CSF Oligoclonal bands
Acute disseminated encephalomyelitis (ADEM): The age of onset is highly variable 2nd to 6th decades. ADEM follows viral exanthema, respiratory and other infections (measles, rubella, corona virus, mycoplasma, chlamydia, campylobacter, streptococcus, influenza, parainfluenza, CMV, EBV, HSV-6, chicken pox, HIV and hepatitis A and B) or vaccinations for smallpox, rabies (Semple vaccin), mumps, hepatitis B, diphtheria-tetanus-pertusis, polio, rubella, influenza and live measles in almost 50% of patients. However in over 45% of cases ADEM is reported to be idiopathic. The clinical course is highly variable, ranging from a slow progression over weeks to a fulminant course over hours to days. Characteristic clinical features include a monophasic focal or multifocal neurologic disturbances particularly sensory deficits and pyramidal motor signs, brainstem dysfunction, and less frequently visual field defects, aphasia, ataxia, myelitis and signs of acute meningoencephalitis with meningismus, alteration in consciousness, focal and generalized seizures, and psychosis. Optic neuritis is rare. Maximal deficits are reached within several days, weeks or even months. CSF shows pleocytosis (up to 150-200 WBCs) in 80%, protein level is usually elevated, but generally not higher than 180 mg/dl, and OCB may be found. In the acute phase, CSF studies may show increased cell counts (initially neutrophils predominance) with elevated protein and decreased glucose levels as sign of active inflammatory process. Despite this, CSF may be normal in up to 20% of cases. Finding the causative agent is most often elusive. Screening for antibodies against HSV, EBV, CMV, VZV, Coxsackie, adenovirus, enterovirus and B. Burgerdorfi in CSF is advised. MRI reveals large, confluent asymmetric multifocal areas of increased signal intensity on T2-weighted sequences, affecting predominantly white matter in addition to brainstem and thalami (unlike MS). Unlike in MS, corpus callosum is rarely affected. Mass effect can be present and florid gadolinium enhancement can be found. With respect to enhancement and unlike in MS, all lesions should have the same enhancement properties. CSF and MRI can however not fully discriminate between ADEM and MS. 50% of patients with ADEM have MRI features of MS. In addition 35% of patients with ADEM develop clinical definite MS over a mean period of 3 year. In 26% of patients MRI lesions resolve. Dramatic improvement of neurological deficit is observed with high-dose corticosteroids (methylprednisolone 1g over 30 minutes for 5 days). In addition, iv immunoglobulin have been proven to be effective. The definitive diagnosis of ADEM requires biopsy. ADEM usually resolves in a few weeks or months and complete recovery occurs in about 50%. Mortality is 10-30%. Differential diagnosis should include leucodystrophies, multiple cerebral emboli, abscesses, HIV encephalopathy, fungal and bacterial infections (including Lyme disease, brucellosis), postmalarial neurological syndrome (endemic area), toxic encephalopathies, metabolic (including mitochondrial) encephalopathies (e.g. Marchiafava-Bignami disease), RPLE, inflammatory (neurosarcoidosis) and autoimmune diseases (SLE, APLS, neuroBehçet), vasculitis (PACNS), PMFLE, multifocal glioma, CNS lymphoma, Devic syndrome and "Acute MS", which is never monophasic, except Schilder disease and Balo excentric sclerosis. Related disorders are AHLE, Bickerstaff brainstem encephalitis, optic neuritis, ATM, cerebellitis and multiphasic form of ADEM and MS.
