Multiple cranial nerve palsies


Neurosarcoidosis: Although only 5-15% of sarcoidosis patients develop neurosarcoidosis, in 50% of cases neurological involvement may be the first manifestation of the disease. 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% have only bilateral hilar and mediastinal lymph nodes. 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.

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.  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. burgerdorfi 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.

Botulism: There are seven known botulism toxins, but only toxins type A, B, E, and F are harmful to humans. Food-borne (preformed neurotoxin), wound botulism, colonization of the gastrointestinal tract in predisposed patients (achlorhydria, antimicrobial therapy, gastrectomy, intestinal surgery) are causes of botulism. The symptoms of botulism usually begin within a few hours to 72 hours after you eat contaminated food. They may last several days. The key features include acute (2 days) nausea and vomiting leading to ileus, progressive dysphonia, neck flexor weakness, respiratory failure, ptosis, facial weakness, slowly reactive pupils and descending paralysis. Neuroimaging and CSF should be normal. Normal NCVs and F waves in all limbs. EMG shows early recruitment with full interference pattern, small amplitude and brief duration MUPs with increased polyphasia. Repetitive stimulation reveals 60% increment in CMAP. The diagnosis is based on identification of botulinum toxin in stool and serum. Stool culture for Clostridium botulinum. Differential diagnosis include MFS, diphtheric neuropathy, MG, CIP and acute quadriplegic myopathy. The main treatment for botulism is good nursing support often in ICU, with a ventilator as needed to assist breathing. If botulism is diagnosed quickly in an adult, the antitoxin can be given i.v. This antitoxin prevents further paralysis damage from the toxin, but it does not affect symptoms that are already present. The antitoxin is not considered safe for infants. To prevent further release of the toxin, contaminated food in the gut should be removed through induced vomiting or enemas. Wounds that are a source of botulism must be treated with surgery to remove contaminated tissue. Recovery from botulism may take many weeks. Treatment for severe botulism may take several months. Fatigue and shortness of breath may persist for year.

Miller-Fisher syndrome (MFS): Constitutes 5% of cases of GBS and consists of a triad of acute onset ophthalmoplegia (most often abducens palsy followed by others progressing over days, ptosis occurs in most patients), ataxia, and areflexia. Acral and facial paresthesias occur in some patients, and there may be mild limb weakness and pupillary abnormalities (sluggishly reactive pupils). Restricted forms exist involving ataxia without ophthalmoplegia. On the other hand, almost 50% of the cases have additional features consistent with peripheral neuropathy (including paresthesias of the distal limbs, oropharyngeal weakness, or bi-facial weakness). Campylobacter jejuni (18%), CMV, EBV, Mycoplasma pneumoniae, mumps virus, VZV, HIV, Coxiella burnetti, Strep. pyogenes, S. aureus and H. influenza have been reported as antecedent agents in MFS. CSF usually reveals albuminocytologic dissociation or may be normal. There is a high association with anti-GQ1b polyclonal IgG antibodies (titers of 1:40 by ELISA are significant). NCV findings include normal motor and sensory conduction velocities with absent H-reflexes, slowed NCVs, reduced SNAP amplitudes, or completely normal studies. Other nerve conductions and F-wave conductions are normal. Sensory findings are affected more than motor. Motor studies can become abnormal late in the course, even as they are recovering. Blink reflex latencies are generally normal. Neuroimaging studies are often normal although cranial nerve enhancement can occur. The symptoms remain steady for 2 - 3 weeks and are followed by a recovery phase, which can take months. Prognosis is good with recovery after a mean of 10 weeks. Favorable response to IV immunoglobulin has been reported.

Cranial variant of GBS: The key features include blurred or double vision, ptosis, oropharyngeal, neck, and shoulder weakness, and respiratory failure. Sensation is normal. Reflexes normal in legs but absent in arms. CSF reveals an albuminocytologic dissociation.

Chronic (meningo)encephalitis: TB, fungal infections (mucormycosis), syphilis.

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 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. Repeat treatment 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 four fold 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.


Systemic vasculitis: PACNS, SLE, Sjögren syndrome, PAN, Wegener granulomatosis, Churg-Strauss syndrome, and Behçet disease. Although MRI and cerebral angiography may both be negative, MRI is usually associated with white matter lesions and cerebral angiography may show segmental narrowing of small blood vessels. A biopsy is needed for the diagnosis of PACNS.

