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The brain consists of both white and gray matter. There is a wide array of disorders that predominantly or exclusively affect the white matter of the brain and lead to a variety of presentations. These disorders, known as leukoencephalopathies, include demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica (NMO; also referred to as Devic syndrome or disease), acute disseminated encephalomyelitis (ADEM), and Weston Hurst syndrome (Hurst disease). Dysmyelinating disorders (eg, leukodystrophies) are also classified as white-matter diseases. Other rare leukoencephalopathies are central pontine myelinolysis (CPM) and posterior reversible encephalopathy syndrome (PRES).
Image from Zephyr | Science Source.
A 25-year-old Pakistani man presents to the emergency department (ED) with a 7-day history of gradual-onset painless diplopia in the left lateral gaze. One year previously, he experienced visual loss in the right eye, with partial recovery over a period of 4 weeks. On examination, he is unable to adduct the right eye and has nystagmus in the left abducting eye. He also has a relative afferent pupillary defect on the right side. Visual acuity is 6/6 on the left and 6/36 on the right. Fundoscopic examination reveals optic disc pallor on the right side. Routine examination of the cerebrospinal fluid (CSF) yields normal results; however, CSF oligoclonal bands (OCBs) are positive. Magnetic resonance imaging (MRI) of the brain shows multiple high-signal areas on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences, especially in periventricular locations, as well as perivenular plaques (Dawson fingers) consistent with demyelinating lesions of MS.
Which of the following is the appropriate term for the ocular syndrome seen in this patient?
Images courtesy of Haris Majid Rajput, MBBS, FCPS.
Answer: D. Unilateral internuclear ophthalmoplegia.
The image in the slide illustrates right internuclear ophthalmoplegia (INO), caused by injury of the right medial longitudinal fasciculus. INO is one of the ophthalmologic manifestations of neurologic disorders. It is a dysfunction of conjugate horizontal gaze that involves restriction or loss of adduction in the diseased eye, usually with an associated nystagmus in the contralateral abducting eye.[1] The lesion has a characteristic localization to the medial longitudinal fasciculus. INO can be unilateral as well as bilateral. The most common cause of unilateral INO in the elderly is stroke. The etiology is different in young patients with unilateral or, more typically, bilateral INO; the most frequently implicated underlying cause in this population is MS.
Image courtesy of Sam Shlomo Spaeth for Medscape.
Clinically, MS is diagnosed on the basis of the dissemination of attacks in time and space in accordance with the McDonald criteria. Workup includes MRI of the brain with contrast, which shows white-matter hyperintensities on T2-weighted imaging and FLAIR sequences, and CSF OCBs. The image in the slide shows immunoglobulin G (IgG) OCBs with IgG unique to the CSF, without corresponding IgG in the serum.[2]
Image courtesy of Medscape.
A 16-year-old Pakistani boy presents to the ED with a 1-week history of weakness of both lower extremities, which progressed to involve both arms over the course of 1 day. About 2 weeks previously, the patient was treated for an upper respiratory tract infection (URTI). On postadmission day 2, the patient becomes drowsy and subsequently has multiple episodes of general tonic-clonic seizures. His Glasgow Coma Score (GCS) drops to 5/15, and he is shifted to the intensive care unit (ICU) for assisted ventilation. MRI of the brain is obtained, with the results shown in the slide. CSF polymerase chain reaction (PCR) assay for herpes simplex virus yields negative results.
Which of the following is the most likely diagnosis?
Images courtesy of Medscape | Sumaira Nabi, MBBS, FCPS (top left and right), and Sumaira Nabi, MBBS, FCPS (bottom left and right).
Answer: C. Acute disseminated encephalomyelitis.
As depicted in the slide, MRI reveals bilateral asymmetric high-signal-intensity areas in the subcortical and deep white matter on T2/FLAIR sequences (arrows). ADEM is an inflammatory demyelinating disease of the nervous system that usually develops in the wake of a clearly identifiable febrile prodromal illness or immunization.[3] Typically, ADEM is monophasic, but it can also be recurrent, relapsing, and multiphasic. The hallmark clinical feature is encephalopathy, which can range from simple lethargy to frank coma and seizures. MRI of the brain with contrast is the imaging modality of choice, typically showing bilateral, asymmetric, poorly marginated lesions in the deep and subcortical white matter, with relative periventricular sparing on T2-weighted images and FLAIR sequences. Once the diagnosis of ADEM is established, steroids—in particular, high-dose intravenous (IV) corticosteroids—are the mainstay of treatment.
Images courtesy of Medscape | Sumaira Nabi, MBBS, FCPS (top left and right), and Sumaira Nabi, MBBS, FCPS (bottom left and right).