Neurosyphilis: Syphilitic meningitis: This type of meningitis presents with meningismus, headache and fever. Cranial nerve palsies are found in 45% of patients. Meningovascular syphilis is characterized by weeks to months of episodic prodromal symptoms and signs, including headache or vertigo, personality and behavioral changes, insomnia and seizures. In addition focal neurologic deficits occur reflecting the vascular ischemic effects. Both serum RPR and VDRL, and FTA have a specificity of 97 to 99%; RPR sensitivity is 71% and FTA-ABS sensitivity is 96%. The diagnostic requirements for neurosyphilis consist of: reactive VDRL and FTA-ABS tests in CSF with pleocytosis (CSF WBC count >10/mm3) and CSF protein elevated (> 0.50 g/l). CSF VDRL has low sensitivity (22-69%), and may however be positive in only 30% of late syphilis cases. Due to contamination possibility, a reactive VDRL on CSF in the absence of blood contamination is sufficient to diagnose neurosyphilis, but a nonreactive result does not exclude the diagnosis. Hence a positive VDRL always needs to be confirmed by FTA-ABS. Although nonreactive CSF FTA-ABS test rules out the likelihood of syphilis, the diagnosis of neurosyphilis is still based on elevated CSF WBC (>10/mm3) and/or protein CSF in the appropriate clinical and serologic setting. False-negative syphilis tests occur in patients with HIV infection. Treatment consists of 18 to 24 million IU of iv penicillin each day for 10 to 14 days. CSF leukocyte count should decrease within 6 months after therapy. Protein levels are expected to drop at a slower rate and normalize within 2 years. CSF VDRL is also useful for monitoring the effect of antibiotic therapy for syphilis. Although CSF VDRL titers decrease, it may be years before they become nonreactive. Tabes dorsalis: This late meningoradiculitis form of neurolues is often referred to as progressive locomotor ataxia. The rise in incidence of sexually transmitted diseases and HIV has been accompanied by a resurgence in the incidence of neurosyphilis. Two years or more after exposure to syphilis a period of tertiary syphilis develops with tabes dorsalis being one of the manifestations. The initial symptoms consist of diplopia due to paralysis of the 3rd, 4th, or 6th cranial nerves, irregular pupils, paresthesia and hyperesthesia. Pupillary abnormalities (including Argyll-Robertson pupil) are present in 90% of patients. Ptosis and poor facial tone can develop as a result of cranial neuritis and produces the tabetic facies. Patients may also complain of lightning pains mainly in the extremities although no part of the body is spared. Visceral crisis is sometimes seen and patients may complain of abdominal, rectal, and laryngeal pain. Because of involvement of the dorsal root ganglia and posterior columns there is loss of vibratory and position sense in the legs. Analgesia may be seen over the breasts, medial sides of the forearms, lateral aspects of the legs, and perianal regions (Hitzig lines). As the condition progresses, difficulties in coordination and balance develop. These are worse in the dark but are also present when the patient has good visual input. The syndrome is also characterized by the loss of reflexes in the legs, sphincter dysfunction, and sexual dysfunction. The loss of sensation which occurs in the legs may lead to Charcot joints. CSF protein and pleocytosis may be elevated in early disease, but later in the course, return to normal. The serum RPR is usually reactive at a dilution of less than or equal to 1:16, but it may be negative late in the disease. The serum MHA-TP (or the FTA-ABS) is positive; a negative result essentially excludes the diagnosis of tabes dorsalis. In the early stages, the CSF VDRL is abnormal and the WBC count is elevated; most of the cells are mononuclear. In later, burned out cases the VDRL may normalize and the cell count may be normal. The CSF protein is usually elevated to more than 100 mg/dl in active disease, but slowly returns towards normal as the disease "burns out". After an intensive iv penicillin course (Pen G for 3 weeks), quantitative blood serology is determined at 3 month intervals and usually shows a decline in titer. The CSF is examined at 6 and 12 months. If not normal, CSF is reexamined at 2 years. After 3 years, if the patient has improved and is clinically stable, and if the CSF and serological tests are normal, neurological and CSF examinations are discontinued. Retreatment is recommended with high doses of iv penicillin G under the following circumstances if: 1) clinical neurological findings progress without finding another cause, especially if CSF pleocytosis persists, 2) the CSF cell count is not normal at 6 months, 3) the VDRL test in the serum or CSF fails to decline or shows a 4x increase; 4) the first course of treatment was suboptimal. The degree of recovery depends on the extent of the disease at the time of starting treatment, but is usually minimal.
HTLV-1 associated myelopathy (tropical spastic paraparesis):
Endemic areas for HTLV-1 occurrence include the Caribbean (3-4%
seropositive), north to equatorial Africa, and southwest Japan. In general, 9%
of iv drug users and 0.025% blood donors are seropositive. The median time to
seroconversion is 51 days following exposure (packed red cells, whole blood, and
platelet fractions to a lesser extent fresh-frozen plasma). Transmission by
sexual contact occurs at rates of approximately 5% in females married to
infected males and approximately 1 % in males married to infected females.
Symptoms typically become evident during the 4th and 5th
decades of life. This chronic or subacute
disorder develops in 1-2 % of HTLV-1 seropositive patients and
is clinically characterized by prominent
weakness in proximal lower extremities with pyramidal signs (slowly
progressive spastic paraparesis), loss of
vibration sense and proprioception, urinary bladder dysfunction, impotence and
low back pain. In some patients muscle wasting and fasciculations are found.
