This article is written by Justina
"Sister Lu! hurriedly! Come with me, something is wrong with the eye clinic."
I was sneaking around in the office to revise my sister's thesis, pushing the door into a hurried white coat, which was the small beam of the emergency department.
"Ophthalmology clinic?" What situation does it take from God to help?" I'm a little confused about that.
"A young man, who had a seizure at the door of the clinic, had four consecutive seizures, and it was difficult to suppress it with medicine." Xiao Liang explained to me as he walked outward, "Also, the patient's brain magnetic system is also a bit of a problem, I just glanced at it, like there is a big blood clot in the upper sagittal sinus, this must be your god's work, right?"
Superior sagittal sinus thrombosis, a type of thrombosis in the cerebral venous system, is rare and has a dangerous course. I didn't ask any more questions and followed Dr. Liang all the way to the emergency room.
01.
The first time I saw Ah Feng, I had only one feeling: so high...
By this time he had regained consciousness, and although he was lying on the hospital bed, he could still feel that he was at least one meter nine or more tall.
In such a comparison, the small beam that usually hates to write "one meter eight" on the face is a bit insufficient.
Although there was no abnormality in the initial neurological physical examination, Ah Feng's BRAIN magnetic results clearly showed a thrombus in the anterior part of the superior sagittal sinus and a convex cortical vein in the right frontal lobe, and there was a significant edema of the right frontal upper gyrus cortex and the white matter of the right frontal lobe.
Source: Reference 15
This is most likely the cause of his recurrent seizures.
Although Ah Feng's temporary state is acceptable, the two blood clots in his skull, once completely occluded to the blood vessels, are likely to cause more serious seizures and even life-threatening.
Must be hospitalized immediately!
First, I went to heparin to prevent the thrombus from expanding further, and I arranged key tests such as CT cerebral angiography for Ah Feng. Next, there is an important problem that needs to be solved: what is the cause of Ah Feng's sudden blood clot?
Thrombosis of the cerebral venous system, the overall annual incidence of the disease is around 1 in 100,000, with a male-to-female ratio of 1:3, which is more rare in the male population.
In the vast majority of male patients, a variety of causes such as trauma, postoperative, hereditary thrombophilia, congestive heart failure, cachexia, cancer, drugs, infectious diseases, and immune diseases need to be considered.
"First of all, we must exclude trauma." After hearing the news, he followed the sister who came to study and analyzed, "Although he broke his head during the eye clinic, it should be caused by a seizure, and the trauma-induced thrombosis will not be so rapid."
I nodded, and the results of the brain mrimetry also suggested that Ah Feng's epilepsy was secondary to a blood clot.
What else is possible?
"Thrombosis in part of the cerebral venous system can be caused by an infectious or immune disease, such as lupus..." Shi Jie said as she thought.
"But the patient's white blood cell count is completely normal, the erythrocyte sedimentation rate is only mildly elevated, and there are no signs and symptoms associated with these diseases." I took her word for it.
"His platelet count has been slightly reduced, and the activation prothrombin time has also been slightly prolonged, will it be..."
I interrupted my sister's conjecture: "This blood has just been collected, he has used a large dose of heparin, and the abnormal coagulation index should be the pharmacological effect of heparin."
In fact, except for a gallbladder removal operation four years ago, Ah Feng's body has always been very healthy, with almost no intersection with the hospital, and he has not taken drugs related to thrombosis.
The diagnostic idea is stuck here, and I can only sort out the case data and prepare to report the situation to the director tomorrow.
02.
The next morning, I reported Ah Feng's condition to the director, and decided to give Ah Feng another physical examination during the rounds, asking the patient's medical history and family history in detail, hoping to further screen the cause of blood clots from possible clues.
When a large number of rounds arrived at the ward, Ah Feng was talking and laughing with his patients, not at all like a person with two "time bombs" buried in his skull.
Ah Feng's height is 1 meter 90, and the physical examination shows that the arm span has reached a staggering 1 meter 92.
"It's so high..." The sister standing behind me whispered through the crowd, and then pulled my clothes again, "Sister Eh, do you think... Does this guy look a bit like Marfan syndrome?"
Marfan? My brain automatically started searching for this keyword.
