. When we ask about her accent, Ms. D, who is African American, does not disclose her ethnicity and seems to be unaware of her accent. We did not question the authenticity of her accent until after we obtained collateral information from her family.

The authors’ observations

Based on the available information, we make a provisional diagnosis of psychotic disorder NOS and Ms. D is admitted involuntarily because of concerns about her safety. She is reluctant to accept any treatment and receives an involuntary probate commitment for 90 days. At admission, Ms. D is evasive, guarded, secretive, and at times hostile. Her physical examination reveals no signs or symptoms of focal neurologic deficits. Laboratory testing, including urine toxicology, is unremarkable. She refuses an MRI. Later testing reveals a critical ammonia level of 143 μg/dL, warranting an axis III diagnosis of asymptomatic hyperammonemia.

HISTORY: Paranoia and delusions

Ms. D says she was born and raised in a southern state. She reports that she was born to an Egyptian mother who died during childbirth; her father, who is white, was an ambassador stationed abroad. Ms. D attended school until the 11^thgrade and was married at age 19 to a Secret Service agent. She says she has a son who was kidnapped by her husband’s enemies, rescued by paying ransom, and currently lives with his grandfather. Ms. D is paranoid and fears that her life is in danger. She also believes that she has gluten sensitivity that could discolor and damage her hair, which is why she always keeps a scarf on her head for protection.

Through an Internet search, we find articles about Ms. D’s son’s kidnapping. The 7-year-old had been missing for weeks when police found him with his mother in safe condition in another state, after Ms. D called her mother to ask for money and a place to stay. The child was taken from Ms. D’s custody because of concerns for his safety. We also find Ms. D’s mother. Although Ms. D insists her mother is deceased, after some persuasion, she signs a release allowing us to talk to her.

Ms. D’s mother reports that her daughter’s psychiatric problems began when she was pregnant. At the time Ms. D did not have a foreign accent. She had started to “talk funny” when her psychiatric symptoms emerged after she married and became pregnant.

Foreign accent syndrome

A foreign accent can be acquired by normal phenomena, such as being immersed in a foreign language, or a pathological process,¹ which can include psychiatric (functional) or neurologic illness (organic causes). Foreign accent syndrome (FAS) is a rare speech disorder characterized by the appearance of a new accent, different from the speaker’s native language, that is perceived as foreign by the listener and in most cases also by the speaker.² Usually an FAS patient has had no exposure to the accent, although in some cases an old accent has re-emerged.^3,4

FAS can result from lesions in brain areas involved in speech production, including precentral gyrus, premotor mid-frontal gyrus, left subcortical prerolandic gyrus, postrolandic gyri, and left parietal area.⁴ Most FAS cases are secondary to a structural lesion in the brain caused by stroke, traumatic brain injury, cerebral hemorrhage, or multiple sclerosis.² There are a few cases in the literature of acquired foreign accent with psychogenic etiology in patients with schizophrenia and bipolar disorder with psychotic features.⁵

TREATMENT: Combination therapy

Based on Ms. D’s unstable mood, irritability, delusional beliefs, and paranoid ideas, we start divalproex, 500 mg/d titrated to 1, 750 mg/d, and risperidone, 3 mg in the morning and 4 mg at bedtime.

The unit psychologist evaluates Ms. D and provides individual psychotherapy, which is mainly supportive and psychoeducational. Ms. D gradually becomes cooperative and friendly. She is not willing to talk about her accent or its origin; however, as her psychiatric symptoms improve, her accent gradually diminishes. The accent never completely resolves, but reduces until it is barely noticeable.

The authors’ observations

Ms. D’s foreign accent was more prominent when she displayed positive psychotic symptoms, such as delusions and disorganized thinking, and gradually disappeared as her psychotic symptoms improved. Ms. D’s case was peculiar because her accent was 1 of the first symptoms before her psychosis fully manifested.

How are FAS and psychosis linked?