Very commonly, patients with HTLV-1 associated myelopathy develop polymyositis
(85% IgG anti-HTLV-1 antibodies). Other coexisting disorders are: peripheral
demyelinating or axonal polyneuropathy,
polyradiculopathy, cranial neuropathies (optic atrophy and deafness),
meningitis, cerebellar ataxia and encephalopathy. The diagnosis is one of
exclusion (MS, compressive lesions, neoplasms, vascular malformations,
infectious and parainfectious conditions, MND and PLS). MRI shows multiple foci
of signal abnormality in T2 weighted images of spinal cord and sometimes brain
similar to that of MS. CSF shows
elevated protein, oligoclonal bands and mild lymphocytic pleocytosis.
Detection of HTLV-1 specific antibodies in blood and CSF is supportive of
the diagnosis. Confirmation of positive serologic studies may be accomplished by PCR amplification of proviral DNA fragments
from infected lymphocytes or HLTV-1 DNA in CSF (sensitivity 93%, specificity 85%). The combination of these
investigations (in italic) provides a sensitivity of 96% and specificity of
100%. However since up to 98% of the HTLV-1 virus infected patients are
asymptomatic the interpretation of the results need to fit the clinical
picture. Fewer than 2 % of HTLV-1 seropositive patients develop other
inflammatory conditions, including uveitis, dermatitis, polymyositis, HTLV-1
associated arthropathy and Sjögren syndrome. About 95% of HTLV-1 seropositive
patients appear to be asymptomatic carriers. Intrathecal hydrocortisone,
intravenous high-dose methylprednisolone, and interferon-a
have all been tried with variable results.
Neurologic abnormalities occur in 10 to 20% of patients with Lyme disease
starting a few weeks to several months after the tick bite. Human infections are
usually seasonal (summer) and occur in patients who have been in woodlands
populated by rodents, squirrels and deer. History of tick bite is absent in over
50% of patients. The most common early neurologic manifestations are aseptic
meningitis, meningoencephalitis following erythema migrans by 2-10 weeks, often
associated with cranial neuropathy, motor or sensory polyradiculoneuritis
(typically cauda equina neuritis) and peripheral neuropathy.
Lyme meningitis presents like classical
meningitis with about 2/3 of patients having systemic manifestations, including
malaise, fatigue, myalgia, arthralgias and weight loss. Untreated the duration
of symptoms ranges from 1-9 months and the patients experience recurrent attacks
of meningeal symptoms lasting several weeks. Other manifestations may include
somnolence, emotional lability, depression, memory impairment, and behavioral
abnormalities. Cranial neuropathies, particularly bilateral facial nerve palsy,
transverse myelitis, spastic paraparesis, disturbances in micturition, Babinski
sign are also observed during this stage.
Cranial neuritis - uni- or bilateral facial
palsy with subjective sensory disturbance occurs often during the early weeks of
Borrelia infection. Recovery can be spontaneous, but oral antibiotic therapy
should be instituted.
Polyradiculopathy - Shooting pain in the
territories of the affected nerve roots with loss of reflexes and sensorimotor
abnormalities in the limbs may last months but recovers spontaneously. Sharp
chest-wall pain reflect involvement of the thoracic nerve. 50% of patients have
also facial palsy.
Peripheral neuropathy - mononeuritis multiplex,
polyneuropathy, and acute brachial neuralgia may all occur in Lyme disease and
can be associated with any of the other neurologic abnormalities. Mononeuritis
multiplex and acute brachial neuralgia may occur within the first few months of
the infection. Polyneuropathy is a manifestation of post-treatment Lyme
disease syndrome (PTLDS).
Late neuroborreliosis or PTLDS develops
weeks/months or years after disease onset and may cause symptoms of mild
encephalopathy, such as memory impairment and concentration deficits, or
chronic mild, multifocal, patchy axonal polyneuropathy manifested as
distal intermittent paresthesias or radicular pain with preserved reflexes and
motor function. Other non-focal symptoms are headache, mild depression,
irritability, fatigue, myalgia and sleep disturbances. CSF shows striking
lymphocytic pleocytosis (up to 700 cells/mm3), but may be normal in
isolated facial palsy or peripheral polyneuropathy. CSF protein is elevated (up
to 600 mg/dL) and CSF glucose normal or decreased in long-standing disease.
Although this patients with Lyme encephalopathy often have normal findings on
CSF analysis. Culture from CSF are very disappointing (5% success rate). NCVs
show reduced and slowed SNAPs, and sometimes increased distal motor latencies.
