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"What's the differential diagnosis for writing G's like a junior high school girl?" - Dr. House

Chief Complaint: Double vision, night terrors

History of Present Illness: Dan is a 16-year-old man with no significant medical history who presents today with a recent episode of sudden-onset diplopia and a 3-week history of night terrors. He has been seen by 2 neurologists, who could not discern a cause. The patient's denies a history of post-traumatic stress disorder, though he does admit to a recent hit during a lacrosse game which occurred after the episode of diplopia. His family denies a history of sexual abuse.

Past Medical History: None.

Medications: None.

Allergies: No known allergies.

Social History: The patient lives with his parents at home. He plays lacrosse for his high school team. Use of alcohol, tobacco, and drugs is unknown.

Family History: No significant history.

Physical Exam: Nonfebrile.
Gen: Observed a myoclonic jerk of the right leg.
HEENT: Macular margins within normal limits and no lesions observed on retinal exam. "Color is good" [whatever that means].
Neuro: Left eye nonreactive to finger-flick [an approximation of the corneal reflex?]. Patient is only able to recite one animal that begins with "b" (baby elephant) [This does exist as a neuropsych test but by itself doesn't really tell you much].

Labs/Imaging:
CBC, basic metabolic panel within normal limits. LFTs normal.
Chest x-ray showed no abnormalities.
CT head showed no abnormalities.
MRI brain: No lesions in the white matter. No structural abnormalities. No space-occupying tumors.

Medical Decision Making: Given the patient's history of night terrors prior to the recent onset of diplopia, a polysomnograph was performed, during which the patient experienced a night terror. A head CT scan and brain MRI were both reported as normal. A closer look at the MRI revealed meningeal enhancement and bowing of the corpus callosum, causing pressure on the cortex and brainstem, which may account for the patient's neurological symptoms. A radionucleotide cisternogram was ordered, which demonstrated blockage of CSF flow. Neurosurgery was consulted, who placed a shunt into the right lateral ventricle to relieve the blockage. CSF fluid analysis revealed oligoclonal bands and increased intrathecal IgG, consistent with a diagnosis of multiple sclerosis. A visual evoked potential was performed, which demonstrated slowing.

The patient was found to be absent and was eventually located on the roof of the hospital, hallucinating that he was standing on the lacrosse field. Given the patient's age (and likelihood of sexual contact), a diagnosis of neurosyphilis was considered, which represents the final stage of syphilis. The patient was treated empirically with intrathecal penicillin. The patient began experiencing auditory hallucinations [while looking at Dr. Cameron's breasts] and became extremely agitated. The patient was given Ativan.

The diagnosis was reconsidered. LFTs, BUN, and creatinine were normal. The patient had no history of diabetes, and examination of electrolytes demonstrated no anion gap. MRA showed no vasculitis. The patient's young age makes a degenerative cause very unlikely. No neoplasm was demonstrated on MRI. The WBC count was on the high end of normal, but the patient had experienced no fevers, making infection unlikely. A CT scan ruled out trauma as a cause of the symptoms.

An EEG, left and right EOG were conducted, revealing no epileptiform activity. BP was 110/70. An EKG demonstrated normal QRS with T-wave inversions in multiple precordial leads [This finding suggests that the heart isn't getting enough oxygen. I'm surprised that this wasn't pursued further by checking troponin levels and maybe an echocardiogram given that a person this young shouldn't be having a heart attack.] LFTs at this point were 2 times the normal range. DNA testing was performed on the parent's saliva from their coffee cups. It was discovered that Dan's parents were not his biological parents. His adopted parents were confronted with the question of Dan's biological parents' family history. They revealed that the family history they had given had been that of the biological parents, though the immunization status of the patient's biological mother was unknown. If the parent's mother had not received the measles vaccine, the patient could potentially have subacute sclerosing pancencephalitis. A retinal biopsy was done to confirm the diagnosis, and an Omaya reservoir was placed for delivery of intraventricular interferon. The patient's condition improved.