Language dysfunction in schizophrenia is common and characterized by derailment and disorganization. Severity of language dysfunction in schizophrenia is directly proportional to overall disease severity.^6,7 Various hypotheses have suggested the origin of FAS. In patients with FAS secondary to a neurologic disorder, a lesion usually is found in the dominant brain hemisphere, but the cause is not clear in patients with psychosis who have normal MRI findings. One hypothesis by Reeves et al links development of FAS to the functional disconnection between the left dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus (STG) during active psychosis.⁵ In normal speech production, electric impulses originate in the DLPFC and are transmitted to STG in Wernicke’s area. From there, information goes to Broca’s area, which activates the primary motor cortex to pronounce words. In healthy individuals, word generation activates the DLPFC and causes deactivation of the bilateral STG.⁸ In schizophrenia, the left STG fails to deactivate in the presence of activation of the left DLPFC.⁹ Interestingly, STG dysfunction is seen only during active phase of psychosis. Its absence in asymptomatic patients with schizophrenia and bipolar disorder^10,11 suggest that a foreign accent-like syndrome may be linked to the functional disconnection between the left DLPFC and left STG dysfunction in patients with active psychosis.⁵

Performing functional neuroimaging, including positron-emission tomography, functional MRI, and single-photon emission computed tomography, of patients with FAS could shed more light on the possible link between FAS and psychosis. In a case report of a patient with bipolar disorder who developed FAS, MRI initially showed no structural lesion but a later functional imaging scan revealed a cerebral infarct in the left insular and anterior temporal cortex.²

One of the limitations in Ms. D’s case is the lack of neuroimaging studies. For the first few weeks of her hospitalization, it was difficult to communicate with Ms. D. She did not acknowledge her illness and would not cooperate with treatment. She was withdrawn and seemed to experience hysterical mutism, which she perceived as caused by extreme food allergies. Later, as her symptoms continued to improve with pharmacologic and psychotherapeutic interventions, neuroimaging was no longer clinically necessary.

OUTCOME: Accent disappears

As Ms. D improves, psychotherapy evolves to gently and carefully challenging her delusions and providing insight-oriented interventions and trauma therapy. As her delusions gradually start to loosen, Ms. D reveals she had been physically and emotionally abused by her husband.

At discharge after 90 days in the hospital, Ms. D’s symptoms are well managed and she no longer shows signs of a thought disorder. Her thinking is clear, rational, and logical. She demonstrates incredible insight and appreciation that she needs to stay in treatment and continue to take divalproex and risperidone. Her delusions appear to be completely resolved and she is focused on reuniting with her son. Many of her previous delusions appear to be related to trauma and partly dissociative.

Ms. D contacts the psychologist several months later to report she is doing well in the community, staying in treatment, and working on legal means to reunite with her son. No trace of any foreign accent is detectable in her voice.

Related Resources

• Miller N, Lowit A, O’Sullivan H. What makes acquired foreign accent syndrome foreign? Journal of Neurolinguistics. 2006; 19: 385-409.
• Tsuruga K, Kobayashi T, Hirai N, et al. Foreign accent syndrome in a case of dissociative (conversion) disorder. Seishin Shinkeigaku Zasshi. 2008; 110(2): 79-87.

Drug Brand Names

• Benztropine • Cogentin
• Diphenhydramine • Benadryl
• Divalproex • Depakote
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Lorazepam • Ativan
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CT scan wasn’t ordered, diagnosis was delayed

A 9-YEAR-OLD BOY fell and hit the left side of his head on a coffee table while playing at a friend’s house. His father, who was present, applied ice to the child’s head and took him home. The child subsequently vomited and complained that his jaw hurt. He was given ibuprofen and taken to the emergency department (ED).

The ED physician determined that he needed stitches in his left ear. After the ear was sutured, the child was discharged, even though he had vomited in the examination room.

The child vomited again around midnight, then awoke around 2:30 am and went back to sleep. Around 5:00 am he vomited again and was gasping for air and breathing with difficulty. A call to 911 resulted in the child being airlifted to a trauma center, where a computed tomography (CT) scan revealed a massive hematoma. The brain was herniated and protruding from the bottom of the skull.

After undergoing emergency surgery, the patient spent 3 days in the ICU, some of that time on a ventilator, and several weeks in the hospital. After discharge, he underwent intensive therapy to relearn how to eat and talk. He suffered cognitive losses, emotional difficulties, left-sided weakness, and hemiparesis.

