Leone M, Franzini A, Bussone G: Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 345:1428–1429, 2001.

Mathura MS, Goadsby PJ: Persistence of attacks of cluster headache after trigeminal root section. Brain 125:976–984, 2002.

May A, Leone M: Update on cluster headache. Current Opinion in Neurology 16(3):333–340, 2003.

111 CREUTZFELDT–JAKOB DISEASE

046.1

Catherine Creuzot-Garcher, MD, PhD

Dijon, France

prodrome of fatigue, improper sleep or vertigo. Cognitive impairment made of change in personality, behavioral change, disorientation and memory loss will occur during the course of the illness in 100% of cases. Cerebellar abnormalities are present in about 2/3 of the patients in the later stages as well as myoclonus. Motor dysfunction and visual impairment are frequent. Visual loss is a revealing symptom reported in about 1/5 of the patients. Heidenhain’s variant is characterized by early cortical blindness and visual apraxia. On the contrary, lower neuron dysfunction and seizures are rare. All these data confirmed that the distinctive quadrate findings of cognitive change, myoclonus, cerebellar dysfunction and akinetic mutism occurring in a patient over the age of 60 indicate high risk of having CJD.

NwCJD differs from sCJD with the prominent psychiatric disturbance occurring in a younger patient presenting with painful dysesthesia and cerebellar symptoms. Genetic predisposition seems to be essential.

ETIOLOGY/INCIDENCE

Creuztfeldt–Jacob disease (CJD) is a rare and fatal neurodegenerative disorder belonging to a larger family called ‘prion disease‘ or subacute spongiform encephalopathies (SSEs) caused by a proteinaceous particle discovered by Prusiner in 1997. The agent responsible for the infection is an altered form PrPsc of a normal host-encoded glycoprotein (PrPc).

It can be divided as sporadic (85%) (sCJD), familial (10%) and acquired (5%). The former is the commonest SSE with an incidence of 1 per million per year and primarily affects the elderly. The latter includes iatrogenic CJD (iCJD) resulting from medical exposure. Recently, a form coined new-variant CJD (nwCJD) was described; it could be related to the same strain as bovine spongiform encephalopathy with strong concerns about crossspecies transmission. Genetic predisposition could enhance transmission susceptibility.

The risk factors include a familial history of CJD, a treatment with native growth hormone before 1985, dura mater graft that first risk was recognized in the mid-1980s. There is emerging evidence about the potential transmission owing to ophthalmic surgery involving the retina, the optic nerve and the cornea as well.

Laboratory findings

Biological detection

Serum S-protein is considered as a marker of activated glial cells seen in all stages of CJD.

CSF proteins are often moderately elevated but without any specific alteration: Neuron specific enolase, a non specific marker of neuronal degeneration is found in the early and middle stages of the disease. Increased amounts of 14-3-3 family of proteins, a marker of neuronal death, are detected by electrophoresis as two spots designed as p130 and 131.

MRI

Areas of symmetrical hyperintensities denoting the extent of the spongiosis are considered as nearly specific whereas cortical atrophy is not. Diffusion-weighted MRI is highly sensitive showing bilateral symmetrical hyperintense signals. PET and SPECT scan can guide the site of brain biopsy showing areas of abnormal metabolism and perfusion.

Electroencephalography findings

Characterized by a progressive slowing of the waveforms with disorganization of background rhythms, periodic sharp-wave complexes, triphasic sharp waves and giant responses to flash stimuli are present in about 2/3 of patients.

COURSE/PROGNOSIS

The disease duration sCJD is about 4 months and mainly occurs at a median age onset of 60 years. The minimal incubation period for iCJD has been shown to range from 5 months to as long as 30 years. However the death usually occurred between 8 months to 2 years after the onset of the symptoms. NwCJD lasts longer (12 months) and involves younger patients (median 29 years).

DIAGNOSIS

Diagnosing CJD is a challenging task as presumptive diagnosis is based on clinical and biological tests but there are no available methods for reliable laboratory findings of CJD.

Clinical diagnosis

Clinical features of CJD are due to the progressive neuronal loss and gliosis of the brain. Some patients report on a vague

Brain biopsy

Brain biopsy is interesting to detect the altered PrPsc form which is a marker of infectivity but lacks sensitivity. Neuropathology is the only definitive test for the diagnosis of CJD. It reveals a spongiform change with a fine-vacuole-like appearance involving all the cerebral cortex accompanied by gliosis and atrophy.

Differential diagnosis

Alzheimer’s disease

Other SSEs: Kuru, Gerstmann–Straussler–Schneiker disease, fatal familial insomnia. Abnormal neurodegenerative changes (metabolic encephalopathies, toxicity, stroke, etc.).

TREATMENT

There is no curative treatment but symptomatic one can be proposed (neurological trouble).

PREVENTION

Treatment of the devices

Any tissue being discarded from a CJ suspect should be incinerated. Fully effective decontamination methods are steam autoclaving for one hour at 132ºC and immersion in 1 N sodium hydroxide for 1 hour at room temperature. However, some devices cannot endure such procedures and methods such as steam autoclaving for a shorter period of time or lower temperature, or immersion in diluted solution of sodium chloride have to be considered as partially effective. All other methods (quaternary ammonium, ultraviolet, ethanol, etc.) are ineffective. The procedure according to the risk sub-groups has to be clearly defined before the situation raises (destruction, quarantining, declaration). Changes to improve the traceability of instruments and devices are needed. This point emphasizes the need to develop a full range of single-use devices that could be used, at least, in patients at risk of CJD and routinely in all circumstances increasing the risk of transmission (for instance retinal surgery or involvement of optic nerve).

Screening to prevent contamination

Screening before eye surgery is mandatory to minimize the risk of nosocomial spread of any form of prion-related disease. It should be based on both historical queries and clinical exam to detect the main clinical signs.

112 DYSLEXIA 784.61

Marshall P. Keys, MD, PA

Rockville, Maryland

Dyslexia is a congenital difficulty in learning to read despite intact senses, normal intelligence, appropriate instruction and adequate motivation. Dyslexia must be differentiated from secondary learning disorders such as mental retardation, emotional disorders, seizure states, environmental deprivation, poor teaching and physical handicaps (including eye and ear defects).

