Andrew N. Wilner, MD

A 60-year-old man is brought to the emergency department (ED) because of increasing confusion.* According to his roommate, the patient had not been eating well for about 3 weeks and was drinking less alcohol than usual. When the patient could no longer carry on a coherent conversation and was “acting like a baby,” the roommate took him to the ED.

Past medical history includes coronary artery disease, chronic obstructive pulmonary disease, and a gunshot wound to the left leg. The patient takes no medications, has no allergies, smokes a pack of cigarettes a day, drinks a pint of liquor a day, and smokes marijuana several times a week. He is single and unemployed.

The patient is cachectic and disheveled. He is afebrile. Blood pressure is 150/110 mm Hg; pulse, 110 beats/min; and respiration rate, 24 breaths/min. He answers questions but is disoriented to person, place, and time. He thinks he is in a restaurant.

He does not cooperate with the neurological examination. Horizontal nystagmus is present bilaterally in the direction of gaze. Otherwise, the results of cranial nerve, motor, reflex, and sensory examination are grossly normal.

A complete blood cell count, electrolyte levels, and metabolic and liver panels are normal. Alcohol level is undetectable. A thyroid panel and vitamin B12 level are normal. Rapid plasma reagin and HIV tests are negative. An urgent head CT scan is normal. An electroencephalogram reveals mild to moderate generalized slowing consistent with a toxic/metabolic encephalopathy.

The patient is given intravenous fluids, multivitamins including thiamine, and acyclovir for possible herpes simplex encephalitis. A lumbar puncture is traumatic and reveals 4 white blood cells, 2000 red blood cells, a protein level of 88 mg/dL, and a glucose level of 57 mg/dL. Gram staining and culture, cryptococcal antigen, and herpes polymerase chain reaction tests are negative. Acyclovir is discontinued.

MRI reveals increased signal in the periaqueductal gray matter (

), which is suggestive of Wernicke encephalopathy. Thiamine, 100 mg/d, is continued throughout the patient’s hospital stay.

The patient becomes increasingly agitated on hospital day 2 and is treated for delirium tremens with benzodiazepines. He has three generalized tonic-clonic seizures, and phenytoin is started. The patient is unable to feed himself and receives parenteral nutrition. Eventually, he requires a percutaneous endoscopic gastrostomy feeding tube.

Over a period of several weeks, the patient’s level of consciousness slowly improves. After 3 weeks, he can participate in a conversation and follow simple commands but has poor attention and strays off topic. Because he is unable to care for himself, he is discharged to a nursing facility.

First described by Carl Wernicke in 1881, the classic clinical triad of 

 is ataxia, confusion, and ocular signs. However, the majority of patients do not present all three findings.

 Ataxia was not appreciated in this patient, in part because he was too weak to walk. However, he exhibited two cardinal features of Wernicke-horizontal nystagmus and encephalopathy.

Symptoms and signs in Wernicke encephalopathy are due to thiamine (vitamin B1) deficiency and constitute a neurological emergency. Thiamine is essential in glucose energy-using pathways, particularly in the central nervous system. Thiamin deficiency also disrupts the blood-brain barrier.

Although a thiamine level was not obtained in this patient, MRI findings were consistent with Wernicke encephalopathy. The likely etiology of thiamine deficiency was chronic alcohol abuse coupled with poor nutrition. Since the human body maintains only a 2- to 3-week thiamine reserve, this patient’s 3 weeks of poor oral intake was sufficient to result in life-threatening thiamine depletion.

While horizontal nystagmus is the most common ocular sign in Wernicke encephalopathy, other eye findings may include anisocoria, lateral rectus palsies, and papilledema. Encephalopathy can progress to coma. In the chronic phase, the condition may evolve to 

, a neuropsychiatric condition characterized by confabulations.

Unlike brain CT, MRI has a high diagnostic sensitivity for Wernicke encephalopathy. In this case, 

 included increased signal in the periaqueductal gray matter (

), which are two anatomic regions frequently affected in Wernicke.

 Other typical MRI findings include symmetric signal intensity alterations in the mammillary bodies and tectal plate.

Although Wernicke encephalopathy is often associated with alcoholism, malnourishment due to anorexia nervosa, chemotherapy-induced prolonged vomiting, chronic gastrointestinal disease, hemodialysis, and hyperemesis gravidarum can also result in this syndrome.

