November 18, 2003
Medscape Neurology & Neurosurgery 5(2), 2003
Rohit Bakshi, MD
Rohit Bakshi, MD, http://www.drbakshi.com, neurologist and research scientist at the Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts
The American Neurological Association held its 128th annual meeting in San Francisco. From October 19-22, approximately 900 top-level clinicians and scientists came together to share the latest research data in the field of neurology and neuroscience. Abstracts based on these presentations were published in a special supplement issue of the Annals of Neurology (registration required).
[Multiple Sclerosis section]
Fabry's disease (FD) is an X chromosome-linked disorder of fat storage caused by a deficiency of ceramidetrihexosidase (also called alpha-galactosidase A), an enzyme used in the degradation of lipids. The mother of the affected individual must be a carrier to produce the disease in a child. Affected individuals typically develop a range of multiorgan-related symptoms, including burning and pain in the hands and feet, a spotted dark red skin rash (angiokeratomas), reduced ability to perspire, gastrointestinal hypermotility, and corneal changes. Symptoms of cardiac and renal involvement typically occur in middle age. Ringing of the ears (tinnitus) is common, and hearing defects also have been reported. Treatment for FD typically has been limited to symptomatic therapy. The disease is chronic and progressive in most cases.
Hajioff and colleagues enrolled 15 male patients with FD in a randomized, placebo-controlled, double-blind study of enzyme replacement therapy (ERT) using agalsidase alfa 0.2 mg/kg for 6 months, followed by a 2-year open-label treatment extension in 10 of the patients. High frequency sensorineural hearing loss (HF-SNHL) was present in 12 of 15 patients (80%) at the outset of the study. After 6 months, HF-SNHL progressed similarly in both groups. However, in the open-label ERT phase, HF-SNHL improved by 2.1 dB at 18 months (P = .02) and by 4.9 dB at 30 months (P = .004), compared with baseline.
These data suggest that ERT leads to delayed (but significant) progressive improvements in high frequency hearing function for patients with FD. The presenting investigator stated, "The improvement we saw was marginal yet significant. If this progressive improvement is sustained beyond the period we studied, this might have a significant impact on patients over the long-term." Regarding tolerability and safety of ERT, the presenter noted, "We did not observe any significant side effects in this study. However, the long-term effects of ERT are not known."
Alzheimer's disease (AD) is a progressive neurologic disorder characterized by memory loss, confusion, personality changes, impaired judgment, and language dysfunction. The prevalence of this dementing illness continues to rise. In the United States, approximately 10% of individuals older than age 65 years and nearly half of individuals who are in the ninth decade of life have AD, contributing to a total prevalence of 4 million individuals. AD is expected to affect 22 million people worldwide by 2025. The cause of AD is unknown and treatments are limited. One of the keys to disentangling the mystery of AD is to understand the difference between the disease and normal aging. Through a better understanding of normal aging, clues should emerge about the underlying pathophysiology of neurodegeneration.
Bartzokis and colleagues studied the structural integrity of myelin sheaths during normal aging by evaluating the genu of the corpus callosum (Gcc) and the splenium of the corpus callosum (Scc) in 252 normal adults (age range,19-82 years) and in 34 subjects with AD (age range, 59-85 years). Magnetic resonance imaging (MRI) of the brain was performed to derive transverse relaxation rate (R2), a marker of white matter structural integrity. An inverted U-curve best represented the relationship between age and R2 in the Gcc, whereas R2 in the Scc declined in a linear fashion with aging. In AD, R2 was significantly lower in both regions, compared with age-matched controls.
This study illustrates the differential effect of aging on compact white matter tracts and the increased vulnerability of the Gcc to this process. By contrast, patients with AD show an accelerated pattern of myelin breakdown. These findings provide important normative data and a potentially new surrogate marker of AD that should be tested in longitudinal studies.
Intracranial hypotension (IH) is a treatable disorder of cerebrospinal fluid (CSF) circulation typified clinically by postural bilateral headaches that are worse when the person is upright. Patients also may develop a variety of associated symptoms, such as nausea, vomiting, dizziness, photophobia, and hearing disturbances. IH is usually caused by a meningeal defect and CSF leak (eg, spinal cyst, lumbar puncture, trauma/surgery, or ventricular shunts). The disorder also may occur without an identifiable cause and is then known as spontaneous IH (SIH). Postcontrast brain MRI showing diffuse, intense, symmetric, contiguous dural-meningeal (pachymeningeal) enhancement of the intracranial dura with expansion of other extra-axial structures, such as the venous sinuses and pituitary gland, is helpful in diagnosing IH. One the most commonly recommended treatment modalities for IH is an epidural blood patch.