ETIOLOGY/INCIDENCE

Anatomic research and functional magnetic resonance imaging studies have delineated focal aberrations in areas of the brain that are associated with the ability to relate letters with appropriate sounds. The genetic basis of dyslexia is evidenced by the high incidence of the problem among family members.

The lack of specific diagnostic criteria confuses the figures, but it is estimated that between 4% and 6% of school-age children in the United States are dyslexic. Other forms of learning failure account for problems in 10% to 20% of children.

REFERENCES

Billette de Villemeur T, Deslys JP, Pradel A, et al: Creutzfeldt-Jakob disease from contaminated growth hormone extracts in France. Neurology 47:690–695, 1996.

Brown P, Brandel J-P, Sato T, et al: Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55:1075–1081, 2000.

Creuzot-Garcher C, Lafontaine PO, Zabee L, et al: A screening questionnaire for determining risk of Creuzfeldt-Jacob disease transmission during ophthalmic examination. J Fr Ophtalmol 27:19–23, 2004.

Head MW, Nothcott V, Rennison, et al: Prion protein accumulation in eyes of patients with sporadic and variant Creuztfeldt-Jacob disease. Invest Ophthalmol Vis Sci 44:342–346, 2003.

Head MW, Peden AH, Yull HM: Abnormal prion protein in the retina of the most commonly occurring subtype of sporadic Creutzfeldt-Jakob disease. Br J Ophthalmol 89:1131–1133, 2005.

Hogan RN, Brown P, Heck E, et al: Risk of prion disease transmission from ocular tissue transplantation. Cornea 18:2–11, 1999.

Kennedy RH, Hogan RN, Brown P, et al: Eye banking and screening for Creutzfeldt-Jakob disease. Arch Ophthalmol 119:721–726, 2001.

S-Juan P, Ward HJT, de Silva R, et al: Ophthalmic surgery and CreutzfeldtJakob disease. Br J Ophthalmol 88:446–449, 2004.

Pedersen NS, Smith E: Prion diseases: epidemiology in man. APMIS 110:14–22, 2002.

Prabhakar S, Bhatia R: Diagnosis of Creutzfeldt-Jakob disease. Neurol India 49:325–328, 2001.

Shroter A, Zerr I, Henkel K, et al: Magnetic resonance imaging in the clinical diagnosis of Creutzfeldt-Jakob disease. Arch Neurol 57:1751– 1757, 2000.

Ward HJ, Everington D, Croes EA: Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls. Neurology 59:543–548, 2002.

COURSE/PROGNOSIS

●Dyslexia is noted when a child has difficulty learning letters and performing well in school during the early years.

●The dyslexic child has problems in relating letters and groups of letters with appropriate sounds (phonologic coding).

●Dyslexia may be associated with attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD).

●Dyslexic children usually have normal or superior intelligence.

●Secondary emotional problems may result from poor school performance.

●In true dyslexia, the reading difficulties are permanent but remedial education techniques can help the patient to compensate.

DIAGNOSIS

A multidisciplinary team that can provide diagnostic and prescriptive services may involve some or all of the following:

●A specialist in learning disabilities to classify various areas of strengths and weaknesses and offer plans for appropriate instruction;

●A primary care physician to screen for auditory and visual disorders and rule out any physical or emotional factors that may be contributing to poor school performance;

●An ophthalmologist, who is experienced in the care of children to screen for any contributory oculomotor, optical, or organic eye problems;

●A neurologist to rule out any problems in the central nervous system that may contribute to learning disabilities;

Ocular

●For more than 200 years, occlusion of the sound eye is the mainstay of treatment. However, opinions vary on the number of hours that should be prescribed for daily patching. In clinical practice, part-time patching (6–8 hours daily) is more commonly used as an initial therapy. The Pediatric Eye Disease Investigator Group compared patching treatment in a prospective, randomized study and reported that two hours of daily patching appears to be as effective as six hours in treating moderate amblyopia. Patching should be done according to the age of the patient and the severity of the visual loss. The occlusion must be applied directly on the eye instead of the spectacles in order to avoid peeking. Opaque contact lenses can be used as an occluder in selected patients.

●Full-time occlusion is preferred in severe amblyopia cases or in cases with no fusion potential. Near visual tasks such as reading or video games during a portion of the occlusion time may contribute to the improvement in visual acuity. Treatment is continued until visual acuity is same in both eyes or no improvement is achieved after 6 months with a reliable compliance. The success of occlusion therapy is dependent on compliance mainly.

be explained to the parents as a desired result. After discontinuation of patching therapy some degree of recurrence can be seen but this can be prevented with maintenance therapy.

●Skin irritation during patching therapy and light sensitivity, lid or conjunctival irritation, eye pain or headache and facial flushing during atropine penalization are the other main adverse effects of the therapy.

COMMENTS

Amblyopia is a developmental anomaly of spatial vision, occuring as optically uncorrectable subnormal visual acuity in an otherwise normal eye. Early detection and early treatment are critical in treatment. Patching has the potential advantages of a more rapid improvement in visual acuity and possibly a slightly better acuity outcome, whereas atropine has the potential advantages of easier administration and lower cost.

REFERENCES

Flynn JT: Amblyopia revisited. 17th Annual Frank Costenbader Lecture. J Pediatr Ophthalmol Strabismus 28(4):183–200, 1991.

Medical

●Penalization with atropine aims to blur the image in the preferred eye so that the fixation can be switched to the amblyopic eye. Pharmacologic penalization has generally been advocated only for mild and moderate amblyopia (20/100 or better) because the blurring effect on the sound eye may be insufficient when visual acuity in the amblyopic eye is worse than 20/100. Recent reports of randomized clinical trials showed that substantial improvement in the visual acuity of the amblyopic eye occurred with either daily patching or atropine treatment regimens and the difference between the patching and daily atropine regimens was clinically insignificant after 6 months. After a randomized trial of atropine regimens in moderate amblyopia cases, it was found that weekend atropine can provide an improvement in visual acuity of a magnitude similar to that of the improvement provided by daily atropine.