 Symptoms may improve with thiamine supplementation, but complete remission may not occur.

 Mortality is 10% to 20%, but early treatment is associated with a better prognosis.

 Intravenous thiamine supplementation is often recommended at 100 mg/d, although alternative dosing has been proposed.

*Details of this case were significantly changed to protect patient confidentiality.


	Andrew Wilner, MD, is a neurologist who blogs at 

The Locum Life: A Physician’s Guide to Locum Tenens

1. Zuccoli G, Siddiqui N, Bailey A, Bartoletti SC. 

Neuroimaging findings in pediatric Wernicke encephalopathy: a review

2. Chiossi G, Neri I, Cavazzuti M, et al. 

Hyperemesis gravidarum complicated by Wernicke encephalopathy: background, case report, and review of the literature

MR imaging: an increasingly important tool in the early diagnosis of Wernicke encephalopathy

. 2012;33:E92; author reply E93. doi: 10.3174/ajnr.A3152.

4. Berdai MA, Labib S, Harandou M. Wernicke’s encephalopathy complicating hyperemesis during pregnancy. 

5. Ashraf VV, Prijesh J, Praveenkumar R, Saifudheen K. 

Wernicke’s encephalopathy due to hyperemesis gravidarum: clinical and magnetic resonance imaging characteristics

6. Cruz LCH, Domingues RC, Vilanova I, Gasparetto EI. 

MRI imaging findings in Wernicke encephalopathy: nonalcoholics may be similar to alcoholics

. 2010;31:E54-E55; author reply E56. doi:10.3174/ajnr.A2113.

Articles

What’s in your differential diagnosis for this cachectic, disheveled patient who can no longer carry on a coherent conversation?

Increasing Confusion in a Man With Chronic Alcohol Abuse

Advances in multiple sclerosis (MS) continue to dominate other therapeutic areas in neurology. MS presentations accounted for approximately 15% of the more than 3000 scientific presentations at the 71st 

Pregnancy outcome and disease-modifying therapies

Multiple sclerosis (MS) occurs more frequently in women, often during childbearing years. Although women with MS require no special gynecologic care during pregnancy, MS management requires close observation and possibly drug or dose adjustment. The Food and Drug Administration (FDA) has not approved any disease-modifying agent for use during pregnancy.

 reviewed the outcome of 142 pregnancies in 120 women with MS. During 80 of the 142 pregnancies (56.3%), the fetus was exposed to a disease-modifying agent. The most common disease-modifying agents were beta interferons (35.2%), natalizumab (19.7%), fingolimod (16.9%), and dimethyl fumarate (3.5%). Premature birth occurred in 5% of the exposed group vs 3.2% of the nonexposed group (

=NS). The rate of abortions was also similar (10% in the exposed group vs 11.3% in the nonexposed group). Major fetal malformations did not occur in either group. In this 

, there was no difference in pregnancy outcomes in pregnant women who received disease-modifying agents vs those who did not.

It is unlikely that there will ever be a definitive study comparing the potential teratogenicity of different disease-modifying agents for MS. Consequently, physicians and their patients must rely on retrospective and registry data. This study should reassure women who become pregnant while under treatment, but more data are needed before disease-modifying agents can be recommended as safe during pregnancy.

Natalizumab (Tysabri) is a recombinant humanized anti-alpha4-integrin antibody indicated for the treatment of relapsing forms of MS. One of the risks of natalizumab is the occurrence of progressive multifocal leukoencephalopathy (PML), which can result in morbidity and mortality. Risk factors for PML include duration of natalizumab therapy, presence of the JC virus, and prior immunosuppressive therapy. The possibility that extended interval dosing (EID) rather than standard interval dosing (SID) might decrease the risk of PML is under investigation. Typically, patients receive natalizumab as a monthly infusion. All patients treated with natalizumab must be registered in the manufacturer’s TOUCH (Tysabri Outreach: Unified Commitment to Health) prescribing program.

 reviewed the TOUCH dataset as of June 2018 to determine whether the incidence of PML differed between patients on EID or SID. Patients were divided into three groups: (1) primary analysis (EID/SID over the past 18 months), (2) secondary analysis (prolonged period of EID/SID), and (3) tertiary analysis (dosing primarily of EID/SID).

