United States

Introduction


Clozapine is an atypical antipsychotic, which has offered a ray of hope to many patients afflicted by treatment resistant schizophrenia including treating its positive symptoms and bipolar disorder. Nevertheless, the drug`s side effect profile limits its use. This case report emphasizes that the side effects are not solely confined to clozapine but can be dosage related and can be potentiated by anticholinergics.
Recent studies show that the case fatality rate is as high as 27.5 % in patients affected by gastrointestinal hypomotility rather than agranulocytosis.


Case presentation
A 34‐year‐old man was brought to the emergency department in refractory circulatory shock following a 2‐day history of profound diarrhea, abdominal distension, and vomiting. GCS score was below 8, Patient was intubated and transferred to ICU.
His medical history is significant for Resistant Bipolar disorder type 1 and chronic constipation. He was on quetiapine, benztropine and clozapine. Clozapine was gradually increased from 100 to 450 mg a day over three months that worsened his constipation despite being on senna.


He was resuscitated with crystalloids and started on vasopressors. Labs showed Acute kidney injury, rhabdomyolysis, and elevated liver enzymes. CT of the abdomen pelvis without contrast revealed fecal impaction with diffuse enterocolitis with distal colonic obstruction. The patient was treated initially with crystalloids, bowel rest, nasogastric decompression, and broad-spectrum antibiotics. Patient required enema and manual disimpaction. Enteral feeds were started. Patient`s ICU stay was prolonged secondary to relapse of his symptoms including agitation and anxiety requiring dexmedetomidine. He was transferred to floors on lorazepam and quetiapine on day 10 and discharged on day 30 with 100 mg of clozapine and benztropine.




Discussion
Randomized controlled trials (RCTs) have demonstrated significant decline in hospital admissions and length of stay following the initiation of clozapine in individuals with bipolar disorder and schizophrenia, along with an increase in quality-adjusted life years (QALYs). However, the relative prevalence of intestinal side effects associated with clozapine, ranging from constipation and ileus to bowel perforation are reported to be as high as 33%. Consequently, it is crucial to implement measures that allow for its continued use to benefit patients, rather than replacing it with alternative treatments. 
Conclusion
We offer the following suggestions to patients on clozapine:
Increased surveillance for bowel dysfunction and proactive management of early bowel dysmotility by ensuring daily bowel opening.
Add an extra dose of osmotic laxative with colonic stimulant monthly if needed.
Xray abdomen every 3 months.


AMA Research Challenge 2023

Clozapine and benztropine associated functional bowel obstruction, an un-noticed dreadful adverse effect: A case report


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AMA would like to thank Laurel Road for sponsoring a $10,000 grand prize for the winner of the AMA Research Challenge. Laurel Road is not involved in the judging or scoring process to select the winner. The winner will be announced on February 4, 2024 during the AMA Research Challenge finals. Payment of the grand prize will be directly from Laurel Road. See the AMA Research Challenge Official Rules for terms and conditions.

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A rare case of Vancomycin and Piperacillin-Tazobactam induced transaminitis

Is empiric therapy best for everyone? A rare case of Vancomycin and Piperacillin-Tazobactam induced transaminitis in the setting of fatty liver disease 


Background: 
Tricuspid endocarditis (TE) associated with intravenous drug use (IVDU) presents unique management challenges, including recurrent infections and poor treatment adherence. The pathophysiology involves direct inoculation of pathogens through contaminated injection equipment, leading to valve colonization and infection. While most cases of tricuspid valve infective endocarditis can be managed with antibiotics alone, surgical intervention is considered in specific circumstances. The choice between prolonged oral (PO) antibiotics and intravenous (IV) antibiotics in patients with active IVDU requires careful evaluation of risks and benefits. 

Case Presentation: 
We present the case of a 49-year-old female with active IVDU and TE, complicated by infective endocarditis and treatment noncompliance. Initially, the patient was not recommended a prolonged course of IV antibiotics due to concerns about the risk of relapse. However, the patient's father, recognizing her high-risk profile for suicide and death, emphasized the need for IV antibiotics, further complicating the decision-making process. Five months later, the patient's noncompliance with PO antibiotics resulted in a severe decompensation, leading to admission into the intensive care unit. The patient ultimately underwent tricuspid valve replacement and pacemaker placement, followed by another prolonged course of antibiotics. 