MRI on PTLDS is often normal or difficult to differentiate from MS. The
diagnosis is based on the demonstration of elevated serum or CSF IgM or IgG
antibody titers to B. burgerdorfi (ELISA). The sensitivity/specificity of
ELISA for B. burgdorferi varies from 58% to 92%, improving with longer
duration of disease (> 10 months). However this test is very insensitive with
respect to the stage of the disease. Furthermore if serum titers are positive,
CSF titers are not necessary. Serum titers should be repeated if there is high
suspicion of Lyme disease. Positive or equivocal ELISA results should be
confirmed by Western blot to rule out a false-positive result. The Western blot
has a high sensitivity and specificity for IgG. The Western blot has poor
specificity earlier after infection (less than 10 months), and high
cross-reactivity with any other immune responsive disorder.
Subacute sclerosing panencephalitis (SSPE): SSPE is a neurodegenerative disease due to persistent measles (rubeola) infection that affects children and young adults. Onset of the disease is insidious (incubation time 6-8 years) and often only recognized after significant neurologic deficits occur. The diagnosis of SSPE can be made if three of the following five criteria are fulfilled: 1) typical clinical presentation with progressive cognitive decline and stereotypical myoclonus (sustained myoclonus e.g. truncal myoclonus, limb extension associated with tongue protrusion and momentary speech arrest followed by loss of tone in all total lasting seconds), 2) characteristic EEG changes, 3) elevated CSF IgG levels without pleocytosis, 4) elevated CSF measles antibody titers, and 5) typical histopathologic findings in a brain biopsy or autopsy. Affected individuals progress through four loosely defined clinical stages at differing rates. Stage I is characterized by subtle behavioral changes, cognitive decline, emotional lability, lethargy, and nonspecific neurologic symptoms. This stage may last for weeks to months. Stage II includes continued intellectual decline, myoclonus, focal seizures with secondary generalization, choreoathetosis, apraxia, and visual changes with optic atrophy, dysarthria, and tremors. A wide variety of visual disorders have been associated with SSPE, including papilledema, (chorio)retinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. This stage may last three months or less. Neurologic decline persists in stage III (decreased level of consciousness, autonomic instability (with a variable heart rate and widely fluctuating temperatures and blood pressures), dystonia and rigidity, decorticate/decerebrate posturing), but the pace slows down, and symptoms may stabilize for one to two years. Features of stage IV include active startle reflex, flexor limb positioning, quadraparesis, akinetic mutism, wandering eye movements and coma. At this time, myoclonus, seizures, and rigidity are less frequent than in prior stages. CSF reveals markedly elevated intrathecal IgG synthesis rate and multiple oligoclonal bands on high-resolution electrophoresis, without a cellular reaction. Serum and CSF measles IgG titers are elevated with normal IgM titers. The EEG exhibits periodic complexes with generalized bilateral, usually synchronous and symmetrical sharp and slow wave complexes of high amplitude (greater than 500 uV), classically occurring every 5-10 seconds. Early in the course of the disease these periodic discharges may occur on a normal background but later the background becomes increasingly slower and disrupted. These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity. MRI may be normal or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter in the frontal, temporal, and occipital white matter; late changes include significant white matter loss, approximately 30% of patients show basal ganglia changes, while 25% have cortical changes. Fifty percent of patients who develop SSPE had measles before two years of age, and 80% before age four years. Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months. Death occurs in stage IV, often the result of intercurrent illnesses such as pneumonia. MS (visual changes, oligoclonal bands) is often considered in the differential diagnosis of SSPE. Treatment is disappointing. The most promising results to date have used a combination of inosiplex, an antiviral agent, and intraventricular or intrathecal alpha-interferon as an immunomodulator, with stabilization or improvement in some patients. If successful CSF titer of measles antibodies should decrease over the months to come. Early childhood measles vaccinations remain critical in limiting the incidence of SSPE.
