Clinical Cases in Neurology From Johns Hopkins Case 16: Chasing the Dragon (for Dr.)

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J. Dedrick Jordan, MD, PhD; Thomas Lloyd, MD, PhD

Preceptor: Carlos Pardo-Villamizar, MD
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Case Presentation

A 36-year-old right-handed man is transferred to Johns Hopkins Hospital for worsening altered mental status.
History of Present Illness

The family and a friend report that the patient had been binge-drinking for 2-3 days before being admitted to an outside hospital. Even after he had stopped drinking, he experienced worsening confusion and gait instability. He had been healthy and the family reported that 1 week before this episode, he had no complaints and had suffered no recent illnesses. After this binge-drinking episode he was forgetful, easily confused, and was having recurrent falls. They described a staggering gait, which had become progressively worse over the days prior to admission. The family and the patient's roommate reported that he had not had any further alcohol to drink since these symptoms developed.

The patient was admitted to an outside hospital and treated with a benzodiazepine taper for presumed alcohol withdrawal given his agitation, confusion, and tachycardia. His admission labs, including blood counts, liver function tests, and renal function, were normal. A toxicology screen was negative for alcohol but positive for cocaine and heroin. A noncontrast head CT was performed and was unremarkable. Two days after admission the patient became tachypneic, tachycardic, and obtunded and was intubated after experiencing respiratory failure. The chest x-ray demonstrated an infiltrate and the patient was treated for pneumonia.

The patient's mental status did not improve. Four days after admission, he developed extensor posturing of the upper extremities. At that time, he was transferred to Johns Hopkins Hospital.
1. Which of the following features of the history initially suggests the possibility of alcohol withdrawal?
A) Pneumonia likely due to aspiration

B) Gait instability and falls

C) Onset of altered mental status 1 day after discontinuing alcohol

D) Tachycardia

E) Extensor posturing in the upper extremities

Symptoms of Alcohol Withdrawal

Alcohol withdrawal is a life-threatening condition that is easily misdiagnosed. Early signs and symptoms include anxiety, tremulousness, diaphoresis, tachycardia, and hypertension, and usually resolve within 24-48 hours. Although hallucinations and seizures typically occur about 24 hours after the last drink, delirium usually does not appear until 2-4 days after cessation of alcohol. Delirium tremens is characterized by delirium with autonomic instability, including fever, hypertension, tachycardia, and sweating. Gait instability, falls, and aspiration pneumonia would be more likely to occur with alcohol intoxication than withdrawal and can occur with any cause of encephalopathy. Extensor posturing is not a feature of delirium tremens.

Past Medical History

The patient is an alcoholic. He suffered a leg fracture 4 months prior to admission. He has no other history of medical problems.
Medications

The patient does not take any prescribed or over-the-counter medications.
Allergies

The patient has no known drug allergies.
Social History

The patient is single and lives with a friend. He has smoked 1 pack of cigarettes per day for 20 years and drinks 10-12 beers 3-4 times per week. His family and friend deny that he uses any illicit drugs and the patient has no known HIV risk factors. He works with his brother and father in construction but has been on leave for 2 months because of leg pain from the previous leg fracture.
Family History

The patient's maternal grandmother died of a stroke in her 80's. Otherwise, no neurologic diseases have been diagnosed in the family. His mother, father, and a sibling are alive and healthy.
Review of Systems

The family denies that the patient had any recent symptoms of fever, chills, weight loss, nausea, vomiting, diarrhea, or skin rash. He has no history of alcohol withdrawal or seizures. He has not had any complaints nor has the family noted any headache, diplopia, vertigo, hearing loss, swallowing difficulty, focal weakness, sensory changes, or changes in his speech. Furthermore, the family has not noticed any change in his personality or behavior before the onset of the confusion.
Physical Exam

The patient is a thin, young-appearing man who is intubated and on full respiratory support. He is afebrile and his vital signs are all within normal limits. His oropharynx is clear and his neck supple without evidence of lymphadenopathy or thyromegaly. His lung sounds are coarse and diminished at the bases. His heart is regular with normal heart sounds and no audible murmur, rubs, or gallops. His abdomen is benign with normoactive bowel sounds. His peripheral pulses are full and there is no rash on the skin.