Surgical

●Surgery for the underlying causes such as cataract, corneal opacities or ptosis is an essential part of the treatment.

●In strabismic amblyopia cases, correction of the misalignment will be a part of the treatment, however strabismus surgery is usually performed after improvement in vision of the amblyopic eye.

●Patients with unilateral high myopia can be a candidate for refractive surgery after 9–10 years of age.

COMPLICATIONS

●Amblyopia in the occluded eye is the most expected complication of treatment. Fortunately this is rare and easily reversible after cessation of occlusion. In children under one year of age, part time occlusion and close follow up are recommended.

Holmes MJ, Beck RW, Repka MX: Amblyopia: current clinical studies. Ophthalmol Clinics N Am, Pediatric Ophthalmol 14(3):393–398, 2001.

Hussein MAW, Coats DK, Muthialu A, et al: Risk factors for treatment failure of anisometropic amblyopia. J AAPOS 8:429–434, 2004.

Leguire LE, Rogers GL, Brmer DL, et al: Levodopa/carbidopa for childhood amblyopia. Invest Ophthalmol Vis Sci 34:3090–3095, 1993.

Nucci P, Drack AV: Refractive surgery for unilateral high myopia in children. J AAPOS 5:348–351, 2001.

Olitsky SE, Nelson BA, Brooks S: The sensitive period of visual development in humans. J Pediatr Ophthalmol Strabismus 39(2):69–72, 2002.

Pediatric Eye Disease Investigator Group: A randomized trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol 120:268–278, 2002.

Pediatric Eye Disease Investigator Group: A randomized trial of patching regimens for treatment of moderate amblyopia in children. Arch Ophthalmol 121:603–611, 2003.

Pediatric Eye Disease Investigator Group: A randomized trial of atropine regimens for treatment of moderate amblyopia in children. Ophthalmology 111:2076–2085, 2004.

114 HYSTERIA, MALINGERING AND

ANXIETY STATES 300.10

August L. Reader, III, MD, FACS

San Francisco, California

ETIOLOGY

Psychogenic ocular disease can be confounding to the ophthalmologist, as psychologic factors of stress and anxiety commonly

venous sinuses limiting cerebrospinal fluid (CSF) outflow. The osteopathic literature describes a craniosacral pump which fails because of alterations in spinal configuration of markedly obese patients, leading to increased intracranial pressure (ICP). This information is not widely available in allopathic journals but should not be simply dismissed.

Inflammatory and prothrombotic disease states associated with PTC include systemic lupus erythematosis (SLE), periarteritis nodosa, uremia, antiphospholipid antibody (APA) syndrome, anticardiolipin antibody syndrome (ACA), sarcoidosis, inflammatory bowel disease, Lyme disease, protein C and S deficiencies, multiple sclerosis and meningitis. Pregnancy is a significant risk factor for PTC, possibly because of weight gain or increased risk of thrombosis.

PTC can accompany post-concussion syndrome, Chiari malformation, sleep apnea, anemia, sickle cell disease, polycystic ovary syndrome (PCOS), mastoiditis (via secondary venous sinus thrombosis), hypoparathyroidism (from hypocalcemia) and thoracic outlet syndrome.

Drugs implicated in PTC include the tetracycline class antibiotics, nalidixic acid, growth hormone, vitamin A congeners, Synthroid, Norplant, oral contraceptives, danazol, lithium, cyclosporin A, cytarabine, nitrofurantoin, prednisone, thiazide diuretics and nonsteroidal anti-inflammatory drugs. Some of these drugs have a dual effect. Prednisone can both cause and treat PTC, and PTC sometimes accompanies prednisone tapering regimens. Hyperand hypo-vitaminosis A both have been associated with PTC. Thiazide diuretics that can be used to treat PTC might also cause it through the side effect of hypocalcemia.

Drug-disease combinations often make for a confusing clinical picture regarding the etiology of PTC. For example, PTC can be seen with Lyme disease, hypothyroidism and sarcoid and also with the treatments therein (i.e. tetracyclines, thyroid replacement and steroids, respectively). Patients often have multiple risk factors. It would not be unusual for an obese woman with sleep apnea and anemia (from the menorrhagia associated with PCOS) to use tetracyclines or vitamin A products for acne (associated with PCOS).

acuity, photophobia, vomiting and dizziness. Children may present with irritability, listlessness, somnolence or nervousness. Back pain and loss of bladder control can be seen with PTC due to a low spinal tumor. Depression often accompanies patients with PTC. While it is likely that PTC can cause or even present as depression, it must be remembered that some patients with bipolar disorder develop PTC from lithium therapy.

We have noted an extremely high frequency of convergence insufficiency in all age groups and a higher-than-expected frequency of attention deficit disorder (ADD) in our pediatric patients.

Headache is the most common presenting sign. Headache can range from disablingly severe to mild; it is usually constant although it fluctuates in severity. Many of our patients report that headache severity is altered in response to atmospheric barometric changes. Headache is usually worse in the morning, and is aggravated with Valsalva or bending. Visual obscurations occur with bending as well. Dizziness seems to be worsened by rapid head turns. Headache may not accompany PTC at all; this phenomenon may be more common in pediatric patients. In patients with headache, we often employ a 3 day therapeutic trial of acetazolamide (0.5–1.5gm qd) as part of our evaluation.

Signs of PTC include papilledema, esotropia from unilateral or bilateral sixth cranial palsy, convergence and accommodative insufficiency, hypertropia from fourth cranial nerve palsy, seventh cranial nerve palsy and hemifacial spasm.

Although papilledema facilitates the diagnosis, many patients do not show display this. The loss of spontaneous venous pulsations (SVPs) at the optic nerve head is also imperfectly correlated with PTC. Twenty percent of normal patients do not have SVPs and some confirmed PTC patients have normal SVPs. The absence of papilledema (i.e. PTC sine papilledema) is likely a significant risk factor for diagnostic delay.

Other ophthalmic findings include retinal hemorrhages, cotton wool spots (infarcts in the nerve fiber layer), macular exudate, choroidal breaks, and retinal folds concentric about the disc (Paton’s lines).