Discussion: 
This case underscores the challenges of balancing treatment options and addressing patient and family concerns in the context of active IVDU. Treatment noncompliance and relapse pose significant hurdles in addiction management, contributing to recurrent infections and complications. Strategies such as close follow-up, addiction counseling, and multidisciplinary support are crucial in optimizing treatment adherence and outcomes. Successful examples include programs like the Boston Health Care for the Homeless Program and Vermont Hub-and-Spoke Model which integrate medical treatment, addiction counseling, harm reduction strategies, and social support, resulting in improved outcomes like reduced mortality rates, lower reinfection rates, and increased treatment engagement. 

In conclusion, tricuspid endocarditis in the setting of IVDU requires comprehensive care and individualized treatment approaches. The decision between prolonged PO or IV antibiotics should consider factors such as treatment adherence, severity of infection, and close monitoring. Effective management necessitates open communication, shared decision-making, and ongoing support to mitigate treatment noncompliance and relapse risks. Collaboration with community organizations and care coordination are vital for success in providing comprehensive care. It underscores the need for further research, innovative approaches, and enhanced collaboration among healthcare providers, addiction specialists, and support networks to improve outcomes in this challenging patient population.

Tricuspid Endocarditis in the Setting of Active Intravenous Drug Use: Navigating Complexities for Comprehensive Care and Addressing Treatment Challenges

Background
X-linked Creatine Transporter Deficiency (CTD) is caused by pathogenic variants in SLC6A8 and is characterized by intellectual disability, behavioral / developmental disorders, and seizures. The SLC6A8 protein has critical roles in synthesis and distribution of creatine throughout the body. The central nervous system is especially reliant on SLC6A8 to allow creatine to cross the blood brain barrier. Cerebral creatine deficiency disorders are found in up to 2.6% of males with intellectual disability, but few female cases have been reported. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males and improve symptoms in females with CTD, though only four females on this therapy have been reported in the medical literature. We offer a case of a female with a de novo pathogenic SLC6A8 variant who significantly improved with supplementation. 

Case Presentation
At time of diagnosis, the reported patient had weight loss, mild intellectual disability, attention deficit hyperactivity disorder, generalized anxiety disorder, and intermittent explosive disorder. Magnetic resonance spectroscopy (MRS) of the brain showed reduced creatine on all acquired spectra. Based on literature review of previously treated female patients, the reported patient was started on creatine-monohydrate at 200 mg/kg/day, L-arginine at 400 mg/kg/day, and L-glycine at 150 mg/kg/day. Within three weeks of starting supplementation, her caregiver reported that she was “doing better in almost every way.” She gained 5 kg and symptom improvement was also seen through her mood: she was sleeping through the night, was more alert during the day, and was showing more appropriate behaviors. After 8 months of supplementation, MRS showed improved creatine concentrations with normalizing semi-quantitative ratios with other brain metabolites. 

Discussion
Previous small cohort studies of male patients with SLC6A8 deficiency demonstrated neither improvement nor decline on treatment. One female supplemented only with creatine showed increased aggression and worsening of self-injurious behaviors. However, two female patients in the literature supplemented with dosages of creatine, arginine, and glycine demonstrated improvement in neuropsychiatric symptoms. The reported patient provides an additional example of a female who responded to supplementation. Females are thought to better respond to supplementation because they are presumed to have at least one partially functioning copy of the SLC6A8 transporter on their second X chromosome, while more severely impacted males are more likely to have no residual transporter function and do not respond to supplementation. Clinicians treating females with CTD should consider treatment with creatine, arginine, and glycine supplementation.

Arginine, Glycine, and Creatine Supplementation Improves Symptoms in a Female with SLC6A8 Creatine Transporter Deficiency