PLAINTIFF’S CLAIM The ED physician should have ordered a CT scan, which would have revealed the hematoma and prompted emergency surgery to relieve the pressure. The physician didn’t tell the parents how to observe the child for a head injury.

THE DEFENSE A CT scan wasn’t necessary. The patient appeared fine in the ED and was neurologically intact with a perfect Glasgow coma score of 15. Hematoma was a low possibility. The parents were told to watch the child and received head injury instructions.

VERDICT $2.4 million Ohio verdict.

COMMENT A variety of decision support tools would suggest CT in the face of vomiting 2 or more times, even with a Glasgow coma score of 15 (see the discussion of the Canadian CT Head Rule and New Orleans Criteria at http://guidelines.gov/content.aspx?id=136&search=neuroimaging+children+head+trauma). Clinical judgment alone may be insufficient to detect potentially catastrophic injury—particularly in younger children.

Stroke symptoms blamed on food poisoning

AN ISCHEMIC, LEFT-SIDED STROKE with left inferior frontoparietal lobe, occipital lobe, and cerebellar infarcts left a 33-year-old man with unclear speech, difficulty walking, major headache, and other stroke symptoms. He was taken by ambulance to a hospital within 1 hour of the onset of symptoms.

Hospital staff diagnosed food poisoning and discharged the man even though he couldn’t walk or speak coherently. The patient suffered brain damage resulting in cognitive impairment with memory loss and confusion.

PLAINTIFF’S CLAIM A proper neurologic work-up wasn’t done; hospital staff should have consulted a neurologist. The patient should have received tissue plasminogen activator (t-PA).

THE DEFENSE The history provided at the hospital mentioned that the patient had eaten chocolate cake before the onset of symptoms; the symptoms weren’t significant enough to consider stroke in the differential diagnosis. The plaintiff couldn’t prove that his condition would have been significantly better even if he’d received t-PA.

VERDICT $2.1 million California arbitration award.

COMMENT This story is difficult to believe—food poisoning causing trouble speaking, difficulty walking, and a headache?! One can only wonder whether better documentation of medical decision making would have produced a more understandable response.

CT scan wasn’t ordered, diagnosis was delayed

A 9-YEAR-OLD BOY fell and hit the left side of his head on a coffee table while playing at a friend’s house. His father, who was present, applied ice to the child’s head and took him home. The child subsequently vomited and complained that his jaw hurt. He was given ibuprofen and taken to the emergency department (ED).

The ED physician determined that he needed stitches in his left ear. After the ear was sutured, the child was discharged, even though he had vomited in the examination room.

The child vomited again around midnight, then awoke around 2:30 am and went back to sleep. Around 5:00 am he vomited again and was gasping for air and breathing with difficulty. A call to 911 resulted in the child being airlifted to a trauma center, where a computed tomography (CT) scan revealed a massive hematoma. The brain was herniated and protruding from the bottom of the skull.

After undergoing emergency surgery, the patient spent 3 days in the ICU, some of that time on a ventilator, and several weeks in the hospital. After discharge, he underwent intensive therapy to relearn how to eat and talk. He suffered cognitive losses, emotional difficulties, left-sided weakness, and hemiparesis.

PLAINTIFF’S CLAIM The ED physician should have ordered a CT scan, which would have revealed the hematoma and prompted emergency surgery to relieve the pressure. The physician didn’t tell the parents how to observe the child for a head injury.

THE DEFENSE A CT scan wasn’t necessary. The patient appeared fine in the ED and was neurologically intact with a perfect Glasgow coma score of 15. Hematoma was a low possibility. The parents were told to watch the child and received head injury instructions.

VERDICT $2.4 million Ohio verdict.

COMMENT A variety of decision support tools would suggest CT in the face of vomiting 2 or more times, even with a Glasgow coma score of 15 (see the discussion of the Canadian CT Head Rule and New Orleans Criteria at http://guidelines.gov/content.aspx?id=136&search=neuroimaging+children+head+trauma). Clinical judgment alone may be insufficient to detect potentially catastrophic injury—particularly in younger children.

Stroke symptoms blamed on food poisoning

AN ISCHEMIC, LEFT-SIDED STROKE with left inferior frontoparietal lobe, occipital lobe, and cerebellar infarcts left a 33-year-old man with unclear speech, difficulty walking, major headache, and other stroke symptoms. He was taken by ambulance to a hospital within 1 hour of the onset of symptoms.