The patient is not pharmacologically sedated. He does not open his eyes or move his extremities spontaneously. He does open his eyes to noxious stimuli and he exhibits roving eye movements with full excursions in lateral gaze. He does not attend to external stimuli. His pupils are symmetric and reactive. He has no blink to threat. The vestibulo-ocular reflex is present and corneal responses are present and symmetric bilaterally. He coughs in response to deep endotracheal suctioning. The patient has extensor posturing of the upper extremities with noxious stimuli and has triple flexion of the lower extremities to stimuli. His tone is increased throughout with evidence of spasticity. His reflexes are brisk but symmetric without clonus. A jaw jerk is present.
2. All of the following should be considered in the differential diagnosis in this case except:
A) Wernicke's encephalopathy

B) Cocaine-induced infarction

C) Psychogenic coma

D) Anoxic brain injury

E) Hepatic encephalopathy

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Case Differential

Although psychiatric comorbidities are common in alcohol and drug abuse, the presence of hard physical exam findings, including a frontal release sign (positive jaw jerk reflex), diffuse spasticity, and decerebrate (extensor) posturing, would strongly suggest an organic rather than psychiatric disease. Wernicke's encephalopathy refers to the triad of encephalopathy, ataxia, and ophthalmoplegia and is usually seen in malnourished alcoholics because of thiamine deficiency. Thiamine deficiency is a potentially reversible cause of delirium if treated early, and thus thiamine should be given before glucose immediately in all alcoholics presenting with altered mental status. Cocaine is a risk factor for stroke (brain infarction), and anoxic brain injury is not uncommon following an overdose of alcohol, heroin, and other drugs of abuse. Chronic alcoholism frequently leads to cirrhosis, in which portovenous shunting of neurotoxins such as ammonia can cause hepatic encephalopathy.

Radiologic Studies

An MRI was performed before transfer to Johns Hopkins Hospital. Axial FLAIR sequences of the brain are shown (Figure 1). Gadolinium-enhanced sequences were not obtained.

(Figure 1. (click image to zoom)

Axial FLAIR sequences demonstrate numerous areas of increased T2 signal in bilateral cerebral hemispheres mainly involving the centrum semiovale and deep white matter but sparing the subcortical white matter. There is also an area of increased T2 signal in the left middle cerebellar peduncle denoted by an arrow.)

We performed a lumbar puncture; the CSF analysis demonstrated 5 white blood cells, all of which were lymphocytes, and a normal protein and glucose level. Viral PCR reactions in the CSF were negative for herpes simplex virus, varicella zoster virus, enterovirus, Epstein-Barr virus, cytomegalovirus, and JC virus. CSF cytopathology and flow cytometry were also unremarkable. CSF VDRL was also negative. Gram stain and cultures were negative. HIV and Lyme disease antibody testing were reported negative and an RPR was nonreactive, Other laboratory testing included a normal ESR and CRP, as well as normal values for serum ammonia, lactate, pyruvate, thyroid-stimulating hormone, vitamin B12, and cortisol, and unremarkable urine organic acids.

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Hospital Course

The patient continued to worsen clinically; he developed sympathetic storms manifested clinically by tachycardia, tachypnea, diaphoresis, fever, and spasms of extensor posturing of all 4 extremities. These episodes were refractory to all but high doses of benzodiazepines. An EEG demonstrated moderate-to-marked intrusion of diffuse slowing without lateralizing features or seizure activity.

A repeat MRI was performed without and with gadolinium 10 days after the onset of symptoms because the patient had continued to deteriorate clinically. His repeat brain MRI is shown with FLAIR sequences in Figure 2 and with gadolinium enhancement in Figure 3.(Figure 2. (click image to zoom)

Axial FLAIR sequences demonstrate now confluent areas of increased T2 signal in bilateral cerebral hemispheres involving the white matter and, again, the increased T2 signal in the left middle cerebellar peduncle.



Figure 3. (click image to zoom)

Axial gadolinium-enhanced T1 sequences demonstrate numerous areas of gadolinium enhancement in the cerebral hemispheres consistent with breakdown of the blood-brain barrier.)

3. The radiologic differential diagnosis would include all of the following except:
A) Acute disseminated encephalomyelitis (ADEM)

B) Progressive multifocal leukoencephalopathy

C) Toxic leukoencephalopathy

D) Multiple sclerosis

E) Gliomatosis cerebri

Radiologic Differential

While all listed choices are diffuse white matter diseases, progressive multifocal leukoencephalopathy (PML) does not show gadolinium enhancement and preferentially affects the subcortical white matter rather than the deep white matter seen in this case. A large number of toxins, including cocaine and heroin, can cause diffuse, symmetric deep white matter lesions, although gadolinium enhancement indicating blood-brain barrier breakdown is less common. Multiple sclerosis and ADEM can present with multiple enhancing white matter lesions and are commonly periventricular. Gliomatosis cerebri is an aggressive infiltrating glioma and might show diffuse deep white matter involvement with little mass effect; however, it would be unusual for the radiographic findings to progress as rapidly as is seen in this case.