Background:​
Wilson Disease, also called hepatolenticular degeneration, is a rare autosomal recessive mutation of ATP7B, which links copper to ceruloplasmin for elimination. In symptomatic patients, unbound ceruloplasmin is degraded in the bloodstream and free copper deposits in tissues, notably the basal ganglia, kidneys, and cornea. Despite dietary management and copper chelation, it is progressive and incurable, so early identification is key.​
Case Presentation:​
A 68-year-old Caucasian male presented for increasing peripheral neuropathy, myelopathy, and Parkinsonism. Labs revealed serum ceruloplasmin of 5.7 mg/dL; serum copper of 22 ug/dL; normal urine copper. Neurology suggested liver biopsy but his team was reluctant to pursue Wilson given his age and lack of Keyser-Fleischer rings. A second opinion from external neurology suggested copper supplementation, suspecting Menke. A Rowan medical geneticist suggested utilizing 23&Me data for deeper investigation of the ATP7A and ATP7B genes. Visualization of this data through genomic servers showed poor coverage, with sequence gaps and potential mutations of uncertain significance in ATP7A and ATP7B possibly contributing to Menke or Wilson; two mutations in PANK2; and none in ceruloplasmin or other copper metabolic genes. These unsatisfactory 23&Me results prompted the patient to privately obtain 40x whole genome sequencing, which demonstrated a likely pathogenic ATP7B c.3243+1G>A variant, not previously reported, predicted to disrupt a consensus splice site, and a variant of unknown significance, ATP7B c3243+5G>A, previously reported within an intron in Wilson Disease patients. His liver biopsy was fibrosis-negative; quantitative liver tissue copper testing he requested from gastroenterology showed 402 mcg/g dry weight, roughly 8 times the normal level; 250 mcg is diagnostic. He therefore self-referred to the Seattle Children’s Hospital Wilson Disease Center of Excellence, where DAT scan showed decreased radiotracer uptake in right caudate and bilateral right greater than left putamina consistent with Wilson’s Disease or Parkinson’s. He worsened slightly on trientine, but plateaued on zinc. SynOne testing was positive for Parkinson's and moderately improved on carbidopa-levodopa. ​
Discussion:​
Despite being a retired physician living near one of 18 centers for this condition nationwide, he encountered many barriers to diagnosis, followup, and management. Overreliance on pathognomonic signs may have contributed to missing this case. This was the first patient at Rowan-Virtua medical genetics identified for specific testing and follow up based on consumer genetic testing. On 7/11/23, the ATP7B c3243+5G>A allele was reclassified as likely pathogenic. Increased copper accumulation is associated with Parkinsonism.

A Case in Verdigris: Late-Life Onset of Wilson Disease Identified by Genomic Data

Distal renal tubular acidosis is an uncommon disorder in adults. The primary defect in distal RTA is
impaired distal acidification. Causes of distal RTA in adults are autoimmune diseases, hypercalciuria, and
medications. This is an interesting case of a young woman found to have distal renal tubular acidosis in
the setting of Sjogren syndrome and nephrolithiasis.

Distal Renal Tubular Acidosis in the Setting of Sjogren Syndrome and
Nephrolithiasis

Introduction
Renal medullary carcinoma (RMC) is an exceedingly rare and devastating malignancy that primarily affects adolescents and young adults between the ages of 11 and 39 years with sickle cell trait (SCT) or sickle cell disease. RMC is characterized by early and widespread metastases, leading to late-stage diagnosis and poor prognosis. The tumor suppressor gene SMARCB1/INI1 is inactivated in all cases, resulting in the loss of expression of INI1 protein. RMC also shares similarities with collecting duct carcinoma (CDC), including a predilection for the right kidney and the renal medulla as the epicenter, as well as aggressive clinical behavior.
Case Report
We present the case of a 27-year-old male with a medical history of asthma, HIV, and
nephrolithiasis. The patient presented with worsening right flank pain, testicular swelling, rapid weight loss, and a history of hematuria. Physical examination revealed mild tenderness in the right flank and scrotal edema. Imaging studies demonstrated infiltrative liver lesions, moderate pleural effusion, and renal abnormalities. Biopsy confirmed INI-deficient renal cell carcinoma associated with sickle cell trait. Palliative chemotherapy was initiated. RMC is an exceptionally rare malignancy that is often diagnosed at advanced stages. Loss of INI1 and its correlation with sickle cell trait are diagnostic hallmarks. Our case demonstrates an aggressive and rapidly progressive clinical presentation, including right-sided involvement and metastasis to the liver, lung pleura, cardiac pericardia, and omentum. The treatment options for RMC are limited, and the prognosis remains unfavorable.
Discussion
The discussion highlights the rarity and diagnostic challenges of RMC, which has fewer than 220 reported cases in the literature. RMC is distinguished by the presence of SCT and loss of SMARCB1/INI1 expression. It primarily affects African Americans and shows a right-sided predominance, often presenting with advanced disease and widespread metastases. Clinical manifestations include flank pain, hematuria, abdominal mass, and weight loss. Histologically, RMC displays anastomosing tubules and cords forming microcytic structures with a reticular appearance.
This case report emphasizes the importance of early recognition and prompt management of RMC. Despite its rarity, clinicians should consider RMC in young patients with sickle cell trait presenting with renal abnormalities. Timely collaboration between various medical specialties is essential for tailored therapeutic approaches, considering the aggressive nature of this malignancy. Further research is warranted to explore more effective treatment strategies and improve outcomes for this devastating disease.