Marfan syndrome is a hereditary systemic connective tissue disorder in which patients are usually unable to maintain normal function due to abnormalities in the fibrin-1 gene (FBN1), resulting in systemic clinical manifestations and complications such as aortic root lesions, heart disease, abnormal bone growth, and ocular lens dislocation.
Clinically, due to excessive linear growth of long bones and joint relaxation in patients with Marfan syndrome, the vast majority of patients can often be screened out by typical "Marfan syndrome faces" such as spider fingers, chicken breasts, slender limbs and scoliosis.
No, it has nothing to do with intracranial thrombosis. I suppressed these messy thoughts, turned my head sideways and said to my sister, "You don't want to 'judge people by their appearance.'"
Unfortunately, this time we still did not find any key clues during this round.
After returning to the ward, Shi Jie rushed to the bookcase and turned out the thick "Internal Medicine".
"What do you see?" I leaned over and looked at what she was studying, "You're still thinking about Marfan!" Have you finished your paper?"
"I've already changed my email!" You just said don't 'judge people by their appearance' and now come and take me by their appearance..."
The sister-in-law turned to the part of Ma Fan syndrome, and I unconsciously followed it.
First of all, Marfan syndrome is almost always autosomal dominant, but the medical history shows that relatives within three generations of Ah Feng, although they do not explicitly deny the history of Mafan syndrome, they all indicate that they are very healthy, except for some common chronic diseases, basically have not been admitted to the hospital, and there is no aortic lesion.
Second, one of the diagnostic factors for Marfan syndrome is the presence of aortic root lesions or aortic aneurysms. Ah Feng had an echocardiogram 10 years ago and 2 years ago, and found no problems involving the aorta, valves or myocardium. These are also areas where Marfan syndrome is often affected.
"That can only be genetically tested?" The last time we went to listen to Director Xinnai Wang's open lecture on Ma Fan, didn't we say that there are many patients with Ma Fan syndrome who have new mutations in genes and will not show family history." Shi Jie is not dead yet.
I quickly stopped her delusional delusion: "You have only listened to half of the class, Director Wang also said, at this stage there are more than 1,000 FBN1 gene mutations involving Marfan syndrome, if you consider that 10% of Marfan syndrome is caused by other genetic mutations, then we have to measure thousands of genes."
What's more, there is no evidence link between Marfan syndrome and thrombosis, and patients have no cardiovascular symptoms, are we just diagnosing for the sake of diagnosis?"
Shi Jie finally calmed down: "Oh, come up and let people check the genes, no one can understand it."
03.
I was in the office reading my sister's revised paper, and unexpectedly, it was indeed changed well, no wonder she always condemned me for "taking her by her appearance", it seems that I will have to exaggerate more in the future...
Just thinking about it, someone knocked on the office door.
"Hello Doctor, excuse me, can you please help us read the report?" It seems to be a bit of a problem, but we don't quite understand..."
I looked back and saw that it was Ah Feng's mother standing in the doorway.
In recent days, Ah Feng's condition has been quite stable, and there are no signs of accelerated thrombosis under heparin treatment. Interestingly, not only the sister, but also other people in the department have asked about the situation of Marfan syndrome, but this has not helped our diagnosis.
The cause of thrombosis remains unknown.
"What report?" I got up from my computer.
"Before we didn't do a check-up in the ophthalmology department of our hospital, the child was myopic from an early age and wanted to have a myopia surgery." Who knows, there was an accident without waiting for the result, and then I was admitted to the hospital, and I forgot when I was busy, and today the doctor at the emergency department helped send this report back, and I thought about asking who I should look for..."
"Ophthalmology report sheet... Ophthalmology, we can't see this, we are a god of internal medicine, you have to go to the outpatient clinic to hang up the number of ophthalmology." I didn't finish my mouth, and my body had already habitually taken the report sheet and glanced at it.
Slit Lamp Inspection Report... Binocular lens subluxation to the lower nose...
Well? Lens subluxation?
I also remembered the Marfan syndrome that I discussed with my sister a few days ago, and one of the most typical ophthalmic manifestations is early-onset myopia with binocular lens subluxation.
Could it really be Marfan?
After helping Ah Feng's mother contact the ophthalmology department, I hurried back to the computer to check the information - the last lecture of director Wang of the Department of Cardiology PPT.