COURSE/PROGNOSIS

Pseudotumor cerebri can develop acutely, such as with use of tetracyclines or after head trauma, or can be chronic, as with obesity or sleep apnea. Response to therapy is usually rapid but may be short-lived. Papilledema can linger for years however. It has been reported that long term vision loss can occur even after the apparent resolution of papilledema.

Acute vision loss can occur from breaks in Bruch’s membrane and secondary subretinal hemorrhage. This predisposes patients to develop subretinal neovascularization. Papilledematous nerves are at risk for central retinal vein occlusion and nonarteritic anterior ischemic optic neuropathy.

Recurrence does occur and patients might have different symptoms and signs than they did at initial presentation.

DIAGNOSIS

Clinical signs and symptoms

Symptoms of PTC include head-, neckor ear-ache, diplopia, tinnitus or pulsatile whooshing, transient visual obscurations (TVOs), peripheral vision loss, severe acute reduction of visual

Laboratory findings

Imaging studies are key to making the diagnosis of PTC. Magnetic resonance imaging (MRI) is particularly useful when looking for tumors of the brain and spinal cord (particularly ependymoma); magnetic resonance venogram (MRV) can detect venous sinus thrombosis. Common MRI findings in PTC include a flattened pituitary (pancake sign), empty sella, optic nerves bathed in CSF, slit-like ventricles and prominence of the temporal horns of the lateral ventricles. It is common to find cerebellar tonsillar herniation in patients with PTC, strongly suggesting that Chiari malformation and pseudotumor cerebri are related. Hyperintense white matter lesions on MRI are more common in patients with vasculitidies such as Lyme disease, MS, SLE and sarcoid.

Lumbar puncture (LP) is a crucial diagnostic test, as well as a potentially curative one. We recommend measuring the opening pressure with the patient lying prone or on the side. Radiographic guidance during LP is a safety measure for larger patients to help avoid injury. The ICP should be measured in every patient; if the pressure is elevated (above 250 mm water), 30cc should be drawn off for tests and to provide headache relief. The CSF should be sent for laboratory evaluation of markers of MS (oligoclonal banding, immunoglobulin synthesis rate and myelin basic protein) and Lyme disease (preferably

Ocular

Optic nerve sheath fenestration is the only periocular therapy for PTC and is recommended where visual loss is predominant over headache. During this procedure, the surgeon cuts a window from the meningeal sheath of the optic nerve, preferably through a medial orbital approach to avoid the ophthalmic artery. The medial rectus must be surgically disinserted to gain sufficient exposure.

COMPLICATIONS

Acetazolamide can cause hypokalemia, acidosis and secondary calcium oxylate nephrolithiasis. Invariable but sometimes intolerable side effects also include dysgeusia, fatigue, anorexia and paresthesias. Because CAIs are sulfonamides, there is risk of allergy and bone marrow suppression. We recommend a baseline serum potassium and CBC prior to long-term therapy. Corticosteroids, even in short term dose, cause hyperglycemia and immunosuppression.

Aside from the usual complications associated with any surgery done under general anesthesia, blindness and double vision might follow optic nerve sheath fenestration. The unique concerns of even completely successful shunting procedures are blockage (with an estimated risk of 80% at 12 years postoperative), and migration of the shunt tip.

COMMENTS

For many, PTC is vision threatening and disabling. The protean manifestations demand that physicians consider this diagnosis much more often. Considering that patients suffering from this condition, i.e. women, obese individuals and chronic headache sufferers, have been reported to receive suboptimal care, it must be assumed that PTC is significantly underdiagnosed.

Support groups and patient registries are available to help both patients and caregivers cope with PTC. With further research into therapies and etiologies, it is hoped that the idiopathic form will disappear.

REFERENCES

Johnson S: The PTC primer . . . living with pseudotumor cerebri. Pseudotumor Cerebri Support Network, Powell, Ohio, 2000. Online. Available at: www.findmemyhouse.com/ptc/ptc_book/book_index.html.

Krishna R, Kosmorsky GS, Wright KW: Pseudotumor cerebri sine papilledema with unilateral sixth nerve palsy. J Neuroophthalmol 18:53–55, 1998.

McGirt MJ, Woodworth G, Thomas G, et al: Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes. J Neurosurg 101:627–632, 2004.

Milhorat TH, Chou MW, Trinidad EM, et al: Chiari I malformation redefined: clinical and radiographic findings for 364 symptomatic patients. Neurosurgery 44:1005–1017, 1999.

Nord JA, Karter D: Epub 2003 Lyme disease complicated with pseudotumor cerebri. Clin Infect Dis 37:e25–e26, 2003.

Spoor TC, McHenry JG: Long-term effectiveness of optic nerve sheath decompression for pseudotumor cerebri. Arch Ophthalmol 111:623– 635, 1993.

116 MULTIPLE SCLEROSIS 340

(Sclérose en Plaques Disseminées, Disseminated Sclerosis)

Amit Kumar Ghosh, MD, FACP

Rochester, Minnesota

Multiple sclerosis (MS) is the most common cause of disabling nontraumatic neurological disorder in the young adults. MS is a clinical disorder characterized with neurological attacks followed by remissions. Pathologically MS is characterized by multiple sharply delineated plaques reflective of demyelination in the CNS white matter affecting the optic nerves, periventricular areas, brain stem and spinal cord. The plaques are areas of active demyelination with loss of oligodendrocytes and astroglial scarring. Recent studies on active MS lesions also indicate the presence of substantial axonal injury with axonal transactions. The mean lifetime cost per case of MS is around $2.2 million.

ETIOLOGY/INCIDENCE

The risk of developing MS is around 0.1% in US. It is estimated that the prevalence in USA is approximately 350,000 with an annual incidence of about 12,000. The prevalence varies geographically reaching as high as 60 per 100,000 in North America and Europe and is lowest among Eskimos, Native Americans and Africans. Onset of the disease is between 20 and 50 years with the female to male ratio of 2 : 1. The peak onset is around 5 years earlier in women.