Neurosarcoidosis: Although only 5-15% of sarcoidosis patients develop neurosarcoidosis, in 50% of cases neurological involvement may be the first manifestation of the disease. The majority of patients (90%) with sarcoidosis have lung involvement (bilateral symmetric hilar and mediastinal lymph nodes). Radiologic manifestations are often far more impressive than the clinical findings. Neurosarcoidosis occurs particularly in older patients, females and involves multiple cranial neuropathies (II and VII)(53%), hypothalamic dysfunction, intracerebral mass lesions, chronic aseptic basilar meningitis (22%)(can lead to hydrocephalus), encephalopathy, spinal cord lesions (meningeal or intramedullary) with radicular involvement, neuropathy (mononeuropathy including truncal nerves, acute multifocal or purely sensory or sensorimotor polyneuropathy)(17%), and myopathy (15%). The myopathy may be either chronic, frequently asymptomatic, or acute with rapidly progressive proximal muscle weakness that may mimic polymyositis or dermatomyositis. ESR is increased in 40% of the cases. Over 75% of neurosarcoidosis patients have abnormal chest X-ray and 54% bilateral hilar lymph nodes only. CSF analysis typically reveals reduced glucose in addition to non-characteristic findings such as elevated pressure, small increase in total protein, oligoclonal bands and mononuclear pleocytosis. Serum calcium is elevated in 17% and ACE is increased in serum (normal < 55 UI/L) or CSF in 50-70% of the cases. Brain MRI gadolinium scan shows focal or diffuse meningeal thickening and/or hyperintense focal parenchymal masses and periventricular white matter lesions (~ MS) on T2-weighted images. Single lesions may mimic meningioma. Sensorimotor polyneuropathy may be associated with granulomas in nerve biopsy. Mediastinoscopy with biopsy can confirm the diagnosis. Eye and myocard involvement can be found. Corticosteroid therapy may result in complete resolution of the dural lesions. Response to steroid treatment (prednisone 1 mg/kg as a starting dose) is often dramatic in patients with acute sarcoid myositis. Methotrexate (7.5 to 15 mg per week) may provide benefit or allow reduction of the steroid dose.
Sjögren syndrome: CNS involvement occurs in about 20% of patients with Sjögren syndrome and is often misdiagnosed as MS at onset. Particularly, female and patients aged >40 years with progressive MS-like presentation should be screened for Sjögren syndrome. Neurological manifestations of this systemic disease are transverse myelitis, dorsal root ganglionitis (ataxic sensory neuronopathy with associated Adie pupil) and multiple cerebral white matter lesions. Neurologic symptoms often appear long before the syndrome is recognized. Diagnostic criteria include: (1) clinical keratoconjunctivitis sicca, (2) positive Schirmer test (less than 5 mm of filter moistened after 5 minutes), (3) clinical xerostomia, (4) salivary gland scintigraphy (grade III or IV), (5) salivary gland biopsy, and (6) autoantibodies positive Ro (SS-A) and La (SS-B). Other findings include Raynaud phenomenon, arthralgia, parenchymal and diffuse pulmonary abnormalities and mediastinal lymph nodes. ESR is invariably increased and other autoantibodies are positive: RF (1/40) and ANA (1/80). Screening for Sjögren syndrome should be consider in all patients with primary progressive MS. However SS-A and SS-B autoantibodies are positive in only 50% of patients with CNS involvement. Oligoclonal bands in CSF are found in less than 40% of cases. VEP may be abnormal in 60 % of patients. Brain MRI is abnormal in 70% of patients and may mimic demyelinating lesions.
Systemic lupus erythematosus (SLE): Nervous system dysfunction occurs in 50 - 90% of patients with SLE. Neurologic involvement is more common in patients with APLS. SLE-related nervous system involvement encompasses a wide spectrum of overt neurologic and psychiatric features ranging from subtle cognitive abnormalities (such as attention, memory, visuospatial abnormalities) to dementia (80%), headaches (including migraine and benign intracranial hypertension) (54%), seizure disorders (42%), visual failure (32%), mood disorders and psychosis (44%), cerebrovascular disease, demyelinating disease, movement disorders, myelopathy, (9%), acute confusional states (7%), cranial neuropathy (7%), cognitive dysfunction, anxiety disorders (13%), mood disorders and psychosis, stroke (15%), acute aseptic meningitis (2%), chorea, demyelinating syndrome and myelopathy are all recognized as common manifestations of CNS lupus. Peripheral nervous system involvement includes mild (or even asymptomatic) symmetric distal sensory or sensorimotor polyneuropathy (including mononeuritis multiplex, GBS-like, CIDP, CTS or chronic sensorimotor axonal neuropathy)(28%), and, rarely, MG. Presentation with neurologic features at onset of disease is rare and occurs in only 3%. Arthralgias, pulmonary involvement, proteinuria, hypertension, DVT, Raynaud's phenomenon, skin rash are the most common systemic manifestations preceding neurological SLE. Smith antibodies are very specific but are only found in 30% of patients. CSF findings are often non-specific. A modest protein elevation and pleocytosis are seen in the CSF of 25-60% of patients with CNS lupus. Damage to the blood-brain barrier is present in about 30% of CNS lupus patients, as evidenced by elevated Q-albumin. An elevated IgG index, indicating the presence of intrathecal IgG production, is present in 25-60% of