Differential Diagnoses:
Dr. Cameron: Leukoencephalopathy
Dr. Chase: Infection, liver process, kidney process, viral meningitis, neurosyphilis
Dr. Foreman: None.
Dr. House: Movement disorder, degenerative brain disease, multiple sclerosis, infection in his brain, subacute sclerosing pancencephalitis

Commentary: This episode embodies why this show enthralls medical professionals. How many physicians have actually ever seen a case of subacute sclerosing panencephalitis? If you have, please comment (at the bottom) on how it presented. If there is power in numbers, I expect no responses, because any place with a high enough likelihood of this disease occurring also has a high likelihood of not having internet access.

Subacute sclerosing panencephalitis (SSPE) is a sequelae of rubeola virus, also known as measles. This means that if a person had measles as a child, he or she would have a 8.5 out of a million chance of developing measles. In a country with a population of roughly 300 million (like the U.S.), about 2,550 people would develop this potentially fatal complication of measles. This is why some smart person invented the measles-mumps-rubella (MMR) vaccine. There is some controversy in the public about the possibility of MMR actually causing SSPE.

"I knew that MMR was a mistake from the start. Within 10 seconds I could see that it was a bad idea. All the vaccinations prior to MMR could occur in nature; they had never been combined before. Normally, viruses can't infect at the same time, so if you put more than one virus into a body at once you are making a grave error. Surely the point of vaccination is to make it safer for children, but with MMR a child could be overwhelmed, and might not recover. The deaths and severe reactions to MMR are just the tip of the iceberg. The Government should stop lying and recognise that MMR is one step too far. It's all nonsense. It's all about greed, and the gullibility of buyers at the Department of Health. These people are acting on behalf of the nation and they should be more sceptical."-- Dr. Peter Mansfield

With the MMR vaccine, about 0.7 people per million can develop SSPE, which would translate to 210 people in the U.S. (instead of 2,550). I guess I'm trying to make a few points.

Get your kids vaccinated.
The number of people in the U.S. who have SSPE is slim to none.
The number of doctors who have diagnosed SSPE is probably slim to none.
The writers of the show can get away with a lot in this episode because there are very few doctors who could refute the disease presentation from their personal experience.

Anyways, let's get to business. A 16-year-old comes in with double-vision (diplopia) and night-terrors. Double-vision is actually a very telltale sign. In a young person, I personally would worry about multiple sclerosis and myesthenia gravis (2/3rds of myesthenia gravis cases present with diplopia as the first symptom). It would be nice if Dr. House had done an actual neurological exam, which might help tease these apart. Nonetheless, I found it interesting as to the things that he did test. By flicking his finger, he was maybe trying to approximate the corneal reflexes, which tests the the V1 branch of the trigeminal nerve and the facial nerve. If that's true, then Dan didn't blink when his left eye was flicked at, which would point towards a problem with the left trigeminal nerve, indicating a neurological problem. The other possibility is that Dr. House was just pretending to do a physical exam, and that this was entirely pointless. The other interesting thing is that Dr. House makes a big deal out of night terrors, which are generally considered a benign condition where a person wakes up at night out of deep sleep with a look of terror on their face and then goes back to bed with no memory of what happened (as opposed to a nightmare). The polysomnograph (sleep test) seemed completely unnecessary to me and certainly not something that needed to be done emergently as an inpatient.

Since I'm thinking (based on the diplopia) that Dan might have myasthenia gravis or multiple sclerosis, I'd check the thymus gland on my physical exam, which if enlarged, would raise the possibility of myasthenia gravis. In terms of labs, I'd check for acetylcholine receptor antibodies (and MuSK antibody) and thyroid function tests. In terms of ruling out multiple sclerosis, I'd want to check the CSF for oligoclonal bands and increased IgG, though this could certainly wait until after the imaging.

First up on the priority list for imaging would be an MRI of the brain. Because of the relative lack of MRI machines and the long times that MRI scans take, a head CT would probably be done first while the patient was in line to get their MRI. In this case, the head CT was normal, and an MRI read was normal (though House picked up on some "bowing" of the corpus callosum).