The exact pathogenesis of MS is unclear. Most cases are sporadic, though first degree relatives of a person with MS have a 20 to 40 times increased risk than general population of developing MS. The presence of HLA-DR2 allele is associated with an increased risk. Recent studies have dispelled the belief, that immunization with hepatitis B or other vaccines increase the risk of developing MS. Other theories have suggested Epstein–Barr virus reactivation, and smoking as possible risk factors. Migration from a high to low risk area during earlier childhood might confer lower risk of MS and vice-versa. Migration from higher to lower risk areas after reaching puberty seems to mitigate this advantage.

COURSE/PROGNOSIS

MS could present in several different courses. Around 85% of patients start out as relapsing and remitting (RRMS), characterized by self-limited attacks with complete or partial recovery and the patient is neurologically stable between attacks. The RRMS is followed in 50% of cases by secondary-progressive (SPMS) which is marked by gradual neurological deterioration between relapses. Approximately 15% patient begin with primary-progressive (PPMS) form that is characterized by gradual disease progression from onset with plateaus and minor fluctuations but no distinct relapses. A rarer form of MS is the

progressive-relapsing (PRMS) that presents initially as PPMS with clear relapses with or without complete recovery. Progression continues between relapses.

Relapse is often referred to as acute or subacute worsening of clinical function that might peak in days to weeks and maybe followed by remissions where the symptoms and signs might resolve partially or completely. Relapse tend to occur frequently in the initial years (average 0.4 to 0.6/year) and decrease with time.

The course of MS is highly variable even in the same individual. Factors that might suggest a worse prognosis include, frequent relapse in the first 2 years, progressive type of MS, male sex, early motor and cerebellar disorder. Patient with optic neuritis, women, early age of onset, and predominantly sensory signs may have a better prognosis. Patients with no neurological disability after 15 years of the disease are often referred to have benign MS.

sum, brain stem, cerebellum, optic pathways. The plaques are located perpendicular to ventricular surface and appear hyperintense on proton density and T2-weighted studies. Gadolinium (Gd) enhancement usually suggest new or active plaques in MS.

Cerebrospinal fluid abnormalities in MS includes mononuclear cell pleocytosis, increased CSF IgG index, increased IgG synthesis rate and oligoclonal banding.

In 2001, The International Panel on MS proposed guidelines for diagnosis based on the objective demonstration of dissemination of lesion in time and space. Patients with two or more clinical attacks and 2 objective signs do not need any further tests to confirm the diagnosis of MS. In all other cases diagnosis of MS is made by a combination of clinical history and MRI, CSF evaluation and/or other ancillary testing (VER, BAER, VES). Patients should be classified as MS, ‘possible’ MS (those at risk for MS, but evaluations are equivocal) or ‘not’ MS.

DIAGNOSIS

Clinical signs and symptoms

Common symptoms and signs include numbness, weakness, visual lose, diplopia, limb weakness, ataxia, Lhermitte’s phenomenon, cognitive and affective disorder and bowel and bladder problems. Neurological symptoms maybe acute, chronic or progressive. These signs indicate involvement of corticospinal tract, posterior columns, brain stem, anterior visual pathways and cerebellum. The symptoms should last more than 24 hours and occur as discrete episodes separated by over a month or more.

Optic neuritis (ON) is the most common inflammatory condition involving the visual pathways. The presentation maybe acute or subacute unilateral eye pain with decrease in visual acuity, central field scotomas, relative afferent pupillary defect (Marcus Gunn pupil), normal fundus examination ( retrobulbar neuritis) and less frequently optic disk edema ( papillitis). Uveitis, retinitis and retinal periphlebitis are less frequent. Diplopia result from intranuclear ophthalmoplegia (INO), and is the most common eye movement disorder in MS, with loss or delayed adduction and nystagmus of the abducting eye on lateral gaze, due to lesion of the medial longitudinal fasciculus (MLS) on the side of adducting eye. Diplopia could also occur due to cranial nerve palsies (usually 6th cranial nerve, rarely 3rd and 4th cranial nerve palsy). Other visual disorders include pendular nystagmus with oscillopsia and defective ocular saccades and pursuits, Uhthoff’s symptom (transient visual blurring after hot shower of physical exercise). The risk of development of MS after an episode of ON varies from 15 to 75%.

Laboratory findings

MS is a clinical diagnosis that includes demonstrating evidence of multiple neurological events (two or more symptoms and signs) separated in space (different anatomical location) and time. Several laboratory testing have been approved to support the diagnosis including, Brain MRI, cerebrospinal fluid (CSF) oligoclonal band, CSF albumin and IgG index, visual evoked response(VER), Brainstem auditory evoked response (BAER) and somatosensory evoked potentials (SEP).

Magnetic resonance imaging (MRI) demonstration of the characteristic brain and spinal cord plaque remains the test of choice to support the diagnosis of MS. These plaques are seen in the periventricular region, deep white matter, corpus callo-

TREATMENT

The treatment of MS involves:

●Treatment of acute attacks;

●Treatment to reduce the activity of MS using disease modifying therapy; and

●Symptomatic treatment.

The Kurtzke Expanded Disability Status Score ( EDSS) are commonly used to measure clinical disability in MS. Most patients with RRMS have EDSS scores of <3.5 and can walk normally as opposed to patients with progressive MS (SPMS , PPMS) who have gait impairment with EDSS scores of >5.5.

Treatment of acute attacks

Corticosteroids are typically used to treat first episode or acute attacks of MS. They help in the short term by reducing the severity and duration of these attacks, however long term benefits on the course of MS is unclear. Mild attacks should not be treated.

Treatment for acute monosymptomatic optic neuritis (ON) is based on the results of two studies; the Optic Neuritis Treatment Trial (ONTT) with methylprednisolone and more recently the Controlled High-Risk Avonex MS Prevention Study (CHAMPS) with interferon β-1a (Avonex). Current recommendations for patients with ON with high risk of developing MS (two or more white matter lesions) include the use of intravenous methylprednisolone 1000 mg daily for 3 days , followed by oral prednisone (1 mg/kg per day for 11 days followed by a 4 day taper, [MP+ prednisone]) , and interferon β-1a (Avonex 30 μg intramuscular once weekly). Patients with less than two MRI white matter lesions can be treated with IV MP+ prednisone. Oral prednisone alone without prior treatment with methylprednisolone should not be used as the findings in ONTT showed an increase in the risk of recurrent ON in the group that received oral prednisone only.