In all groups, EID patients had longer median natalizumab exposure durations than SID patients, suggesting better tolerability. In addition, the hazard ratio (HR) for PML was 0.10 (

<.001) for the primary analysis group and 0.20 (

<.001) for the secondary analysis group, both favoring EID. Consequently, EID may be an effective strategy to reduce the risk of PML in patients with MS treated with natalizumab.

It is unknown whether EID decreases the risk of PML, but 

 suggests that spacing out natalizumab dosing may postpone the occurrence of this devastating complication of treatment. The issue of efficacy also needs to be considered-some patients with MS may require monthly natalizumab dosing to prevent relapses. Much more data regarding dosing frequency and dose adjustments are needed to provide guidelines for practitioners to individualize and optimize natalizumab therapy.

Monitoring disease activity with serum neurofilament light chains

Medical management of relapsing-remitting MS relies on monitoring disease activity via clinical symptoms and MRI findings. Serum biomarkers of MS activity would potentially reduce reliance on MRI and facilitate disease management. Recently, it has been observed that serum neurofilament light chain (NFL) levels, which represent axonal breakdown, correlate with disease activity.

 measured serum levels of NFL with a single molecule array assay in two MS cohorts. In the SET group, there were 163 patients with relapsing-remitting MS (405 samples). In the GeneMSA group, there were 179 patients with relapsing-remitting MS (664 samples). NFL levels were compared with radiological activity on annual MRI scans.

Of the patients with NFL levels higher than the 90th percentile, 81.6% of the SET patients (odds ratio [OR]=3.4) and 48.9% of the GeneMSA patients (OR=2.6) had active radiological disease. Conversely, NFL levels lower than the 30th percentile were associated with the lack of active radiological disease-only 29.3% of the SET group and 10.9% of the GeneMSA group showed any MRI activity. Based on 

, it appears that NFL levels tend to agree with MRI findings and may become a useful biomarker of MS disease activity.

The old adage, “treat the patient, not the MRI,” has fallen by the wayside when it comes to MS. It has become apparent that many patients, even if asymptomatic, have ongoing disease activity that can be detected by periodic MRI scans. How often to perform MRI and when to change therapy due to detection of disease activity remain active areas of investigation. If NFL levels reflect disease activity as well as MRI, they may provide a less cumbersome and perhaps less expensive method of monitoring disease activity in people with MS. It does not appear that NFL levels have reached that standard yet.

The lay term, “MS hug,” may be used by people with MS to describe dysesthetic sensory symptoms. Wingerchuk and colleagues

 at the Mayo Clinic, Arizona, evaluated the charts of 116 patients with MS (71% female, 76% with relapsing disease) who reported the MS hug. The investigators defined the MS hug as a “unilateral or bilateral segmental constricting (squeezing, band-like, or girdle-like) sensation involving the thorax, abdomen, or both that was associated with objective evidence of a neuroanatomically appropriate current or prior spinal cord lesion and not attributable to another cause.”

Although 116 patients reported the MS hug, only 46 (41%) had symptoms and pathophysiology that met the study definition. In these patients, symptoms occurred during cord relapse evolution (41%), more than 3 months post-relapse or during the progressive phase (39%), or during early recovery (20%). Of the remaining 70 patients who complained of an MS hug, 27 (39%) had other types of neuropathic pain.

Six patients (9%) with symptoms suggestive of the MS hug had serious causes not related to MS that required immediate intervention. These included three patients with herpes zoster and one patient each with cholecystitis, myocardial infarction, and pulmonary embolism. Other non-MS causes of the MS hug included musculoskeletal discomfort, gastroesophageal reflux disease, anxiety, and bowel symptoms. Eleven patients (16%) had no clear etiology. The authors caution that the term MS hug may accurately describe spinal cord symptoms in people with MS but may also indicate unrelated medical problems that may be serious and require immediate treatment.

Although many somatic symptoms in people with MS may be related to their underlying disease, some symptoms may reflect different pathology. 

 emphasizes the importance of investigating all symptoms in people with MS in order to detect and treat potentially serious comorbidities.