It is true that patients with Marfan syndrome do show lens subluxation, but it is an upward dislocation, while A Feng manifests as a dislocation under the nose... How is it almost in line!
I looked at PPT with some irritation and was suddenly attracted to the "Marfan-like performance".
"Marfan-like manifestations" refers to the fact that patients have some of the typical features of Marfan syndrome, but the problem is in other genetic mutations or even acquired diseases.
Source: Precision Medicine in Fuwai
Is it possible for Ah Feng to do this?
I flipped out Ah Feng's case and began to check them one by one against the table.
Considering that Ah Feng's previous echocardiography was completely normal, the phenotypic Malfan syndrome, mitral valve prolapse syndrome, and Ehlers-Danlos syndrome, which are mainly cardiovascular manifestations, can be ruled out.
There are no obvious problems with Ah Feng's spine and joints, and congenital contracture spider fingers are unlikely.
However, if you combine Ah Feng's physical characteristics with the latest information that "binocular lens subnastrual subluxation", the answer seems to be only one - homocysteinuria!
04.
Homocysteinuria is a disorder caused by impaired homocysteine metabolism, which leads to a large accumulation of homocysteine in the urine and blood of patients. Patients with this disease usually have physical features similar to Marfan syndrome, such as spider fingers, chicken breasts, and slender limbs, and lens dislocations.
However, what is easily distinguishable from Marfan syndrome is that the lens dislocation direction of homocysteinuria patients is different from that of Marfan, most of which is dislocated to the lower nose, sometimes outwardly displaced, and there is no Malfan characteristic aortic lesion.
More importantly, almost all patients with homocysteinuria have a tendency to severe thrombosis, and if Ah Feng really has this disease, he can "perfectly" explain the origin of his intracranial thrombosis.
Guessing "perfect" also requires factual verification.
Fortunately, compared to Marfan syndrome, which requires genetic testing to troubleshoot, homocysteinuria is often confirmed by blood testing: by plasma levels of homocysteine and methionine, both of which are often elevated at the same time.
I immediately arranged for Ah Feng to have plasma homocysteine and methionine tests, and began to communicate with Ah Feng's mother about genetic testing.
Soon, the laboratory test results came out, and the homocysteine level of Afeng plasma was as high as 365 μmol/L, which was more than twenty times the normal value, and the methionine level was also as high as 570 nmol/L, which was more than ten times the normal value. At the same time, tests for folic acid and vitamin B12 were also completely normal, ruling out elevated homocysteine levels due to deficiencies in both vitamins.
And this result also explains why Ah Feng has such a sinister brain thrombosis - thromboembolic disease is one of the main manifestations of homocysteinuria.
Homocysteine is an already proven independent risk factor for cardiovascular disease.
It is endothelial cytotoxic and promotes thrombosis by promoting platelet adhesion to collagen and fibrinogen, and increasing fibrinogen levels. In addition, it promotes the proliferation, migration and atherosclerosis of vascular smooth muscle cells.
With the test report, I successfully obtained the consent of Ah Feng and my mother. Subsequently, Ah Feng's blood sample was quickly sent to a third-party laboratory for sequencing, and the results showed that there was an inactivated mutation on each of the two alleles of cystidyl ether-β-synthetase (CBS), which finally confirmed the diagnosis of homocysteinuria.
Fortunately, although a rare disease, the treatment of homocysteinuria is not difficult. After taking vitamin B6 and betaine, Ah Feng's plasma homocysteine level dropped rapidly, and intracranial thrombosis also improved under heparin treatment.
More targeted consultations learned that Ah Feng had been diagnosed with a learning disability and attention deficit hyperactivity disorder as a child, which was once so serious that he needed special care from the teacher, but because he was successfully admitted to the university and everything was normal in the subsequent study, Ah Feng's mother did not care about this matter.
When I first received Ah Feng, I did not notice the reason why Ah Feng went to the ophthalmology department, and also ignored the link between the cholecystectomy he received four years ago and the disease - in fact, most patients with homocysteinuria develop stunting and myopia in childhood, and show obvious gallbladder lesions at a young age.