Rapidly progressive disability in MS often have to be treated with IV cyclophosphamide with corticosteroid and in rare instances with plasma exchanges (every other day for 2 weeks).

Disease modifying agents used in MS

Disease modifying agents are used in RRMS and SPMS with exacerbations. Five agents have been approved in United States

for the treatment of RRMS. These include interferon β-1a (IFNβ1a , Avonex) , interferon β-1b ( IFN β1b, Betaseron), interferon β-1a(IFN-β1a, Rebif), Glatiramer acetate (Copaxone) and Mitoxantrone (Novantrone).

These medications have also been tried in patients with SPMS with exacerbations. Patients receiving IFN-β1a, IFN-β1b, and glatiramer acetate have 30% fewer clinical episodes (measured by EDSS progression) and fewer MRI lesions. Patients with stable RRMS or SPMS without relapses should not treated. This group of patients need be observed by clinical examination and MRI every 6 months.

IFN-β1a (Avonex) is administered 30 μg intramuscular once weekly. IFN-B1b (Betaseron) is administered 250 μg subcutaneously every other day and IFN-β1a (Rebif), 44 μg subcutaneously three times a week. Common side-effects of interferons is outlined in Table 116.1. All interferons stimulate the development of neutralizing antibody that reduce the bioavailability of interferon. The rate of development of neutralizing antibodies after 18 months of treatment with Avonex, Rebif and Betaseron is around 2, 15 and 31 percent respectively. High dose of IFN-β can be tried in patients with SPMS with acute relapses, though this increases the risk of developing neutralizing antibody.

Glatiramer acetate/copolymer 1 (Copaxone) is administered 20 mg subcutaneous injection daily. The side effects include, local site reactions and systemic reactions such as flushing, chest tightness, dyspnea and anxiety after injections occur in around 15% of patients.

Mitoxantrone is given at a dose of 12 mg/m2 every 3 months for a maximum of 2 to 3 years. Mitoxantrone is not a first line medication as its use has been associated with cardiotoxicity. Hence it is reserved for patients with SPMS, PRMS and RRMS with progressive disability who have failed other treatment. The maximum cumulative dose of Mitoxantrone allowed is 140 mg/m2.

There is currently no effective treatment for PPMS despite numerous trails.

Other medications that has be tried in rapidly progressing MS, or RRMS and SPMS with inadequate response to the above disease modifying agents are, Azathioprine, Methotrexate, Cyclophosphamide, Cladribine, intravenous immunoglobulin (IVIg), and monthly high dose methylprednisolone.

ment. Bilateral INO may be treated with alternate compression or temporary press-in prisms. No effective treatment exists for unilateral INO. Oscillopsia arising from primary position nystagmus can arise form cerebellar or brain stem disorder . This can be treated with baclofen 20 mg PO t.i.d., and/or clonazepam 0.5 mg b.i.d.or t.i.d.

Currently several trials with experimental therapies are in progess, including monoclonal antibodies against a4 – integrin, statins, estriol, Schwann cell transplants and bone marrow transplants.

Healthcare providers need to discuss the various aspects of treatment modalities and options with their patients and incorporate their patients values and opinions in making a treatment plan. Finally, a team approach with a primary care provider or neurologist well versed with numerous aspects in the care of MS is paramount for overall successful management.

REFERENCES

Arnold DL, Matthews PM: MRI in the diagnosis and management of multiple sclerosis. Neurology 58(Suppl 4):S23–S31, 2002.

Beck RW, Cleary PA, Anderson MM, Jr, et al: A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med 326:581–588, 1992.

Goodin DS, Frohman EM, Garmany GP, Jr, et al: Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 58:169– 178, 2002.

Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898–904, 2000.

Krupp LB, Rizvi SA: Symptomatic therapy for underrecognized manifestations of multiple sclerosis. Neurology 58(8 Suppl 4):S32–S39, 2002.

McDonald WI, Compston A, Edan G, et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127, 2001.

Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG: Multiple sclerosis. N Engl J Med 343:938–952, 2000.

Optic Neuritis Study Group: The 5-year risk of MS after optic neuritis. Experience of the optic neuritis treatment trial. Optic Neuritis Study Group. Neurology 49:1404–1413, 1997.

Whetten-Goldstein KFA, Sloan L, Goldstein B, et al: A comprehensive assessment of cost and compensation: the case of multiple sclerosis. Mult Scler 4:419–425, 1998.

Systemic

●Anticholinesterase agents (pyridostigmine, Mestinon) are

the first line of treatment but are commonly ineffective. The drug is used four times per day. This may increased to 180 mg four times per day unless there are side effects such as gastric upset or diarrhea. High doses may cause bronchospasm and weakness that mimics myasthenic crisis.

●Adrenal corticosteroids (prednisolone) are frequently used in myasthenia. The dose is progressively increased as high as 1–1.5 mg/kg. When symptoms are adequately controlled the drug is shifted to an alternate-day schedule and then gradually tapered. Blood pressure and blood glucose need to be monitored and H2 antagaonists may be prescribed to prevent peptic ulcer.

affecting up to 1% of the population over age 60. The cause is unknown, although genetic causes are implicated.

COURSE/PROGNOSIS

Parkinson’s disease begins with subtle symptoms and signs, commonly affecting one side of the body initially. It is steadily progressive in all individuals but the rate of progression varies widely. With prolonged drug treatment, involuntary movements become especially prominent. In latter stages, mild dementia is very common.

Clinical signs and symptoms

Neurological signs include tremor, rigidity, bradykinesia, pos-

nia. It may not take effect for 6 months and its potential hematologic and liver toxicity requires monitoring of the blood count and liver function.

●Other immunosuppressive drugs such as mycophenolate mofetil, ciclosporin and cyclophosphamide may be useful in selected cases.

●Plasmapheresis may be temporarily beneficial in acute myasthenia or myasthenic crisis.

●Intravenous immune globulin may be beneficial in acute myasthenia, in patients with refractory myasthenia, and in the perioperative setting.