Hospital staff diagnosed food poisoning and discharged the man even though he couldn’t walk or speak coherently. The patient suffered brain damage resulting in cognitive impairment with memory loss and confusion.

PLAINTIFF’S CLAIM A proper neurologic work-up wasn’t done; hospital staff should have consulted a neurologist. The patient should have received tissue plasminogen activator (t-PA).

THE DEFENSE The history provided at the hospital mentioned that the patient had eaten chocolate cake before the onset of symptoms; the symptoms weren’t significant enough to consider stroke in the differential diagnosis. The plaintiff couldn’t prove that his condition would have been significantly better even if he’d received t-PA.

VERDICT $2.1 million California arbitration award.

COMMENT This story is difficult to believe—food poisoning causing trouble speaking, difficulty walking, and a headache?! One can only wonder whether better documentation of medical decision making would have produced a more understandable response.

CT scan wasn’t ordered, diagnosis was delayed

A 9-YEAR-OLD BOY fell and hit the left side of his head on a coffee table while playing at a friend’s house. His father, who was present, applied ice to the child’s head and took him home. The child subsequently vomited and complained that his jaw hurt. He was given ibuprofen and taken to the emergency department (ED).

The ED physician determined that he needed stitches in his left ear. After the ear was sutured, the child was discharged, even though he had vomited in the examination room.

The child vomited again around midnight, then awoke around 2:30 am and went back to sleep. Around 5:00 am he vomited again and was gasping for air and breathing with difficulty. A call to 911 resulted in the child being airlifted to a trauma center, where a computed tomography (CT) scan revealed a massive hematoma. The brain was herniated and protruding from the bottom of the skull.

After undergoing emergency surgery, the patient spent 3 days in the ICU, some of that time on a ventilator, and several weeks in the hospital. After discharge, he underwent intensive therapy to relearn how to eat and talk. He suffered cognitive losses, emotional difficulties, left-sided weakness, and hemiparesis.

PLAINTIFF’S CLAIM The ED physician should have ordered a CT scan, which would have revealed the hematoma and prompted emergency surgery to relieve the pressure. The physician didn’t tell the parents how to observe the child for a head injury.

THE DEFENSE A CT scan wasn’t necessary. The patient appeared fine in the ED and was neurologically intact with a perfect Glasgow coma score of 15. Hematoma was a low possibility. The parents were told to watch the child and received head injury instructions.

VERDICT $2.4 million Ohio verdict.

COMMENT A variety of decision support tools would suggest CT in the face of vomiting 2 or more times, even with a Glasgow coma score of 15 (see the discussion of the Canadian CT Head Rule and New Orleans Criteria at http://guidelines.gov/content.aspx?id=136&search=neuroimaging+children+head+trauma). Clinical judgment alone may be insufficient to detect potentially catastrophic injury—particularly in younger children.

Stroke symptoms blamed on food poisoning

AN ISCHEMIC, LEFT-SIDED STROKE with left inferior frontoparietal lobe, occipital lobe, and cerebellar infarcts left a 33-year-old man with unclear speech, difficulty walking, major headache, and other stroke symptoms. He was taken by ambulance to a hospital within 1 hour of the onset of symptoms.

Hospital staff diagnosed food poisoning and discharged the man even though he couldn’t walk or speak coherently. The patient suffered brain damage resulting in cognitive impairment with memory loss and confusion.

PLAINTIFF’S CLAIM A proper neurologic work-up wasn’t done; hospital staff should have consulted a neurologist. The patient should have received tissue plasminogen activator (t-PA).

THE DEFENSE The history provided at the hospital mentioned that the patient had eaten chocolate cake before the onset of symptoms; the symptoms weren’t significant enough to consider stroke in the differential diagnosis. The plaintiff couldn’t prove that his condition would have been significantly better even if he’d received t-PA.

VERDICT $2.1 million California arbitration award.

COMMENT This story is difficult to believe—food poisoning causing trouble speaking, difficulty walking, and a headache?! One can only wonder whether better documentation of medical decision making would have produced a more understandable response.