People with MS may suffer chronic symptoms such as depression, fatigue, and pain, which may respond only partially to conventional treatment. In an 

 explored the use of virtual reality in an attempt to alleviate symptoms. Treatment consisted of eight 35-minute sessions with an HTC Vive headset. Patients were randomized to either passive (viewing) or interactive (moving). Patients were monitored by a technician for safety. The Positive and Negative Affect Schedule (PANAS) and Patient Reported Outcomes Measurement Information System (PROMIS) scales were administered prior to and following virtual reality treatment to assess response. Data available thus far for eight patients indicated that all experienced an improved positive affect and reduced negative affect. The authors concluded that virtual reality is a promising tool for symptomatic treatment of patients with MS and other chronic neurologic conditions.

While there have been many advances in the treatment of the inflammatory component of MS, comprehensive patient management demands symptom improvement as well. This study suggests that virtual reality therapy may become a helpful modality.

This brief sample of advances in MS presented at the 

2019 American Academy of Neurology meeting

 includes the effect of disease-modifying agents on fetal outcome, diminished risk of PML via extended natalizumab dosing, the potential of NFL as an MS activity biomarker, the diverse etiologies that underlie the “MS hug,” and the potential for virtual reality therapy to alleviate affective symptoms in people with MS. Many more presentations at the meeting demonstrated progress in the understanding and treatment of MS.

1. Ahmed SF, Almuteri ML, Al-Hashel J, Alroughani R. 

Pregnancy outcome in multiple sclerosis patients exposed to disease modifying therapies

. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P4.2-100.

Reduced risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab extended interval dosing (EID): updated analysis of the TOUCH Prescribing Program database

. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract S26.006.

3. Uher T, Schaedelin S, Benova B, et al. 

Monitoring of subclinical disease activity by serum neurofilament light chain levels in multiple sclerosis

. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract S37.005.

The “MS hug”: definition, characteristics, course, and misattribution risk

. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P5.2-111.

5. Shaw M, Palmeri M, Krupp L, Charvet L. 

Acute and lasting benefits of a virtual reality in multiple sclerosis

. Presented at: American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA. Abstract P1.7-010.

What’s new in MS: teratogenicity of disease-modifying drugs, extended interval natalizumab dosing, a potential biomarker, the “MS hug,” and virtual reality therapy.

Multiple Sclerosis Update: 5 Things to Know

New research in epilepsy accounted for approximately 10% of the more than 3000 scientific presentations at the 71

 American Academy of Neurology meeting in Philadelphia, PA, May 4 to 10, 2019. As a fellowship-trained epileptologist, I focused this brief review on research with clinical relevance to practitioners and people with epilepsy.

Neurologists are frequently consulted to evaluate patients who may have had a syncopal event or epileptic seizure. Because there is rarely the opportunity to witness the clinical event, diagnosis must rely on the history, physical examination, laboratory studies, as well as electroencephalographic (EEG) and magnetic resonance imaging (MRI) results. Even after an extensive investigation, the diagnosis often remains unclear. Reliable biomarkers that discriminate between seizure and syncope would be extremely valuable.

 evaluated 70 patients with syncope and 105 with epilepsy and developed an algorithm to differentiate the two conditions. They concluded that longer duration of loss of consciousness, increased neuron-specific enolase, prolactin, NH3, and myoglobin were more likely in seizure than syncope patients. The most powerful discriminator was NH3-a cut-off value of 45.5 umol/l offered a 71.23% specificity and 68.8% sensitivity. The authors suggest that a combination of biomarkers might assist physicians in differentiating syncope from seizure.

In patients with drug-resistant mesial temporal lobe epilepsy, surgical removal of the anterior temporal lobe is most likely to render patients seizure free. Magnetic resonance-guided laser interstitial thermal therapy (LiTT), which requires only a burr hole and not a craniotomy, has been proposed as a less invasive alternative. Although LiTT is less stressful for patients, it remains unclear whether long-term seizure control equals that of traditional temporal lobectomy.

 performed a retrospective review of their experience with LiTT for intractable mesial temporal lobe epilepsy at the Mayo Clinic, Arizona, from 2013 to 2018. Of 25 patients followed for an average of 1.5 years, eight (33%) became seizure free. Post-operative neuropsychometric testing revealed cognitive decline in 8/10 (80%) patients. Visual field deficits were present in 5/11 (45%). Four patients required a second LiTT treatment or temporal lobectomy to improve seizure control.

The percentage of seizure-free patients (33%) was less than expected with anterior temporal lobectomy. Further, cognitive decline and visual field deficits were not uncommon. The authors concluded that more data is needed to identify patients most likely to benefit from LiTT rather than conventional epilepsy surgery.