Surgical

●Thymectomy is usually performed in patients younger than 50 years who have a thymoma on CT. Its role in nonthymomatous ocular myasthenia is controversial.

REFERENCES

Barton J, Fouladvand M: Ocular aspects of myasthenia gravis. Seminars in neurology 20:7–20, 2000.

toms include fatigue, depression, memory loss, constipation, speech and swallowing difficulties, pain, stiffness and seborrhea.

Biochemically, tremor, bradykinesia and rigidity result from dopamine deficiency and improve with levodopa, dopamine agonists, anticholinergics and other medications. Although levodopa is a mainstay of therapy, choreiform and dystonic involuntary movements develop in most patients after long-term treatment and produce difficulties in symptom control. Adverse mental effects, such as hallucinations and confusion, are common side effects of drug treatment and may limit therapy.

Parkinson’s disease may affect eyelid function and produce reduced blinking, blepharoclonus, seborrheic blepharitis, hordeolum, and rarely, blepharospasm and apraxia of eye opening. Ocular motility disturbances include decreased convergence, hypometric saccades and saccadic pursuit. Although impaired contrast sensitivity can be demonstrated by specialized studies, papillary and retinal function is clinically unaffected, and prominent visual complaints should suggest an alternative diagnosis.

Ertas M, Arac N, Kumral K, et al: Ice test as a simple diagnostic aid for myasthenia gravis. Acta Neurol Scand 89:227–229, 1994.

Jaretzki A, Steinglass KM, Sonett JR: Thymectomy in the management of myasthenia gravis. Seminars in Neurology 24(1):49–62, 2004.

Mee M, Paine E, Byrne J, et al: Immunotherapy of ocular myasthenia gravis reduces conversion to generalized myasthenia gravis. J Neuroophthalmol 23(4):251–255, 2003.

Phillips LH, 2nd, Melnick PA: Diagnosis of myasthenia gravis in the 1990s. Semin Neurol 10:62–69, 1990.

Vincent A, Bowen J, Newsom-Davis J, McConville J: Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets. Lancet Neurology 2(2):99–106, 2003.

118 PARKINSON’S DISEASE 332.0

Stephen Gancher, MD, FAAN

Portland, Oregon

ETIOLOGY/INCIDENCE

Parkinson’s disease is a degenerative neurological illness which results in the loss of dopaminergic neurons in the brain. It is rare before age 40 but is more common in older individuals,

Laboratory findings

None in Parkinson’s disease. Workup in a younger patient to exclude other conditions should include MRI or CT scan, calcium and ceruloplasmin. A screen for the parkin mutation can be a helpful confirmatory test in younger individuals.

Differential diagnosis

●Progressive supranuclear palsy (PSP): the hallmark is supranuclear vertical ophthalmoplegia, although it may not appear initially. Preserved vertical eye movements, produced by passive neck movement in a patient who cannot voluntarily generate vertical gaze is characteristic. A staring expression, lid retraction, slow saccades, impairment in voluntary vertical gaze and neck rigidity are characteristic signs. Visual complaints are more common than in other forms of parkinsonism.

●Multiple system atrophy (MSA, Shy–Drager syndrome): dysautonomia (hypotension, bowel and bladder dysfunction), dysarthria, dysphagia and facial grimacing as a result of levodopa therapy are common manifestations. Tonic pupils may be seen.

●Drug induced parkinsonism: dopamine antagonists such as antiemetics (metoclopramide and prochlorperazine) and neuroleptics (trifluoperazine, haloperidol) can produced drug-induced pakrinsonism. Oculogyric crisis and other dystonic reactions are common, particularly in younger patients.

●Vascular parkinsonism: multiple subcortical infarcts may produce bradykinesia and rigidity. Stroke risk factors, such as diabetes and hypertension, are usually present. A history of stroke or TIA may or may not be present. Multiple whitematter lesions on MRI are present. Vascular parkinsonism is resistant to drug therapy.

●Rare causes include Wilson’s disease, Huntington’s disease, sequelae of viral encephalitis, HIV infection, hypoparathyroidism and structural abnormalities such as communicating hydrocephalus or basal ganglia tumor.

TREATMENT

●Anticholinergics are used early in the course of the disease but commonly produce memory loss and accommodative paralysis.

●Levodopa (sold as a combination of levodopa and carbidopa [Sinemet] in the United States; sold as a combination of levodopa and benzerazide [Madopar] in Europe) is used for treatment of tremor, bradykinesia, rigidity and gait abnormalities and is useful in all stages of disease. Various formulations are available. It is a mainstay of treatment but commonly produces involuntary movements, especially in patients under age 50.

●Dopamine agonists available in the United States include pramipexole (sold as Mirapex), ropinirole (sold as Requip), pergolide (sold as Permax) and bromocriptine (sold as Parlodel). They are used as initial therapy or as an adjunct to levodopa.

●Other drugs include amantadine, the MAO-B inhibitors selegiline and rasagiline (sold as Azilect), and the COMT inhibitors entacapone (sold as Comtan and Stalevo) and tolcapone (sold as Tasmar). These latter four drugs inhibit the metabolism and clearance of levodopa or dopamine and prolong its actions.

●Levodopa and dopamine agonists should be withheld for 4 to 6 hours before surgery to reduce risk of cardiac arrhythmia.

●The combination of selegiline and meperidine is contraindicated.

●Ocular anticholinergics may produce confusion in demented patients.

COMMENTS

The treatment of Parkinson’s disease is challenging and may require input from a variety of specialists. Ocular signs and symptoms, such as slow saccades, difficulty initiating vertical gaze, or saccadic pursuit may precede other neurological manifestations and indicate the possibility that early Parkinson’s disease is the diagnosis. However, prominent ocular or visual complaints, other than accommodative paralysis and druginduced hallucinations, are not part of the spectrum of symptoms of Parkinson’s disease, and their presence suggests that another diagnosis should be considered.

SUPPORT GROUPS

National Parkinson Foundation, Inc. 1501 NW 9th Ave/Bob Hope Road Miami, FL 33136-1494 1-800-327-4545

www.parkinson.org

American Parkinson Disease Association, Inc 1250 Hylan Blvd, Suite 4B

Staten Island, NY 10305 1-800-223-2732 apdaparkinson.org

REFERENCES

drug treatment.