these patients, and an elevated IgM index is even more common. Oligoclonal banding is present in 20-80% of CNS lupus patients indicating that only a few B-cell clones may be responsible for CNS IgG production. The presence of anticardiolipin antibodies and the lupus anticoagulant have also been suggested as risk factors for CNS involvement in SLE. Additional evidence can be episodic polyarthralgias, anemia of chronic disease, transient skin rash, and recurrent pneumonitis, elevated erythrocyte sedimentation rate (50%), depressed complement levels and laboratory reports of high-titer antinuclear antibodies (85%) and antibodies to double-stranded DNA. MRI may be normal in up to 36% of patients, while abnormalities are seen in 15 to 78% of patients with active neuropsychiatric SLE. Many different neuroimaging presentations of CNS lupus can occur. These can include atrophy, infarct, discrete gray matter lesions, diffuse gray matter hyperintensities, focal, diffuse or periventricular white matter hyperintensities, and cerebral edema. MRI may show extensive bilateral white matter abnormalities suggestive of edema in the cerebral hemispheres, the brain stem, in the cerebellum, which may be associated with hypertension, benign intracranial hypertension, immunosuppression or other signs of active CNS lupus. CNS involvement in SLE is often reversible. Recovery from the CNS symptoms is observed in 70-85% of episodes. Treatment for CNS lupus involves high-dose steroids and cytotoxic agents such as cyclophosphamide, as is usually the case in patients with renal glomerular disease or other significant organ system involvement. The prognosis for 5-year survival is >90%.
Chronic focal encephalitis (Rasmussen encephalitis): This slowly progressive (sometimes more than 25 years) disorder with onset in the 1st decade of life. The disorder is characterized by drug refractory unilateral focal seizures (epilepsia partialis continua, SPS and CPS, status epilepticus), slowly progressive aphasia, hemiparesis, and intellectual impairment (encephalopathy) with progressive atrophy of one cerebral hemisphere (neuroimaging). Within 4 months of onset all patients have refractory focal seizures with a predominant motor component, slow focal activity on EEG contralateral to the motor manifestations, and focal contralateral white matter hyperintensity with insular cortical atrophy on MRI. Serum and CSF anti-GluRε2 and 3 antibody (ELISA), CSF oligoclonal bands may contribute to the diagnosis. Follow up may be over 25 years. AEDs fail to control the disease or halt progression.
Neoplastic disease:carcinomatous meningitis
Paraneoplastic disorders: encephalomyeloneuritis, limbic encephalitis and cerebellar ataxia.
Stiff-person syndrome: The mean age of onset is in the early 40s (30 - 70 years of age). Insidious onset and progressive fluctuating stiffness and rigidity of predominantly axial (abdominal and thoracolumbar paraspinal muscles with difficulty in bending and turning) and, predominantly, proximal lower limb muscles (often asymmetric) and episodic painful spasm superimposed in the rigidity, often precipitated by startle, emotional, and tactile stimuli are the clinical characteristics of this rare disorder. Paroxysms of muscle spasm can be accompanied by profuse diaphoresis, hypertension, tachycardia, and extreme dysphoria. Hyperlordosis, need for cane, shortness of breath and task-specific phobias are commonly observed. EMG shows continuous muscle activity despite relaxation abolished by iv diazepam. Stimulation (scratching) of the skin increases the motor unit activity. NCVs and distal latencies are normal. Autoantibodies against glutamic acid decarboxylase (anti-GAD65) (ELISA, Boehringer, Mannheim) in serum (>50 ng/ml psitive) and CSF are found in 90% of patients using currently available assays. CSF studies occasionally show increased IgG levels and oligoclonal bands. An association with DRb1 0301 allele has been established in 70% of patients. Three forms of the stiff-person syndrome are generally recognized: 1) autoimmune stiff-person syndrome associated with other autoimmune disorders, and with anti-GAD antibodies. In this form of the disorder, pancreatic islet cell, parietal cell, and thyroid autoantibodies are frequently found; 2) paraneoplastic stiff-person syndrome (associated with breast and small cell lung cancer) with anti-amphiphysin antibodies can be found in serum and CSF. In paraneoplastic stiff-person syndrome, anti-GAD antibodies are usually, but not always, negative; 3) idiopathic stiff-person syndrome with no detectable autoantibodies or autoimmune glandular dysfunction. Frequently, autoimmune disorders are associated with the stiff-person syndrome, including insulin-dependent diabetes mellitus (up to 30% of patients with stiff-person syndrome), thyroiditis, MG, adrenal and ovarian failure, pernicious anemia, and vitiligo. Diazepam is highly effective at reducing spasms and stiffness, but oral doses of up to 300 mg per day may be necessary in some patients. Baclofen has been used with excellent responses both orally and intrathecally with typical dosage ranges of 10-100 mg per day orally, and 50-1000 µg per day intrathecally. Other agents with reported benefit in some patients are tizanidine, methocarbamol, vigabatrin, and valproate (mainly for spasms). Botulinum toxin has been used occasionally for severe muscle spasms with dystonia. Corticosteroids, plasma exchange and iv immunoglobulin infusions may be helpful.