A few weeks later, Ah Feng was successfully discharged from the hospital. The phrase "judging people by their appearance" has since taken on a new meaning in my heart. (Planner: z_popeye, Producer: Gyouza)
This article is based on real cases [15]
Acknowledgements: This article was professionally reviewed by Qin Lili, attending physician of the Department of Neurology, Liu Yue, chief physician of the Department of Cardiology of the First Affiliated Hospital of Harbin Medical University, and Xu Naijia, attending physician of the Department of Endocrinology of Wuhan Municipal Hospital of Traditional Chinese Medicine, Hubei Province
【Note】
Attending Physician of Neurology Qin Lili's review opinion:
Homocystinuria is a genetic disorder caused by enzyme deficiency in methionine metabolism, it is an autosomal recessive genetic disease, it has at least three different biochemical defect types, namely: cystyl ether synthase deficiency type; methyltransferase deficiency type; 5,10-N-methamene tetrahydrofolate reductase deficiency type. Clinical presentation varies for each type, with patients in this case cystultane synthase deficiency.
The main clinical manifestations of this disease are multiple thromboembolism, neurological symptoms such as epilepsy, convulsive seizures, mental retardation (pediatric stage), lens ectopicity, excessive toes, bone changes, and recurrent infections. Clinically, when considering the possibility of the patient's disease, we can also arrange for the patient to perform x-ray and bone density tests to determine whether the patient has osteoporosis and scoliosis and other bone changes, so as to assist in diagnosis and treatment.
In neurology, homocysteine indicators have a very important value, it is one of the risk factors for cerebral infarction, so we will routinely test the "blood homocysteine" indicator, which is conducive to early detection, early diagnosis, and avoid missed diagnosis.
In addition, it is really important to ask a detailed medical history, and this case has "learning disability and attention deficit hyperactivity disorder" in childhood, which is very important for early and definitive diagnosis.
Image source: YouTube video screenshot
Resources:
[1] Crawford SC, Digre KB, Palmer CA, et al. Thrombosis of the deep venous drainage of the brain in adults. Analysis of seven cases with review of the literature. Arch Neurol. 1995 Nov;52(11):1101-8. doi: 10.1001/archneur.1995.00540350095021.
[2] Coutinho JM, Zuurbier SM, Aramideh M, et al. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012 Dec;43(12):3375-7. doi: 10.1161/STROKEAHA.112.671453.
[3] Ferro JM, Canh o P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004 Mar;35(3):664-70. doi: 10.1161/01.STR.0000117571.76197.26.
[4] Judge DP, Dietz HC. Marfan's syndrome. Lancet. 2005 Dec 3;366(9501):1965-76. doi: 10.1016/S0140-6736(05)67789-6.
[6] Tsipouras P, Del Mastro R, Sarfarazi M, et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study. N Engl J Med. 1992 Apr 2;326(14):905-9. doi: 10.1056/NEJM199204023261401.
[7] Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. doi: 10.1136/jmg.2009.072785.
[8] Beighton P, De Paepe A, Steinmann B, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998 Apr 28;77(1):31-7. doi: 10.1002/(sici)1096-8628(19980428)77:13.0.co;2-o.
[9] Putnam EA, Zhang H, Ramirez F, et al. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet. 1995 Dec;11(4):456-8. doi: 10.1038/ng1295-456. PMID: 7493032.
[10] MUDD SH, FINKELSTEIN JD, IRREVERRE F, et al. HOMOCYSTINURIA: AN ENZYMATIC DEFECT. Science. 1964 Mar 27;143(3613):1443-5. doi: 10.1126/science.143.3613.1443.
[11] Neely DE, Plager DA. Management of ectopia lentis in children. Ophthalmol Clin North Am. 2001 Sep;14(3):493-9. doi: 10.1016/s0896-1549(05)70247-9.
[12] Isherwood DM. Homocystinuria. BMJ. 1996 Oct 26;313(7064):1025-6. doi: 10.1136/bmj.313.7064.1025.
[13] Fatima S, Hafeez A, Ijaz A, et al. Classical Homocystinuria in a Juvenile Patient. J Coll Physicians Surg Pak. 2018 Jun;28(6):488-489. doi: 10.29271/jcpsp.2018.06.488.
[15] Camargo EC, Huang SY, Karaa A, et al. Case 7-2018: A 25-Year-Old Man with New-Onset Seizures. N Engl J Med. 2018 Mar 8;378(10):941-948. doi: 10.1056/NEJMcpc1712226.