Neoplastic disease: Meningeal carcinomatosis and metastasis. Meninges are involved in 5-15% of all patients with solid or hematological tumors: (leukemia (40%), breast (34%), lymphoma (30%), lung (26%), melanoma (25%) and gastrointestinal (9%). About one third of patients with meningeal carcinomatosis have cranial nerve involvement, but less than 50% of patients have nuchal rigidity, headache or vomiting. MRI reveals diffuse dural meningeal enhancement (50-90%) and CSF in over 50% of cases elevated protein and reveals aseptic meningitis. CSF cytology is positive in only 50% of cases. Useful tumor makers in CSF are CEA (breast, lung, gastrointestinal tumors), epithelial membrane antigen, β-glucuronidase, β-2-microglobulin, and lactate dehydrogenase. Similarly, metastasis can also result in multiple cranial neuropathies.

Lymphomatoid granulomatosis: This most commonly occurring after the 5th - 6th decade of life. In 30% of patients nervous system is affected. Cranial neuropathy and necrotic mass in cortex and brain (25%) including mental status changes, ataxia, hemiparesis, and seizures are common findings. Peripheral nerve involvement may include distal sensory neuropathy or mononeuritis multiple. Despite this isolated CNS disease may occur. Cough and dyspnea are almost invariably present and chest X-ray is abnormal including multiple nodules or infiltrates in lungs destroying the lungs. In addition, skin, liver and kidneys are affected in 50% of patients. Signs of lymphoma (fever, weight loss, and malaise) are common. ESR is mildly increased and WBC is normal although leucopenia (20%) and lymphopenia (33%) may be present. CSF shows slightly elevated CSF protein (<100 mg/dl). IgG CSF may be elevated if tumor cells are of B-cell origin. MRI reveals enhancing lesions of brain and spinal cord and non-enhancing periventricular white matter lesions. Skin, meningeal or brain biopsy can be diagnostic. The condition needs to be differentiated from Churg-Strauss syndrome, Wegener granulomatosis and lymphoma.

Multifocal motor neuropathy with conduction block (MMN): This chronic idiopathic neuropathy may occur at any age and presents usually as a slowly progressive asymmetrical distal limb weakness with minimal or no sensory impairment later on followed by muscle atrophy (may be accompanied by fasciculations, cramps and myokymia). The disease usually begins and remains more prominent in the upper extremities. The first symptom is often inability to extend a single finger. The most striking clinical feature is the multifocal distribution of the weakness, which, in the beginning, may be localized within the territory of individual peripheral nerves. Fasciculations are rare and cranial nerve involvement with bulbar palsy can occur. Reflex loss is usually restricted to the affected areas. Sensation is essentially normal. CSF is normal. NCVs show a combination of multifocal motor conduction block, prolonged or absent F- waves, prolonged distal latencies, reduced motor NCVs, or motor axonal loss with EMG evidence of denervation. Motor conduction block occurs most frequently in the ulnar and median nerves, both proximally and distally. But conduction block may be seen at any level of the peripheral nerve including the root, plexus, compression points (elbow for ulnar nerve, tibial head for peroneal nerve, etc.), or along a random segment. If parts of the nerve are not accessible for NCVs significant weakness in non-wasted muscles can substitute for it. A unique electrophysiologic feature of MMN is that sensory NCVs are typically normal, even across a segment of motor conduction block. The EMG in MMN typically shows evidence of axonal degeneration with fibrillation potentials and positive sharp waves in atrophic muscles. Sural nerve biopsies are either normal or show evidence of perivascular inflammation, demyelination, or reduced myelinated fiber density. The diagnostic feature remains the demonstration of conduction block restricted to the motor fibers of a nerve, normal SNAPs, and the presence of serum anti-GM1 IgM polyclonal antibodies found in at least 1/3 of patients. Deterioration is steady or stepwise over years. The major differential diagnosis is CIDP, PMA and ALS. Early in the disease course weakness is more pronounced than atrophy in affected muscles. This is an important clinical feature distinguishing MMN from MND, in which atrophy is generally consistent with the degree of weakness. Note that motor conduction block also occurs in compressive neuropathies, GBS, and CIDP. Human IV immunoglobulin (infused at a dose of 2 grams/kg in divided doses of 0.4 grams/kg on 5 consecutive days) is the treatment of choice. The onset of improvement occurs within 14 days, and the effects last approximately 2 months. Patients, therefore require frequent boosters to maintain their functional gains. Clinical improvement is not associated with a consistent decrease of anti-GM1 antibody titers and is not invariably accompanied by a reduction of motor conduction blocks. In contrast to CIDP, prednisolone and plasma exchange are ineffective or, particularly steroids may dramatically worsen the neurological condition.  Multifocal motor axonopathy (MMA) can present with asymmetric weakness and axonal electrophysiological features. It needs to be differentiated from LMN syndromes in particular adult progressive SMA. EMG and CSF help to distinguish MMN from CIDP and multifocal acquired demyelinating motor and sensory neuropathy. Iv immunoglobulin improve conduction block. Pregnancy may worsen MMN.