Because of the patient's continued deterioration clinically and progression of the lesions radiographically, a brain biopsy was performed. Pathologic specimens are shown in Figures 4-8.

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4. The results of the biopsy would be most consistent with the diagnosis of:
A) Acute disseminated encephalomyelitis (ADEM)

B) Progressive multifocal leukoencephalopathy (PML)

C) Toxic leukoencephalopathy

D) Multiple sclerosis

E) Gliomatosis cerebri


Pathologic Differential

The biopsy was consistent with a reactive inflammatory response secondary to an underlying toxic and/or metabolic process. Although fulminant, ADEM and multiple sclerosis show demyelination that is frequently associated with axonal and oligodendrocyte loss; active lesions in those cases would also demonstrate marked lymphocytic infiltration. In PML, intranuclear inclusions containing the JC virus are observed within oligodendrocytes. No evidence of malignant glial cells (pleomorphic with mitotic figures) or microvascular proliferation is present to suggest gliomatosis cerebri.
Diagnosis

The biopsy was consistent with a reactive inflammatory response secondary to an underlying toxic and/or metabolic process, given the macrophage infiltration and perivascular lymphocytes as well as extensive myelin, axonal, and oligodendrocyte loss within the cerebral white matter. This clinical and radiographic picture has been reported following the use of inhaled heroin, a practice known as "chasing the dragon." "Chasing the dragon" is a mode of smoking heroin in which the heroin is heated on aluminum foil and the vapors are "chased" and inhaled.

The patient's work-up was negative otherwise, and in the setting of the MRI findings and the clinical picture, he was diagnosed with a toxic leukoencephalopathy resulting from heroin use. The patient's repeat MRI 1 week after biopsy is shown in Figure 9, demonstrating extensive confluent increased T2 signal involving the cerebral white matter. The patient remained comatose. He was transferred to a coma rehabilitation program at the family's request after tracheostomy and gastrostomy tubes were placed.

Discussion

Toxic leukoencephalopathy requires 3 criteria for diagnosis: documented exposure to a toxin; neurobehavioral deficits; and neuroradiologic abnormalities. In our case, the patient presented initially with cognitive changes which rapidly progressed to coma in the setting of a toxicology screen that was positive for heroin and cocaine, and an MRI with abnormalities in the white matter; he therefore met criteria for a toxic leukoencephalopathy.

Toxic leukoencephalopathy secondary to "chasing the dragon" has been reported in multiple cases during the past 2 decades and was first described by Wolters and colleagues in 1982. The most distinctive manifestations are an alteration in mental status and, in contrast to disorders of the cortical grey matter, there is typically not a primary effect on language, praxis, or perception. Furthermore, neurologic signs such as hemiparesis, visual loss, and sensory loss are less prominent unless focal necrosis of white matter occurs. The severity can be from minor with mainly behavioral changes to severe, as with the presented case, with fulminant manifestations leading to coma. The neurologic findings can be seen acutely or chronically with repeated exposure and accumulation of white matter damage. However, the development of the leukoencephalopathy does not seem to be closely linked to the cumulative dose ingested.

Clinically, patients with toxic leukoencephalopathy secondary to heroin use progress through 3 stages. Initial symptoms include motor restlessness, apathy, bradyphrenia, and cerebellar ataxia, which are followed by worsening cerebellar symptoms, hyperactive deep tendon reflexes, myoclonic jerks, and hypertonia with hemiplegia or tetraplegia in the second stage. In the final stage, the manifestations include stretching spasms, profuse diaphoresis, central fever, hypotonia and areflexia, and akinetic mutism. Not all patients progress through all 3 stages, and some may only have manifestations of stage 1 when the disorder is mild or, as in our case, all 3 stages with a devastating outcome.

The etiology of toxic leukoencephalopathy subsequent to heroin use is poorly understood at this time. It has been postulated that mitochondrial dysfunction may play a role, in addition to direct toxicity to the myelin and/or axons, and that the lipid-rich myelin may "trap" the toxins, leading to further tissue damage.

The prognosis of this disorder is difficult to predict as there have been too few cases to draw generalized conclusions. However, if the imaging suggests diffuse cortical white matter changes as in this case, the prognosis is likely to be poor. From the limited number of cases, it appears that the rapid forms are invariably fatal or patients have a poor outcome with aggressive care, and that the chronic forms appear to stabilize after removal of the toxin.

Unfortunately, to date no effective treatment has been found aside from removing the toxic exposure and providing supportive care.