I have no idea what "bowing" exactly means, but I do know this. Radiologists are impulsive people. For anyone who's read a radiology report, "There are non-specific changes possibly consistent with the following 100 conditions" is a typical sentence. The only way a radiologist can get sued is if he or she doesn't see something that is there. The way that radiologists compensate for this is to comment on everything, including things that aren't even there. Basically, it's safer for a radiologist (from a medicolegal standpoint) to name every possibility in a given image than to miss something. I generally tend to go by the thinking that if a radiologist didn't see it, then it's not there.

If the labs were fine and everything looked normal on the CT and MRI, I'd probably discharge Dan from the hospital (maybe after a lumbar puncture to test the CSF for multiple sclerosis). I mean, come on! One episode of double-vision and a kick of the leg? That's not enough to get admitted at any hospital in the country! At most, I might offer him some Valium to suppress stage 3 and 4 sleep, during which night terrors are thought to occur (versus nightmares, which occur during REM sleep). Inevitably, Dan would get worse at home and would be back at the hospital in a few days feeling disoriented and hearing voices, and then he would probably be admitted.

At this point, I would certainly do a lumbar puncture to get cerebrospinal fluid (and consider a psychiatry consult). Dan's CSF showed oligoclonal bands and increased IgG. Ninety percent of people with multiple sclerosis have these in their CSF, but not everyone with this finding in the CSF has multiple sclerosis. At one point, Dr. Cameron references the McDonald criteria for the diagnosis of MS. Yeah, Dan has only had one attack and doesn't fit the criteria yet, but given his age where things like strokes are next to impossible, MS would still be at the top of the list. The assumption would be that given enough time, Dan would have a second attack and thus fit the criteria for MS diagnosis. I'd start Dan on Valium 5 mg 1-3 times a day to deal with the spasticity (and the night terrors too -- elegant, no?) and then I'd use intravenous methylprednisolone 1000 mg for 5 days followed by oral prednisode if Dan was having an acute attack of diplopia. Interestingly, a 1981 study published in Science magazine demonstrated that intrathecal interferon reduced exacerbations of multiple sclerosis. This is extremely similar to the final treatment that Dr. House offered Dan (interferon-beta in this 1981 study vs. interferon-alpha used for SSPE).

I would almost be willing to say that Dr. House was being dramatic in misdiagnosing MS as SSPE, but he decided to do a retinal biopsy to confirm, which I wouldn't necessarily have done. Actually, I received an e-mail from a reader of this site that the biopsy wouldn't be appropriate in this situation and that it was done with a needle going through the lens of the eye, which would have left Dan blind! From reading up on this online, I tend to agree that this was conducted improperly and that it wasn't even indicated in this case. I probably would have gone back and checked rubeola IgG titers in the CSF instead and acted based on those results (assuming that I was even vaguely considering SSPE as a possible diagnosis).

Taken from this Baylor case file, here are the diagnostic criteria for SSPE. Findings pertinent to Dan's case are in bold.