Diaz described a series of 22 cases of SIH. The mean age of this cohort was 43 years, with a female to male ratio of 3.4 to 1.0. Women with SIH were significantly younger than men with SIH. Men were more likely to present with cranial nerve palsies and tinnitus, whereas women typically presented with postural headache and nausea. Eight patients were treated with an epidural blood patch, which led to short-term improvement of headache in 5 patients; the patch had no effect in3 patients.
This well-characterized series suggests that headaches associated with SIH are more common in women than in men and are less responsive to epidural blood patch than are nonspontaneous IH-related headaches. In addition, SIH seems to present with myriad neurologic symptoms, perhaps more commonly than described in nonspontaneous IH. This study raises the need to develop better methods of treating SIH and the need for vigilance in detecting the protean manifestations of the disorder.
More than 28 million people in the United States suffer from migraine, with a 3 times greater incidence in women than in men. Although migraine is treatable through a variety of pharmacologic and nonpharmacologic methods, the condition often goes unrecognized by patients and caregivers, as well as by physicians.
Screening for Migraine
Cady and colleagues reported on a study using a simple screening tool designed to improve the ability to diagnose migraine. Investigators administered the tool, a 3-question Headache Screen about disability, headache duration, and change in headache character, to 3014 patients (age range, 18- 72 years) with a known diagnosis of migraine. Approximately three fourths of the patients had a positive Headache Screen (overall sensitivity, 77%). The sensitivity of the Headache Screen was not related to headache frequency or to whether the physician administering the screen was a neurologist or a primary care physician.
This screening tool provides another important step toward improving the recognition of migraine in the general population. Further studies are needed to determine the specificity of this tool, especially the false positives obtained in patients with tension, sinus, or secondary headaches. The tool also should be tested in children, in whom migraine often goes unrecognized but can have a major impact on school performance.
Migraine in Children
Because of the high prevalence, severity and duration of symptoms, and peak age of onset, migraine is associated with significant costs to society in terms of medical care and loss of productivity. In a population-based study, Pesa and Lage evaluated the medical costs associated with migraine in children, including the impact of comorbid conditions. Patients were divided into 3 groups: migraine only, migraine with psychological comorbidity (ie, anxiety and/or depression), or healthy nonmigraine. Investigators assessed the direct medical costs of inpatient or outpatient medical care and use of prescription drugs. After adjusting for the effect of age and sex, children with migraine bore significantly higher outpatient, prescription drug, and total medical costs than did nonmigraineurs (P = .0001). Psychological overlay with migraine contributed significantly to higher costs (6-fold), compared with healthy controls, whereas migraine without depression/anxiety led to only 2-fold greater costs. The difference between costs for migraine only versus migraine with depression/anxiety was significant (P = .0001).
This study emphasizes the important role of psychological comorbid conditions in patients with migraine. In addition to the obvious impairment in quality of life associated with depression/anxiety, these factors increase the cost of medical care in the migraine population. It is likely that psychological issues in migraineurs also contribute to reduced productivity, and in children, to adverse effects on learning . Thus, all patients with migraine should be screened for comorbid psychological conditions that are treatable and that likely require specific assessment and therapy.
Central Nervous System Atrophy in Multiple Sclerosis
The US Food and Drug Administration has approved 5 injectable immunomodulatory treatments for multiple sclerosis (MS): weekly intramuscular interferon beta-1a (Avonex; Biogen, Inc; Cambridge, Massachusetts), thrice-weekly subcutaneous interferon beta-1a (Rebif; Serono; Rockland, Massachusetts), every-other-day subcutaneous interferon beta-1b (Betaseron; Berlex; Montville, New Jersey), daily subcutaneous glatiramer acetate (Copaxone; Teva Pharmaceutical Industries Ltd; Petach Tikva, Israel), and intravenous mitoxantrone (Novantrone; Amgen Inc; Thousand Oaks, California). However, although these agents provide a partial benefit in limiting clinical relapses and volume of MRI lesions, many patients continue to experience disease progression while being treated.
One of the most intractable aspects of the disease process is the relentless transection of axons, loss of central nervous system (CNS) tissue, and atrophy of the brain and spinal cord commonly associated with MS. Although a few studies have suggested a partial benefit of therapy on limiting CNS atrophy, most studies have reported little or no effect. Finding ways to prevent CNS atrophy is a major challenge facing the MS scientific community because atrophy has shown a close association with (and predictive value for) neurologic and neuropsychological impairments related to MS.
The sites involved in brain atrophy and the extent to which atrophy affects various stages of the disease have not been clear. Dalton and colleagues conducted a 3-year longitudinal study of normalized brain volume in 58 patients with a first attack of demyelinating disease (ie, clinically isolated syndrome [CIS]). Brain atrophy was separated into the involvement of gray vs white matter compartments. Patients were subdivided into 3 groups: those who ultimately developed MS (n = 31), those who developed CIS with MRI lesions (n = 13), and those with CIS without MRI lesions (n = 14) at 3 years. Patients converting to MS experienced a significant loss of gray matter volume (P = .037), but not white matter volume or overall brain volume, compared with CIS patients without lesions. Gray matter atrophy during the 3-year period correlated moderately with changes in T2 lesion load (r = 0.41).