Porphyric neuropathy: This familial disorder may affect upper extremities and cranial nerves but is frequently accompanied by confusion (encephalopathy), convulsions, and abdominal pain. Its presentation is acute or subacute. It presents with abdominal pain episodes, skin rash, acute symmetric weakness first arms proximal more than distal. Cranial nerves can be affected particularly ocular, VII and X. Autonomic dysfunction in form of tachycardia, hypertension, and urinary retention. Increased urinary porphobilinogen (normal 0-4 mg/24 hr) and increased total porphyrins (0-300 nmol/24 hr), normal delta-aminolevulinic acid (0-7 mg/24 hr), decreased erythrocytic porphobilinogen deaminase (deficiency) and increased erythrocytic protoporphyrin. NCVs reveal a pure motor neuropathy. Treatment should focus on avoiding drugs which induce cytochrome P 450 system. Besides respiratory support, the following are recommended: beta-blocking drugs for autonomic dysfunction, glucose infusion (decreases ALA synthetase activity), hematin iv (4 mg/kg/d for 3 to 14 days) and pyidoxine 100 mg bd.

Neuroacanthocytosis: The neuroacanthosis exists of three major groups: 1) the core neuroacanthosis syndromes with neurodegeneration of the basal ganglia, comprising autosomal recessive chorea-acanthosis due to mutation of VPS13A (chromosome 9q21) and the X-linked McLeod phenotype (indistinguishable phenotypes) due to mutation of XK gene, 2) conditions with decreased lipoproteins (abetalipoproteinemia and hypobetalipoproteinemia) consisting of peripheral neuropathy and ataxia without movement disorders, 3) associated forms such as HSD (PANK2) and HD (HDL2). The core neuroacanthosis affects men twice as common as women. Symptoms usually start in the 3rd to 5th decade (mean 32 years) and consist of limb chorea, especially affecting the legs, along with parkinsonism, oro-facial dyskinesias, self-mutilation, and dementia. 50% of cases have seizures, areflexia (chronic axonal motor polyneuropathy: small SNAPs; normal CMAPs) with distal symmetric wasting. Elevated serum CK levels and acanthocytes on a fresh wet blood film facilitate the diagnosis. The latter usually precedes the neurologic features. Needs to be differentiated from abetalipoproteinemia (abnormal serum lipoprotein profile) and McLeod syndrome (reduced expression of Kell blood group on RBC and Kx surface antigen (100%)). Brain MRI may show caudate atrophy. Acanthocytes are seen in the peripheral blood smears of some of the asymptomatic family members. Average life span is approximately 14 years from onset of illness.

CMV encephalitis: This infection presents often as ventriculitis in patients with AIDS or post-organ transplantation and is not necessarily preceded by CMV retinitis. The clinical features include subacute or chronic delirium, seizures, cranial neuropathies, and nystagmus. Neuroimaging may show ventricular enlargement and enhancement of periventricular white matter (“owl eyes” sign on FLAIR). Possible differential diagnosis of lesions with periventricular enhancement (and/or calcifications) includes toxoplasmosis, rubella and herpes simplex virus infections (ToRCH infections). CSF analysis shows increased protein and variable pleocytosis (mononuclear cells). Detection of CMV DNA by PCR is the diagnostic test of choice (95% sensitivity and 99% specificity). The same “owl eyes” may be found on pathologic examination (intranuclear and intracytoplasmic inclusions of cytomegalic virus particles. The prognosis is generally bad. Necrotizing ventriculoencephalitis is a rapidly fatal form of CMV encephalitis.