INI Deficiency Unveiled: An Aggressive Case of Renal Cell Medullary Carcinoma.

Background: Dural arteriovenous fistulas (dAVF) are abnormal anastomoses between meningeal arteries and dural venous sinuses and have a yearly incidence rate of 0.15 to 0.29 patients per 100,000 people. Typically, dAVF treatment involves an endovascular or microsurgical approach. A hybrid approach combining endovascular and microsurgical treatment, however, may improve patient outcomes. Few reports of hybrid approaches to dAVF embolization are available, thus, we hope to add to the literature with this case report to support this less explored surgical approach.
Case Presentation: We present the case of a female in her late 60s who presented for headaches. Angiography revealed an extensive superior sagittal sinus dAVF with multiple bilateral arterial feeders, including the superficial temporal artery, the occipital artery and the middle meningeal artery. The fistula involved the superior sagittal sinus with cortical venous drainage. Parts of the sinus around the middle third were thrombosed. Initial attempts at coiling were incomplete due to complicated venous access, however, a second surgery using a hybrid
approach resulted in successful obliteration of the dAVF. Eight months post-operatively, she reports improved personality and irritability symptoms, but continued headaches and blurry vision.
Discussion: Cerebrovascular procedures in hybrid rooms have already been widely described in the literature, however this technology is not available in every neurosurgical center and has been mostly used in the treatment of cerebral aneurysm. This case report exemplifies the potential benefit of a hybrid approach in treating high grade (Cognard class IIa and IIb in this case) dAVFs. With more case reports and large-scale clinical studies examining patient outcomes, the hybrid surgical technique may offer promising prognoses to future patients with complex dAVFs.

Treatment of a dural arteriovenous fistulas (dAVF) in a hybrid surgical setting:

Background
Carotid cavernous fistulas (CCF) are a serious condition that involves spontaneous or trauma-induced disruption in the carotid arteries within the cavernous sinus. This disruption causes blood to leak into the sinus, which impedes the function of cranial nerves III, IV, V1, V2, and VI. Early signs of CCF often include proptosis, glaucoma, severe headaches, partial blindness, and conjunctival hyperemia- especially in patients with preexisting conditions such as atherosclerosis, hypertension, diabetes. If left untreated, patients can develop periorbital disfigurement and permanent vision loss. Despite effective methods of diagnosis using angiography and blood vessel repair, this condition is often misdiagnosed due to it making up only 1.5% of endovascular-treated ruptured aneurysms and its similarity in presentation to cerebrospinal fluid (CSF) leaks. Therefore, CCFs have been under-investigated, and additional research is required to delineate the cause, unique features, and proper treatment of this phenomenon.

Case Presentation
Six weeks following an uncomplicated L4-S1 posterior instrumented fusion with partial laminectomy and bilateral facetectomy, a 78-year-old female developed moderate bifrontal headaches and neck discomfort. In the following weeks, the headaches grew severe with periorbital swelling despite a negative brain CT scan and no findings in an exploratory surgery. Worsening symptoms prompted a brain MRI that showed abnormal superior ophthalmic veins. Diagnostic angiography confirmed a left CCF, and the patient was successfully treated via transvenous embolization in the intercavernous sinus and left cavernous sinus. 

Discussion
Carotid-cavernous fistulas (CCF) are pathological shunts between the cavernous sinus and carotid artery or its meningeal branches. Symptoms include conjunctival injection, blurred vision, pulsating proptosis, and cranial nerve six palsy – all of which may be exacerbated with delayed diagnosis. Historically, etiologies of CCFs have included trauma, ruptured ICA aneurysms, connective tissue diseases, or iatrogenic injury. We present the first reported case of a CCF that occurred in conjunction with spine surgery. We describe the association of prolonged operative time in the prone position and development of CCF using radiographical images and thorough clinical workup. We also describe how the clinical history and symptomology originally indicated a dural tear, although subsequent workup led to the diagnosis of CCF. This case demonstrates a difficult diagnosis of CCF and its potential relationship with spinal surgery.