Ocular

●Lid hygiene is important for the prevention of seborrheic blepharitis and hordeolum.

●Eyes are lubricated with artificial tears or methylcellulose eyedrops.

●Botulinum toxin is used to treat blepharospasm and eyelid apraxia complicating parkinsonism.

●Side effects of drugs, such as visual hallucinations, diplopia and blurred vision, are very common; visual hallucinations may serve as a harbinger of psychotic reactions.

●Diagnosis of narrow-angle glaucoma and the risks of anticholinergic treatment should be discussed in detail with the patient and with other physicians.

●Refraction may vary depending on the dosage and the timing of drug therapy.

●Tremor and bradykinesia may interfere with ocular self-care.

●Ophthalmic evaluation and treatment, such as slit-lamp examination or surgical procedures, may be difficult because of tremor and dyskinesia, and may have to be timed with drug treatment.

●Narcotics and benzodiazepines do not markedly reduce tremor but may suppress both tremor and dyskinesia at sedating doses.

●Intravenous diphenhydramine, administered in 25-mg increments, is useful to achieve partial sedation and reduce tremor.

son’s disease. Neurology 62:177–180, 2004.

Nutt JG, Hammerstad JP, Gancher ST: Parkinson’s disease: 100 maxims. London, Edward Arnold, 1992.

119 TOLOSA–HUNT SYNDROME 378.9

Russell M. LeBoyer, MD

Houston, TX

Rod Foroozan, MD

Houston, TX

ETIOLOGY

The Tolosa–Hunt syndrome is an idiopathic chronic granulomatous inflammation of the cavernous sinus causing episodic unilateral periorbital pain that is often self-limiting, lasting up to 8 weeks without intervention. The pain is often described as ‘gnawing.’ Inflammation of adjacent cranial nerves within the cavernous sinus often causes painful ophthalmoplegia. Contiguous structures, the orbital apex and superior orbital fissure, are often simultaneously affected, and if the optic nerve is affected within the orbital apex visual loss may occur.

COURSE/PROGNOSIS

●Variable involvement of the ipsilateral third, fourth and sixth cranial nerves may occur depending on the extent of infiltration.

●Ophthalmoplegia typically occurs within 2 weeks after the onset of pain, however the pain may begin after the onset of ophthalmoplegia.

●The maxillary and mandibular branches of the trigeminal nerve and periarterial sympathetic involvement may also occur.

●There is no predilection to gender, age or ethnicity.

●Spontaneous remission has been reported in 85% of patients.

●Recurrences are common, occurring in 40% of treated patients at intervals of months to years.

●Long-term corticosteroid therapy may be necessary for recurrent disease.

●Low-dose radiotherapy has demonstrated long-term efficacy and safety for patients with corticosteroid resistance or intolerance.

●Immunosuppressive therapy with corticosteroid sparing agents such as cyclophosphamide and azathioprine can be helpful for some patients.

COMPLICATIONS

Typical side effects from long-term corticosteroid use are common. Although neurologic symptoms typically resolve with treatment, residual deficits, including diplopia, may persist.

sodic unilateral orbital pain, lasting weeks if left untreated, that is associated with paralysis of one or more of the third, fourth or sixth cranial nerves and/or demonstration of a granuloma on magnetic resonance imaging (MRI) or tissue biopsy.

Differential diagnosis

●Other causes of cavernous sinus pathology must be excluded such as aneurysm, neoplasia, vasculitis and inflammation.

similar appearance on MRI. In addition, various parasellar neoplasms such as lymphoma, giant cell tumors and epidermoid tumors, have shown responses to corticosteroid treatment. Therefore, careful follow-up is necessary to ensure adequate response to therapy and the exclusion of these other conditions.

Histopathologic specimens from patients with Tolosa–Hunt syndrome show similar findings to those of idiopathic orbital inflammation (orbital pseudotumor), and some investigators have suggested that these conditions have a similar pathophysiology.

Laboratory findings

●Initial diagnostic studies should include MRI with axial and coronal views of the brain, which typically show thickening and enhancement of the involved cavernous sinus.

●Cerebral angiography can be performed if aneurysm, arteriovenous malformation, or arteriovenous fistula are suspected.

●Hematological testing should be considered for other inflammatory causes. Testing may include complete blood count, erythrocyte sedimentation rate, antinuclear antibody, antineutrophil cytoplasmic antibody and angiotensin-con- verting enzyme levels.

●Cerebrospinal fluid consistency should be normal.

●Tissue biopsy should be considered in patients with progressive deficits, persistent abnormal neuroimaging studies or lack of corticosteroid response.

TREATMENT

●A prompt response to corticosteroids is often considered to be a hallmark of Tolosa–Hunt syndrome.

●Systemic corticosteroid therapy is the mainstay of treatment with starting doses typically in the range of 1 mg/kg of prednisone.

●Some improvement of the pain and other symptoms should occur within 72 hours after the initiation of treatment.

●Periorbital pain often responds before the improvement of the ophthalmoplegia.

●Corticosteroids can be tapered after the first few weeks of therapy in most cases.

REFERENCES

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Hunt WE, Meagher JN: Painful ophthalmoplegia: its relation to indolent inflammation of the cavernous sinus. Neurology 11:56–62, 1961.

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Kline LB: The Tolosa-Hunt syndrome. Surv Ophthalmol 27:79–95, 1982.

Kline LB, Hoyt WF: The Tolosa-Hunt syndrome. J Neurol Neurosurg Psychiatry 71:577–582, 2001.

Mantia L, Erbetta A, Bussone G: Painful ophthalmoplegia: an unresolved clinical problem. Neurol Sci 26:579–582, 2005.

Pless MP: Cavernous sinus disorders. In: Levin LA, Arnold AC, eds: Neuroophthalmology the practical guide. New York, Thieme 2005:301–302.

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Wasmeier C, Pfadenhauer K, Rosler A: Idiopathic inflammatory pseudotumor of the orbit and Tolosa-Hunt Syndrome — are they the same disease? J Neurol 249:1237–1241, 2002.