The diagnosis of SSPE can be made if three of the following five criteria are fulfilled: 1) typical clinical presentation with progressive cognitive decline and stereotypical myoclonus, 2) characteristic EEG changes, 3) elevated cerebrospinal fluid globulin levels without pleocytosis, 4) elevated CSF measles antibody titers [not checked by Dr. House], and 5) typical histopathologic findings in a brain biopsy or autopsy (Dyken 1985, Santoshkumar & Radhakrishnan 1998).
The clinical course of SSPE is variable, but affected individuals generally progress through four loosely defined stages. The first stage is characterized primarily by behavioral and personality changes, and may be heralded by a change in school or work performance. The second stage involves continued cognitive decline as well as myoclonus, seizures, choreoathetosis, apraxia, and visual changes. Features of the third stage include the development of autonomic instability, rigidity, and decreasing levels of consciousness often with decorticate/decerebrate posturing. In the final stage, the patient demonstrates quadraparesis, akinetic mutism, active startle responses and coma. The myoclonus and rigidity is usually less prominent at this point. The overwhelming majority of cases follow a progressive downhill course leading to death; although there have been a few case reports of patients who have apparently gone into remission (Dyken 1985, Santoshkumar & Radhakrishnan 1998). Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months (Singer et al. 1997).
Singer et al. (1997) report that adult-onset patients are more likely than children to present with purely ophthalmologic complaints rather than the classical personality changes as their first symptom of disease. A wide variety of visual disorders have been associated with SSPE, including papilledema, retinitis, chorioretinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. For this reason, and because of the presence of oligoclonal banding on CSF electrophoretic studies, a diagnosis of multiple sclerosis may sometimes be considered in the early stages of SSPE.
The pathognomonic EEG findings in SSPE are periodic complexes with generalized bilateral, usually synchronous and symmetrical slow waves of high amplitude, classically occurring every 5-10 seconds (Dogulu et al. 1995, Gokcil et al. 1998). These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity (Singer et al. 1997). Early in the course of SSPE, the EEG may show normal background activity, even in the presence of the periodic complexes. However, as the disease progresses, the background activity eventually becomes progressively slower, with the emergence of bifrontal slow activity.
Magnetic resonance imaging may be relatively normal, or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter. Later in the disease, MRI may show diffuse cerebral atrophy. Other findings, less commonly encountered, may include pial and parenchymal contrast enhancement, local mass effect of parenchymal lesions, and involvement of the splenium of the corpus callosum. Discrete basal ganglia and brainstem lesions have also been reported. The extent of MRI findings does not correlate well with the clinical neurologic status of the patients (Anlar et al. 1996, Brismar et al. 1996).
Histopathologic findings in SSPE consist of a pattern of gliosis, foamy macrophages in the white matter, perivascular and periventricular inflammatory changes, and Cowdry-A inclusion bodies. Usually, demyelination is symmetric, progressing from the occipital region and extending anteriorly, and involving the thalamus, putamen, and brainstem nuclei as well (Gascon 1996, Singer et al. 1997).

Conclusions: Overall, I think Dr. House did a pretty good job with this case. I think it's extremely odd that he didn't check a rubeola IgG titer in the CSF, as that would have satisfied the 3 (out of 5) criteria needed for the diagnosis of SSPE, which would mean that he wouldn't have needed to get a retinal biopsy.

2 Comments:

farmer said...: My daughter(18) has SSPE. She started life as a healthy infant, although 6 weeks premature. At 13 months she contracted bacterial meningitis, which when treated went away. Unfortunately during her time in the hospital she contracted measles and had a case of measles virus. I remember being relieved it was only the measles, not a recurrence of the meningitis. Fast forward a few years, and she is 5 1/2 years old and doing well in kindergarten. In late winter of her kindergarten year she started to have trouble at school. She also started to need more sleep. We did not think too much of it. One evening she complained to my wife that her legs felt 'funny'. My wife thought that odd. The next day she was vomiting, and had a seizure. The doctors did a CT scan immediately as they worried of a brain tumor. No tumor. Again we were relieved. Over the next few days her condition worsened, and her pediatrician noticed elevated pressure in her brain(looking thru her eyes). Over the next few months she deteriorated rapidly, losing the ability to speak and communicate in any way, and losing all motor skills. Within 4 months she needed total care. The doctors felt the SSPE was progressing so rapidly she would live less than 1 year. However she stabilized after experimental ribavirin treatment into her brain, via a reverse shunt. That was 12 years ago and she is still with us. The doctors say she still has SSPE, although it appears that pnemonia is her biggest enemy today. She is still completely dependant on us as she can not communicate in any way or move voluntarily.; 8:26 PM
bewarne said...: Dear HouseMD-Guide.com,

We’ve noticed that you have provided links from your page, http://www.housemd-guide.com/house-med/2006/10/episode-102-paternity.html to the Cleveland Clinic CME web site. We have recently redesigned and updated the web site and our Multiple Sclerosis Chapter has either changed, or no longer exists. You are linking to it from your site.

We are pleased you have found content on our site that you believe is valuable to your site visitors.

Might we suggest that you share the link to our new MS Chapter, http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/ on your site in place of the one currently shown.; 10:49 AM