LiTT is an exciting new minimally invasive therapy, but its role in treating patients with intractable epilepsy remains to be defined. Studies such as the one above reinforce the need to subject LiTT to more rigorous examination before it replaces traditional temporal lobectomy.

Diagnosis of psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures (PNES) often clinically resemble epileptic seizures but do not respond to antiepileptic medications. Because these patients resemble those with drug-resistant epilepsy, physicians often refer them to an epilepsy center for video-EEG monitoring to determine seizure type.

 performed a retrospective chart review of 480 adults (aged 18 to 92 years) referred to the Creighton University School of Medicine Epilepsy Center for diagnosis between January 2012 to January 2017. Of the 480 patients, 189 (39%) received the diagnosis of PNES followed by psychiatric treatment. Overall, 56.9% of patients with PNES who had follow-up data became seizure free. Older patients with PNES tended to have better outcomes; 69% of those 61 years or older improved vs. 47% of those aged 18 to 30 years. Although psychiatric diagnoses were common in all age groups, they were less likely in older patients (73%) than those between the ages of 18 to 30 (86%).

This is a nice study that provides insights into the characteristics and outcomes of a large population of PNES patients. Video-EEG has been an essential tool for PNES diagnosis for at least the last 30 years and will remain so into the foreseeable future.

Emergency medications for uncontrolled seizures are usually administered intravenously, intramuscularly, or per rectum. The intranasal route has been proposed as a more convenient method to treat breakthrough or acute repetitive seizures.

In this open-label study, Sperling and colleagues

 observed the efficacy and adverse effects of an experimental diazepam nasal spray (Valtoco) under investigation by Neurelis. Of the 109 patients who received at least one dose, a single dose controlled seizures in 92% of episodes. Overall, a total of 1585 episodes were treated with 1 to >40 doses. Adverse events occurred in 67/109 (61.5%) patients. Only 19 patients (17.4%) had adverse events that appeared drug-related. These included nasal discomfort (7 patients), epistaxis (4 patients), and headache (4 patients). There were no serious treatment-related side effects. The authors concluded that intranasal diazepam was safe and well-tolerated.

Rescue medication for seizures are generally limited to intravenous and intramuscular preparations that must be administered by qualified medical personnel. One FDA-approved exception is diazepam rectal gel (Diastat). Because of the awkward route of administration, Diastat use has been severely limited. Research into a more convenient alternative, such as an intranasal spray, has been ongoing for a number of years and finally appears to have borne fruit. If the Neurelis drug receives FDA approval, it may be available before the end of 2019.

Incomplete seizure control due to intractable epilepsy or nonadherence may result in life-threatening status epilepticus. Early readmissions indicate poor seizure control after hospital discharge. The Center for Medicare and Medicaid Services (CMS) imposes financial penalties on hospitals for early readmissions for a number of conditions such as myocardial infarction and pneumonia. Although epilepsy is not yet one of the diagnoses subject to these CMS penalties, the 30-day period without readmission has become a performance benchmark for hospitals.

 addressed the problem of hospital readmissions for status epilepticus in their presentation, “How often and what predicts…30-day hospital readmissions after generalized convulsive status epilepticus?” From a total population of 14,562 adults with generalized convulsive status epilepticus in the 2014 Nationwide Readmission Database, the authors identified 2520 (17.3%) patients who were readmitted within 30 days of discharge. On multivariate logistic analysis, risk factors for readmission included leaving against medical advice (OR: 1.45), length of stay greater than six days (OR: 1.42), discharge to a short-term hospital (OR: 1.39), and the presence of comorbidities (OR: 1.12). Conversely, patients aged 45 years or older and those in high-income households were less likely to suffer early readmission.

In a similar retrospective study utilizing the Nationwide Readmission database, Savani and colleagues

 expanded the study duration to 2010-2014 and examined all patients with epilepsy who were readmitted, not just those with status epilepticus. Their analysis included 622,467 patients with hospitalization for epilepsy using the primary diagnostic ICD-9CM code 345.xx. Of these, 76,911 (12.4%) were readmitted within 30 days. Risk factors for readmission included discharge to another facility (OR: 1.22), higher comorbidity index (1.10), and longer length of stay (OR: 1.01).