This study indicates that selective gray matter atrophy occurs at the very earliest stage of MS, adding more evidence to the growing body of literature on MS as a gray matter disease. Further studies are warranted to determine the clinical relevance and predictive value of gray matter damage and the extent to which the mechanisms of gray matter disease provide a new window into pathogenesis.
MS symptoms typically begin between the ages of 20 and 40 years. However, disease onset also occurs in younger and older individuals, although less commonly. Given the chronic progressive nature of MS and the availability of effective therapies, it is important to recognize the unusual manifestations of the disease, including late onset.
Berlit and colleagues presented clinical, CSF, and MRI data on 52 patients with first symptoms of MS at age 50 years or older (mean age of onset, 57.6 years). The oldest patient was 83 years old. The most common presenting sign was paraparesis or quadriparesis (90%; n = 47), followed by sensory symptoms (71%; n = 37) and gait dysfunction (56%; n = 29). Ocular dysmotility (23%; n = 12) and optic neuritis (10%; n = 5) were infrequent. A primary progressive disease course was present in a large majority of patients (90%; n = 47). MRI showed typical multifocal supratentorial (94%; n = 49) and infratentorial (42%; n = 22) lesions. Of particular interest, spinal lesions were very common (81%; n = 24), much more common than is typically seen in younger MS cohorts, especially in those with relapsing-remitting MS. Gadolinium-enhancing lesions were present initially in 8 patients only. CSF analysis revealed oligoclonal banding in 89.8% of patients and a pleocytosis in 1 case only. A transient response of symptoms to high-dose glucocorticoids was seen in 32 patients (62%).
This study provides valuable data on individuals who develop MS in late adulthood, an interesting subgroup of the MS population. The most striking feature is that the course of the disease, including the attendant clinical and MRI changes, is typically similar to that of primary progressive MS. Vigilance is necessary in recognizing MS in this subpopulation because of its relatively unique presentation.
Wilson's disease (WD), also known as hepatolenticular degeneration,
is an autosomal recessive inherited disorder typified by copper deposition
in multiple organs, particularly in the brain and the liver, resulting
in an extrapyramidal and neurobehavioral neurologic syndrome. The disease
is characterized systemically by low ceruloplasmin and elevated urinary
excretion of copper. MRI scans of the brain commonly show symmetric lesions
in the caudate, putamen, thalamus, midbrain, globus pallidus, and less
commonly, in the pons, substantia nigra, and cerebellar and subcortical
Reich and O'Hearn reported an interesting pitfall that may influence the diagnosis of WD. A 32-year-old man developed choreiform perioral movements during treatment with risperidone for schizoaffective disorder. He was found to have reduced ceruloplasmin (15 mg/dL), but normal 24-hour urine copper level (10.1 mg/L). No evidence of copper deposition was seen by slit-lamp examination. Brain MRI was normal. Although he was diagnosed with tardive dyskinesia, he was found to be a heterozygote for WD. The presenters also reported a second similar case. A 32-year-old woman developed dystonia of the head. Her ceruloplasmin level was decreased (16 mg/dL), but her 24-hour urinary copper level was normal (8 mg/L). No evidence of copper deposition was seen by slit-lamp examination. She was heterozygous for WD.
This study indicates that patients who are heterozygous for WD may carry low serum ceruloplasmin levels, which could lead to diagnostic confusion in the work-up of a movement disorder. Caution should be exercised in interpreting results of serum ceruloplasmin levels. Carriers of WD do not seem to show evidence of systemic copper overload. The diagnosis of WD should rest on other findings and not abnormal ceruloplasmin alone. Genetic testing may be helpful in sorting out these usual circumstances.
Epilepsy is a chronic condition that often strikes in childhood or in young adulthood and leads to impairment of overall quality of life. In addition to treating the underlying causes of the condition and using anticonvulsants to limit seizure activity, comorbid conditions also should be addressed in the care of patients. Cramer and colleagues surveyed a nationwide community sample about seizures and depression, using the Seizure Severity Questionnaire and the Centers for Epidemiological Studies Depression scale. Patients with current major (n = 166), mild-moderate (n = 74), or no depression (n = 443) differed significantly in both partial and generalized seizure severity (all cases, P < .0001). Increased seizure activity was clearly associated with higher levels of depression. Cognitive, emotional, and physical components of recovery from seizures also were related to depression (all cases, P < .05). These data urge the need for carefully screening all patients with epilepsy for depression, because this seems to be a common and disabling, yet treatable, comorbid condition in people with epilepsy.
Rohit Bakshi, MD, has disclosed that he has served as a speaker for Biogen. Dr. Bakshi has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity.
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