Multiple sclerosis (MS): The overall prevalence of MS is estimated at around 100/100,000 population. The prevalence decreases with decreasing latitude. MS is about twice as common in women than men. There is a familial recurrence rate of 15%. Viral infections are often associated with relapse. MS is average first diagnosed at the age of 30 years. Diagnostic criteria require a minimum of two attacks, affecting more than one anatomical site. Assuming an initial presentation suggestive for MS, the second lesion need not necessarily be clinically expressed. Common features are weakness of one or more limbs, optic neuritis, sensory disturbances, vertigo or dizziness and sphincter disturbances. Cerebellar dysfunction, internuclear ophthalmoplegia and lassitude are common features at the time of diagnosis. Several forms have been identified: (1) relapsing-remitting MS and most common form (75%) consist of recurrent attacks that evolve over days or weeks and are followed by complete or incomplete or no recovery, (2) primary progressive MS (20%), consisting of gradual progression of disability from onset, with no distinct relapses, (3) secondary progressive MS, begins as a relapsing-remitting disease but evolves into a gradually progressive course. Primary progressive MS affects predominantly the spinal cord and less frequently the optic nerve, cerebrum or cerebellum. The duration of an episode generally takes 6 to 8 weeks, and the interval between attacks is approximately 15 months. Anti-MOG antibodies were found in the serum of nearly all patients with progressive MS could be a useful marker for disease progression. Oligoclonal bands are found in over 85-95% of cases. IgG synthesis is elevated in 70-90%; and IgG/albumin ratio is abnormal in 60-73%. Intrathecal production of oligoclonal bands occurs however in a variety of other neurological disorders. CRP serum levels, an acute-phase hepatic protein induced by interleukin -6, -1 tumor necrosis factor-alpha and oncostatin, are increased in MS relapses and correlate with MRI activity. Evoked Potentials: visual evoked potentials are abnormal in 80-85%; brainstem evoked potentials in 50-65%; and somatosensory evoked potentials in 65-80% of patients with MS. MRI (gadolinium-enhanced T1-weighted or T2-weighted) is abnormal in 90% of cases. Multiple lesions on MRI but negative EP is not very suggestive for MS. In patients with clinically isolated syndromes compatible with MS, positive MRI together with CSF analysis increase accuracy in predicting MS. Fifteen years after diagnosis, 20% of all MS patients have normal functional abilities and 70% are limited or unable to perform major activities of daily living. The presence of APOE e4 genotype is associated with a significantly faster progression of disability in MS. Variant forms of MS are Marburg disease (acute fulminant MS), Balo concentric sclerosis, tumefactive MS (cystic lesions with fried egg appearance on MRI) and Schilder disease). Important differential diagnosis are hereditary spastic paraplegias and ataxias, leucodystrophies (particularly MLD and X-AMN), CADASIL, and granulomatous angiitis, sarcoidosis, Wegener and lymphomatoid granulomatosis, and vasculitis (SLE, Sjögren disease, Behçet disease, PAN), paraneoplastic encephalomyelopathies, acute disseminated encephalomyelitis, postinfectious/vaccination encephalomyelitis, HIV, neurosyphilis, PML, HTLV-1, Lyme disease and fungal infections. Finally, spinocerebellar disorders, Arnold-Chiari malformations, heroin-induced vasculitis, vitamin B12 deficiency, lymphomas, metastases needs to be ruled out. Interferon (IFN) beta-1a (SC and IM) and -1b (SC) have proven to be effective in MS. The risk of hepatotoxicity (30%) and mild ADRs is higher with the SC IFN forms than with the IM form, however the risk-benefit ratio appears in favor of the SC form (three times in a week). Neutralizing antibodies (NAb) against IFN should be measured in all patients treated with IFN-beta. These NAb may reduce the therapeutic benefits measured by relapses, change in Expanded Disability Status Scale score and MRI activity. They develop in about 50% of patients within 12 to 18 months of therapy. More patients treated with IFN beta-1a (Avonex®) remain NAb negative, whereas there is no difference between the IFN beta-1a (Rebif®) and -1b (Betaferon®). If patients have been persistently NAb-negative for 24 months, measurements can be discontinued. Patients who have been NAb-positive for a period of 18 months or more usually remain NAb-positive for a long time, however NAb may disappear after prolonged therapy with continuous therapy with high-dose interferon beta-1b.