Relevant comorbidities included chronic kidney disease (OR: 1.35); opioid abuse (OR: 1.30); chronic liver disease (OR: 1.26); psychiatric illness (OR: 1.22); heart failure (OR: 1.19); chronic lung disease (OR: 1.17); cocaine (OR: 1.14); diabetes (OR: 1.10); hypertension (OR: 1.07) and hypothyroidism (OR 1.06). Conversely, the following variables decreased readmissions: elective admission (OR: 0.42); self-payment vs. Medicare/Medicaid (OR: 0.67); private insurance vs. Medicare/Medicaid (OR: 0.75); and teaching hospital admission (OR:0.96). The authors suggest that proactively addressing risk factors for readmission may improve patient outcomes.

In my experience in several hospitals, physicians suffer undue pressure to discharge patients at the earliest possible moment. Data such as those provided by Savani and colleagues may help bolster physician decisions to retain patients in hospital until they are truly ready to return home.

’s epilepsy presentations revealed laboratory measures that may help differentiate syncope from seizure; the effect of laser ablation on intractable epilepsy; the importance of video-EEG for the diagnosis and management of PNES; the potential for intranasal diazepam to safely stop seizures; and patient characteristics associated with early hospital readmission. This research all has the potential to improve the care of people with epilepsy.

Andrew Wilner, MD, is a neurologist who blogs at 

1. Kim H, Kim JB. Differential diagnosis of epileptic seizure and syncope using machine learning algorithms. American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (P2.5-031).

2. Patel A, Dawit S, Mastorakos G et al. Long-term outcomes in patients with intractable mesial temporal lobe epilepsy who undergo laser ablation. American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (P5.5-019).

3. Wolfe M, Singh S, Sankaraneni RM. Profile and outcome of psychogenic nonepileptic seizures patients undergoing video-EEG monitoring. American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (P4.5-032).

4. Sperling M, Hogan R, Biton V, et al. A 12-month, open-label, repeat-dose safety study of Valtoco (NRL-1, diazepam nasal spray) in patients with epilepsy: Interim report. American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (P2.5-029).

5. Rahwan M, Looti AL, Bishu K, Ovbiagele B. How often and what predicts…30-day hospital readmissions after generalized convulsive status epilepticus? American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (S36.006).

6. Savani C, Kumar V, Richardson C et al. Predictors of 30-day readmission after index hospitalization for epilepsy: a 5-year national estimate using the Nationwide Readmission (NRD) database. American Academy of Neurology Annual Meeting, Philadelphia, PA, May 4-10, 2019 (P2.5-029).

A combination of biomarkers that might assist physicians in differentiating syncope from seizure; LiTT for intractable mesial temporal lobe epilepsy-these and other insights.

Epilepsy Update: 6 Key Takeaways

A 21-year-old man* was ejected from a speeding motor vehicle after it slammed into a tree. Emergency medical services personnel found him unconscious with stable vital signs. On examination in the emergency department, he became agitated and required intubation, sedation, and transfer to the intensive care unit. His girlfriend, who was not in the car, arrived later and provided his history.

Past medical and psychiatric history is negative; family history is unremarkable. The patient takes no medications and has no allergies. He does not smoke or abuse alcohol; however, he uses marijuana regularly. He is single and works as a chef at a local restaurant. When the accident occurred, he had been on his way to celebrate his birthday.

The next day, the patient wakes up and is extubated. He complains of pain in his right arm and left leg, a severe headache, and blurry vision.

He has a large scalp hematoma and swelling of the right arm and left leg. He can state his name and knows he is in the hospital. He does not know the day of the week or the date. He recalls getting into his car the previous afternoon but has no memory of the accident or transport to the hospital. His speech is so rapid that his words are nearly incomprehensible. He sits up impulsively and almost falls out of bed. The rest of his neurological examination, including cranial nerves, motor, reflexes, sensory, and coordination, is intact.

Results of a routine chemistry panel, complete blood cell count, and coagulation studies are unremarkable. Imaging reveals right arm, left femur, and pelvic fractures. A head CT scan is normal. CT angiography of the neck does not show carotid or vertebral arterial injury. Brain MRI T2 images are normal, but T2 gradient echo (GRE) sequences reveal hypodense lesions in both frontal lobes, the left temporal lobe, and cerebellum (

The following day, the patient undergoes surgical fixation of his limb fractures. By the fifth hospital day, he is fully oriented. His speech has more normal pacing. He still has no recollection of the accident. His girlfriend reports that his behavior is almost normal. The patient is discharged to home to follow up in orthopedic and neurology clinics.