A 34-year-old Pakistani woman presents to the ED with a 4-year history of psychotic behavior and neurocognitive decline. She has been treated as a case of schizophrenia for 3 years. For the past 6 months, the patient has been bedbound with progressive motor regression, incontinence, and loss of speech. On examination, her GCS is 12/15, and her speech is limited to incomprehensible sounds. The findings from fundoscopic examination are consistent with bilateral mild optic disc pallor. The patient has a spastic quadriparesis with hyperreflexia and bilateral extensor plantar response. MRI of the brain with contrast is obtained, revealing areas of abnormal signal intensity that appear hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging and FLAIR sequences. Diffuse involvement of white matter of both cerebral hemispheres is noted in the centrum semiovale and periventricular regions, with relative sparing of subcortical white matter. There is also a mild generalized cerebral atrophy consistent with metachromatic leukodystrophy (MLD).
Which of the following enzyme deficiencies leads to MLD?
Images courtesy of Medscape | Shahzad Ahmed, MBBS.
Answer A. Arylsulfatase A deficiency.
As shown in the slide, MRI reveals areas of abnormal signal intensity diffusely involving the white matter of both cerebral hemispheres in the periventricular regions, predominantly in the posterior parietal and occipital regions (arrows), along with mild generalized cerebral atrophy. Leukodystrophies are a set of rare progressive genetic diseases that affect the growth or maintenance of white matter. Some leukodystrophies have adult-onset variants, including adrenoleukodystrophy, MLD, and Krabbe disease. MLD is one of the most serious and rare inherited demyelination disorders, eventually progressing to a bedbound quadriplegic state with loss of speech and comprehension.[4] It is one of the lysosomal storage diseases and is characterized by destruction of both central and peripheral myelin. The abnormality responsible for MLD lies in the gene for the enzyme arylsulfatase A, which converts sulfatide to cerebroside (a major component of myelin).[4] Mutation in this gene leads to a deficiency of arylsulfatase A, which results in the accumulation of sulfatide in the lysosomes of the brain and peripheral nerves. This accumulation of sulfatide, in turn, affects the oligodendrocytes and Schwann cells, causing progressive demyelination.
Images courtesy of Medscape | Shahzad Ahmed, MBBS.
A 30-year-old Pakistani man presents to the ED with a 2-month history of acute weakness of all extremities. One month previously, he experienced visual loss in the right eye and mild ocular pain. On physical examination, visual acuity is reduced to counting fingers in the right eye, whereas it is 6/12 in the left eye. The patient also has a relative afferent pupillary defect on the right side with optic atrophy on fundoscopic examination. Fundoscopy of the left eye reveals mild disc pallor. The patient has a spastic paraplegia and upper-extremity diparesis. There is hyperreflexia with bilateral extensor plantar response. The patient has a sensory level at C6/C7.
Which of the following is the most likely diagnosis?
Image courtesy of Medscape | Sumaira Nabi, MBBS, FCPS.
Answer: D. Neuromyelitis optica.
The images in the slide illustrate a case of acute optic neuritis (ON). (A) Coronal contrast-enhanced spin echo T1-weighted, fat-suppressed MRI through the orbits shows enlargement and contrast enhancement of the left optic nerve in the retrobulbar portion (arrow). (B) Coronal spin echo T1-weighted, fat-suppressed MRI of the same patient shows enlargement and contrast enhancement of the nerve in a parasagittal oblique section (arrow).
NMO (Devic syndrome or disease) is an idiopathic inflammatory demyelinating disease that is specific to the spinal cord and optic nerves and that results in acute attacks of severe myelitis and acute or subacute unilateral or bilateral ON. MRI of the spine typically reveals longitudinally extensive transverse myelitis with necrotizing and cavitating lesions extending over three or more vertebral segments.[5] NMO has commonly been defined according to the revised diagnostic criteria devised by Wingerchuk et al in 2006,[6] which require the presence of ON and myelitis plus any two of the following: (1) brain MRI not satisfying the McDonald criteria, (2) contiguous spinal cord MRI T2 lesions spanning three or more vertebral segments, or (3) positive serology for NMO-IgG (antibody to aquaporin-4 [AQP4]). However, CNS involvement may be either more restricted or more extensive. In 2015, the International Panel for NMO Diagnosis issued updated consensus diagnostic criteria that defined the collective term NMO spectrum disorder (NMOSD),[7] which can be divided serologically into NMOSD with AQP4-IgG and NMOSD without AQP4-IgG. The former type of NMOSD is characterized by clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. For NMOSD without AQP4-IgG or when serologic testing is unavailable, more stringent clinical criteria and additional neuroimaging findings are necessary.
Images courtesy of Medscape.
The table in the slide summarizes an approach to treatment of NMO. Initial treatment of acute attacks of ON or myelitis consists mainly of high-dose IV corticosteroid therapy.[8] Plasmapheresis (1-1.5 L of plasma per exchange) over a period of 2 weeks may be initiated in patients who do not respond to treatment with corticosteroids. Azathioprine, mycophenolate, and methotrexate with or without prednisolone and rituximab are considered the first-line therapies. Monthly pulse cyclophosphamide, mitoxantrone, cyclosporine, and regular IV immunoglobulin (IVIG)/plasma exchange have been suggested as second-line therapies.