disease (CJD): The
annual incidence of this prion disorder is 1/million in the general population,
90% being sporadic. Libyan Jews, North African immigrants to France
and Slovakians have a higher incidence of developing the disease. Infected
corneal transplants, deep brain electrodes, dural grafts and growth hormone
preparations have been causes of transmission. The peak age of onset ranges from
55 to 75 years of age. The clinical diagnostic criteria for CJD are: rapidly
progressive dementia (confusion, hallucinations, delusions, agitation, changes
in visual perception)(<2 years) with periodic sharp wave complexes in the EEG
in addition to two of the following: stimulus-sensitive myoclonus (startle
reactions), ataxia or visual symptoms, parkinsonism or pyramidal signs, or
akinetic mutism. Associated findings are weight loss, anorexia and insomnia.
There is paucity of lab abnormalities: CSF may show elevated protein (around 100
mg/dl) and up to 20% of patients may have oligoclonal bands on CSF
electrophoresis. CSF 14-3-3 immunoblot (sensitivity 94%, specificity 84-97%) and
tau-protein ELISA (Innogenetics, Ghent, Belgium) (sensitivity 94%, specificity
90%) are positive predictors in over 90% in CJD. EEG findings may be normal or
reveal only slowing of background activity, especially early in the course of
disease. Initially non-specific changes are observed but later on bilateral
synchronous high voltage periodic triphasic sharp wave complexes 0.5 - 2 Hz
(sensitivity 67%, specificity 74-86%) are seen. However, the absence of these
sharp wave complexes does not rule out the diagnosis of CJD. Brain MRI shows
symmetric hyperintense abnormalities in putamen, thalamus and cortex (gyral
swelling) on T2 images, which may be supportive for the diagnosis. On T1 images
these lesions remain isointense and do not enhance after contrast. FLAIR
sequences are preferred, as they may show hyperintense areas of gray matter,
particularly in the cerebral cortex, not otherwise appreciated on conventional
T2-weighted images. Diffusion-weighted MRI scans may suggest that abnormal
cortical signal results from intracellular edema or cytotoxicity. Olfactory (and
brain) biopsy may provide diagnostic information in living patients
(the conversion of a normal cellular protein (PrPC) to an abnormal
isoform, PrPSC). Mean interval between onset and death is 8 months.
Precautions should be taken when handling all body fluids of an infected
patient, especially spinal fluid. Gloves should be worn during procedures (e.g.
lumbar puncture) and accidental skin contamination should be rinsed with a 1:10
dilution of sodium hypochlorite (household bleach). Specimens from known or
suspected infected patients should be marked as such, so that laboratories may
handle and dispose of them appropriately. Several clinical variants have been
described e.g. Heidenhaim variant (typically associated with florid visual
hallucinations and cortical blindness), Brownell-Oppenheimer variant (predominantly cerebellar ataxia with little cognitive involvement)
variant (predominantly basal ganglia and thalamic form).
Varicella zoster encephalitis: Besides cerebellar ataxia which is usually self-limiting and resolves within a few weeks, meningoencephalitis is another but more severe complication of varicella. Advanced age, immunosuppression and disseminated cutaneous zoster are predisposing factors. Headache, fever and vomiting are often accompanied by an altered sensorium with seizures occurring in over one third of cases. Focal neurology symptoms (stroke) may occur due to VZV multifocal vasculopathy (in immunocompromised patients and is associated with encephalopathy) or unifocal granulomatous arteritis (typically in elderly immunocompetent adults weeks to months after contralateral trigeminal zoster (VZV vasculopathy). The latter, contralateral hemiplegia in patients with ophthalmic zoster accounts for up to one third of cases of CNS abnormalities with herpes zoster. TIAs may occur. Myelitis may also occur. CSF analysis shows changes typical for aseptic meningitis with oligoclonal bands and intrathecal immunoglobulin synthesis. MRI shows either unifocal or multifocal ischemic and hemorrhagic infarcts in the cortical and subcortical areas. MRA of the bran reveals focal arterial stenotic lesions. The EEG is usually diffusely abnormal. CSF culture and CSF VZV IgM antibodies (with reduced serum/CSF ratio may be detected. PCR for DNA VZV in CSF is diagnostic in associated VZV meningitis. IV acyclovir is essential and may need to be repeated if ischemia occurs.