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.
Alexander disease: The adult form is usually sporadic or less commonly autosomal dominant. The symptomatology is very heterogeneous with relapsing remitting neurological symptoms mimicking MS. In contrast to the sporadic form, the hereditary adult-onset form shows uniform clinical features; spastic paraparesis, palatal myoclonus, bulbar or pseudobulbar palsy, nystagmus and slight to mild cerebellar ataxia without dementia or seizures. The hereditary form of this disease is associated with unique MRI features consisting of severe atrophy of the medulla oblongata and cervicothoracic spinal cord. The disease is a primary genetic disorder in the glial fibrillary acidic protein of the astrocytes.
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 vaccine), 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 (1g methylprednisolone/day 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 disease and MS. Related disorders are AHLE, Bickerstaff brainstem encephalitis, optic neuritis, ATM, cerebellitis and multiphasic form of ADEM and MS.
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.
SCA-7: This autosomal dominant disorder typically presents with progressive ataxia, upper motor neuron signs (brisk reflexes), macular or retinal degeneration with visual loss, and slow saccades. They often start in childhood. SCA-7 is mapped to chromosome 3p14.1-p21.1. Early onset cases may present with dementia. This form is often misdiagnosed as MS. SCA-7 constitutes about 5% of ADCAs.
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 on postcontrast T1 images 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.
Lyme disease: 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.