Carotid Cavernous Fistula and Its Association with Spine Surgery

Background
Patients who present with cervical dystonia may also present with cervical myelopathy. This presentation can be problematic because patients with cervical myelopathy need fusion surgery such as an anterior discectomy and fusion (ACDF) to stabilize the spine and prevent damage to the spinal cord. The involuntary tremor caused by cervical dystonia can result in problems with boney fusion in the post-operative period. Deep Brain Stimulation (DBS) provides a potential solution to this problem when more conservative treatments like medication, halo vests, and botulinum toxin fail to reduce tremor.
Case Presentation
A 46-year-old female presented to our center with a chief complaint of neck pain. The patient also presented with bilateral upper extremity radiculopathy, paresthesia, and a myelopathic gait. She had a 15-year history of cervical dystonia and had tried various medications and botulinum toxin injections without resolution of symptoms. In addition to this the patient had cervical myelopathy caused by disc herniation at the C5-C6 and C6-C7 level. Although the patient was a candidate for ACDF, she was advised to have her dystonic tremor treated before ACDF to prevent pseudoarthrosis and hardware failure because of the tremor. The patient underwent bilateral DBS in the Globus pallidus interna (GPi) utilizing an Abbott InfinityTM DBS system. After placement of the DBS-GPi leads, batteries were placed, and the system was turned on which was able to provide significant relief of the patient’s tremor. The patient was followed up at 3 months and had a >75% reduction in her tremors. After the significant reduction in tremor, the patient underwent C5-C6 and C6-C7 ACDF at 6 months post DBS-GPi. The patient reported that the paresthesia had improved significantly, and the weakness had gradually improved at 3 months post ACDF. There was no radiographic evidence of hardware loosening or malalignment.
Discussion
The presentation of both Cervical Dystonia and Cervical Myopathy concurrently is a challenging couple of pathologies to manage. Bilateral DBS-GPi prior to ACDF is a viable strategy for managing these pathologies surgically. 


DBS before ACDF for a patient with Cervical Dystonia and Cervical Myelopathy

Background
Spinal manipulation is one of many therapies for back pain. It is typically done by a chiropractor or physical therapist. A systemic review and meta-analysis concluded that spinal manipulation has moderate-quality evidence for improvement in pain scale and function. However, there is insufficient data for chronic back pain treatment. Like most treatments, there are risks associated with spinal manipulation. While serious adverse effects of spinal manipulation are rare, they include disc herniation, cauda equina syndrome, vertebrobasilar and carotid dissection. The incidence of serious adverse events range between 1/100,000 and 1/6 million manipulations. More commonly, minor complaints (dizziness, lightheadedness, headache, and numbness) are reported following spinal manipulation with rates between 25-60%. In this case, a 50-year-old patient underwent chiropractic spinal manipulation for back pain, resulting in bilateral lower extremity paralysis requiring spinal surgery.
Case Presentation
A 50-year-old male with no past medical history presented with back pain. The patient reported that he had back pain for about a month after lifting a heavy object. He went to the chiropractor for an adjustment two weeks prior to admission. Following the adjustment, he felt better, but the next day he had bilateral leg weakness, numbness, and tingling. He couldn’t walk for two weeks and was using a wheelchair. Sensation was intact. Two days ago, he started experiencing urinary incontinence but no bowel incontinence. On examination, the patient had bilateral leg weakness and saddle anesthesia. Thoracic MRI showed a disc extrusion and epidural hematoma at T10-T11 extending superiorly to the T10 superior endplate and inferiorly to the mid-T11 vertebral body with severe mass effect on the spinal cord and canal stenosis. The patient was started on dexamethasone 4-mg q6-hours. A left thoracotomy, T10-11 left transthoracic corpectomy, and T9-11 anterior-lateral interbody arthrodesis was performed and well tolerated. After two months of inpatient rehab, the patient was able to ambulate using a walker, discharged home, and scheduled for outpatient rehab.
Discussion
This case demonstrates an interesting and rare serious adverse event of spinal manipulation. Generally, it is important to avoid spinal manipulation in patients with documented or suspected disc herniation. In this case, it is unknown whether the patient had a pre-existing herniation but considering that the back pain originally began shortly after lifting a heavy object, it is possible that there was a degree of herniation prior to the chiropractor visit that progressed after the spinal manipulation, causing a mass effect and spinal stenosis.

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Is empiric therapy best for everyone? A rare case of Vancomycin and Piperacillin-Tazobactam induced transaminitis in the setting of fatty liver disease

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