To what diagnosis do the T2 GRE images point? >>

Traumatic brain injury (TBI) is defined as a blow or penetrating head injury that affects brain function. In the US, 

 of TBI occur every year, resulting in 235,000 hospitalizations and $48 to $56 billion in costs. TBI is 

 (78.8%) than in females (21.2%). More than half of TBI cases result from motor vehicle accidents. Each year, about 50,000 people die of TBI. It is the 

 cause of death and morbidity in young adults.

 of head injuries are categorized as “mild” TBI or “concussion.”

 Common symptoms include headache and neck pain, but other symptoms may occur as well. These include ageusia, anosmia, behavioral abnormalities, bradyphrenia, dizziness, fatigue, impaired memory, tinnitus, nausea, and vomiting. Symptoms may persist longer than a year. Repeated mild TBI may result in 

Concussion is generally diagnosed after TBI when patients have neurologic symptoms but lack abnormalities on routine brain CT and MRI scans. Persistent symptoms may seem inexplicable in the face of normal neuroimaging results. However, patients with mild TBI may suffer acute brain injury termed 

 (DAI), also known as “shearing injury,” which is not visible on standard CT and MRI scans. DAI is defined as “diffuse damage to axons in the cerebral hemispheres, in the corpus callosum, in the brainstem, and sometimes also in the cerebellum resulting from a head injury.”

DAI results from high-impact, acceleration-deceleration forces that deform and stretch the brain. Once DAI occurs, secondary changes may include inflammation, cellular death, synaptic dysfunction, activation of glial cells, and protein deposition.

Special MRI sequences may reveal DAI, which is characterized by microhemorrhages and edema. For example, T2 GRE is more sensitive than conventional MRI to detect microhemorrhages.

 In this patient, routine CT and MRI sequences were unremarkable, but GRE images revealed multiple hypodense areas consistent with Adams grade 1 DAI (

Several other MRI sequences may reveal DAI. These include susceptibility weighted images (SWI), diffusion-weighted images (DWI) paired with apparent diffusion coefficient (ADC) maps, and diffusion tensor images (DTI).

The severity of DAI can be graded with the 

, which was derived from histopathological post-mortem evaluation of 434 cases of fatal non-missile head injury

:
	
	• Grade 1: axonal injury in the cerebral hemisphere white matter, corpus callosum, brainstem, and cerebellum

• Grade 2: grade 1 plus focal lesion in the corpus callosum

• Grade 3: grade 2 plus focal lesion in the rostral brainstem

 of patients with TBI, DAI increased the risk of an unfavorable outcome by 3 times.

 Furthermore, each Adams grade on MRI increased the risk of unfavorable outcome by 3 times. Consequently, a grade 3 lesion with brainstem lesions predicted a 9 times increased risk of an unfavorable outcome. However, DAI does not always result in an adverse outcome-37% of patients with grade 3 DAI had a favorable outcome.

• Neurological symptoms and signs and behavioral changes commonly occur after TBI.

• In mild TBI, DAI may be present but invisible on routine brain CT and MRI imaging.

• MRI sequences such as T2 GRE, SWI, DWI/ADC, and DTI should be considered when DAI is suspected.

• The presence of DAI indicates brain injury and increases the risk of a worse functional outcome.

• Currently, there is no proven medical treatment other than supportive care that improves prognosis in mild TBI.

1. Grassi DC, da Conceicao DM, da Costa Leite C, Andrade CS. 

Current contribution of diffusion tensor imaging in the evaluation of diffuse axonal injury

Diffusion tensor imaging and magnetic resonance spectroscopy in traumatic brain injury: a review of recent literature

The presence and role of iron in mild traumatic brain injury: an imaging perspective

Diffuse axonal injury in head injury: definition, diagnosis and grading

5. Van Eijck MM, Schoonman GG, van der Naalt J, et al. 

Diffuse axonal injury after traumatic brain injury is a prognostic factor for functional outcome: a systemic review and meta-analysis

A young man sustained a serious head injury in a car accident, but routine brain CT and MRI scans are normal. Your next step?

Author | Andrew N. Wilner, MD

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