Table adapted from Palace J et al.[8]
An 80-year-old Pakistani man presents to the local ED with a 5-day history of mild-to-moderate nonradiating epigastric pain associated with nonprojectile, nonbilious vomiting. On examination, the patient is drowsy and confused. Laboratory analysis reveals a serum sodium level of 99 mEq/L (reference range, 135-150 mEq/L); the hyponatremia is corrected with 3% hypertonic saline. After 24 hours, repeated testing of serum electrolyte concentrations reveals a sodium level of 129 mEq/L. After 2 days, the patient develops difficulty in swallowing and slurred speech, followed by spastic quadriplegia. MRI of the brain is obtained and shows several small high-signal-intensity areas in the central pons on T2/FLAIR sequences.
Which of the following is the most likely diagnosis?
Image courtesy of Medscape | Sumaira Nabi, MBBS, FCPS.
Answer: C. Central pontine myelinolysis.
CPM is a neurologic disorder caused by sudden, severe, noninflammatory demyelination of the brainstem—more precisely, in the area of the pons.[9] It is now generally recognized as a complication of rapid correction of hyponatremia, which causes an osmotic shift of water out of the neurons, leading to shrinkage of their myelin sheaths. This shrinkage, in turn, leads to compression of the tract fibers and demyelination (shown). MRI of the brain with contrast is the imaging modality of choice. Typically, T1-weighted images show symmetric hypointense areas, which then appear hyperintense on T2-weighted images and FLAIR sequences, usually in the basis pontis. The risk that rapid correction of hyponatremia will lead to CPM increases if the patient has a serum sodium level lower than 120 mEq/L for more than 48 hours, which is then briskly corrected by more than 12 mEq/L in the next 24 hours. It is said that the absolute magnitude of the change in serum sodium concentration is more important than the rate of correction. Therefore, correction should be slow and judicious.
Image courtesy of Jensflorian | Wikimedia Commons.
A 25-year-old Pakistani woman presents to the ED with a 2-day history of rapidly progressive weakness of all four extremities, which was followed 1 day later by sudden loss of consciousness. Two weeks previously, she had a URTI. On examination, the patient has a GCS of 3/15. Her brainstem reflexes are intact. Examination of the limbs reveals reduced tone in all limbs, with no movement on painful stimulus. Deep tendon reflexes are depressed, with mute plantar response. MRI of the brain with contrast is obtained (shown); subtle hemorrhagic signals are visible in the pons on T1-weighted imaging, and hyperintense signals are seen in the entire pons on T2-weighted imaging and FLAIR sequences. These findings are reported by the radiologist as Weston Hurst syndrome.
To which of the following diseases is this syndrome closely related?
Images courtesy of Shahzad Ahmed, MBBS.
Answer: C. Fulminant acute disseminated encephalomyelitis.
Weston Hurst syndrome, also known as acute hemorrhagic leukoencephalitis, is a very rare form of demyelinating disease.[10] It is considered a rapidly progressive fulminant form of ADEM. The presentation is variable, with acute onset of fever, headache, nausea, vomiting, seizures, and coma. MRI of the brain is the imaging modality of choice. It may reveal changes like extensive lesions involving the white matter with punctate hemorrhages. Weston Hurst syndrome is managed in essentially the same manner as ADEM, but the prognosis is much poorer.
Images courtesy of Shahzad Ahmed, MBBS.
A 15-year-old Pakistani girl presents to the ED with a 1-week history of ascending flaccid quadriparesis. The findings from her nerve conduction studies are consistent with Guillain-Barré syndrome. Plasmapheresis is initiated. After 2 days, the patient develops acute headache and visual loss and experiences one episode of generalized tonic-clonic seizures. Her blood pressure is persistently high. MRI of the brain is obtained (shown). Altered signals are apparent in the parieto-occipital and frontal white matter: low intensity on T1-weighted imaging and high intensity on T2-weighted imaging and FLAIR sequences, with no postcontrast enhancement. These findings are consistent with PRES.
Which of the following is the cause of hypertension and PRES in Guillain-Barré syndrome?
Images courtesy of Haris Majid Rajput, MBBS, FCPS.
Answer: B. Autonomic dysfunction.
PRES is a clinicoradiologic entity characterized by headaches, visual dysfunction, and fits.[11] It has multiple causes; however, it is most commonly associated with severe hypertension. In this particular patient, hypertension secondary to the autonomic dysregulation of Guillain-Barré syndrome leads to PRES. The typical radiologic finding is white-matter edema that predominantly affects the occipital and parietal lobes of the brain. As noted in slide 16, MRI of the brain shows altered signals in the parieto-occipital white matter (arrows).
Images courtesy of Haris Majid Rajput, MBBS, FCPS.
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