Idiopathic intracranial hypertension (IICHT): This disorder is almost exclusively found in young obese women (>90% of patients are obese women). The female-to-male ratio of this disorder is 8:1. The mean age at the time of diagnosis is around 30 years. Pregnancy and menstrual irregularities are risk factors for developing IICHT. The diagnosis of IICHT is based on the following criteria: 1) signs and symptoms of increased intracranial pressure (headaches with nausea or vomiting and a normal neurological examination with the exception of papilledema (95%), visual loss from optic atrophy (30%), cranial nerve palsy (unilateral or bilateral VI nerve palsy) (25%) or tinnitus; 2) increased CSF pressure (>20 cm H2O in non-obese and >25 cm H2O in obese) with no cytological or chemical abnormalities (occasionally slightly low protein content); and 4) normal to small symmetric ventricles or empty sella syndrome (70%). Conditions that may result in IICHT: Addison disease, hypoparathyroidism, chronic obstructive pulmonary disease, right heart failure with pulmonary hypertension, sleep apnea, renal failure, severe iron deficiency anemia. Certain drugs are known to be a risk factor for inducing IICHT e.g. nalidixic acid, vitamin A, lithium, minocycline, oral contraceptives, thyroid hormone replacement, anabolic steroids and corticosteroids withdrawal. Since 30% of patients with CVT may present with "isolated intracranial hypertension without papilledema" MRV should be considered systematically in these patients.  Furthermore 10% of patients who present with CDH have CVT and almost 50% of these patients have "isolated ICHT without papilledema". Furthermore, all individuals (obese or non-obese) with a CSF pressure > 20 cm H2O should undergo MRV.

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.

HIV-related CNS infections: Most of these infections occur when CD4 counts are <200 cells/L. Toxoplasmosis encephalitis complain of headache, fever, confusion and seizures. Serum anti-toxoplasma IgG is usually positive. PCR detection of toxoplasma in CSF is not sensitive enough. Brain MRI shows single or multiple lesions located at the hemispheric gray-white junction, in the deep white matter, or in the basal ganglia. Thallium SPECT may be useful to differentiate between toxoplasma and CNS lymphoma. A presumptive diagnosis can be made by response to pyrimethamine and sulfadiazine (clinical improvement within 1-2 weeks and radiologically within 2-3 weeks). Brian biopsy may be considered if there is no response to the treatment. Neurosyphilis can present in its different forms. Diagnosis of neurosyphilis should be made by means of FTA-ABS and excludes equivocal cases. Other infections associated with HIV include, trypanozoma cruzi, acanthamoeba, pneumocystis carinii, PMFLE, listeria, salmonella, nocardia and histoplasma.

Anthrax meningoencephalitis: Nicknamed ‘meningoencephalitis with hemorrhagic CSF’. The prodromal period is about 1 - 6 days and consist of fever, headache, nausea and vomiting in association with alteration in the level of consciousness, focal or generalized seizures, focal neurological deficits, cranial neuropathies. Nuchal rigidity may be prominent as anthrax causes leptomeningeal and SAH. With inhalation anthrax there may be additional features prior or during the meningoencephalitis: malaise, myalgias, nonproductive cough, chest pain, dyspnea and stridor. CSF may be cloudy or hemorrhagic. The opening pressure is elevated, there is polymorphonuclear pleocytosis, increased protein content and decreased glucose levels. Gram stain of the CSF reveals large gram-positive bacilli. Hemorrhagic CSF should not be mistaken for bloody tap (differential cell count between 1st and 4th tube). A > 4-fold increase in levels of serum IgG (ELISA) can be demonstrated between the acute and convalescent sera (this will however take 28 days to occur). Brain MRI may show focal intracerebral hemorrhage, SAH, diffuse cerebral edema or prominent leptomeningeal enhancement. Anthrax meningoencephalitis is fatal in 94% of cases with 75% of patients expiring within 24 hours of presentation.

Chronic inflammatory demyelinating sensorimotor polyneuropathy (CIDP): This slowly progressive steroid-dependent polyneuropathy can occur at any age (mean age of onset in the 5th decade). The clinical presentation is that of progressive/relapsing and remitting muscle weakness present for more than 2 months, symmetrical proximal and distal extremity weakness and hyporeflexia. May resemble GBS with the difference that there is no recovery but rather deterioration. In women, relapses are particularly associated with 3rd semester of the pregnancy or immediately postpartum. Up to 30% of patients have a history of viral infection or vaccination. The majority of patients present with relative symmetric numbness and tingling (sensorimotor neuropathy with (sometimes painful) paresthesia), loss of vibratory sensation and joint position sense with positive Romberg sign as common early manifestations. Limb weakness is usually affecting proximal, muscles more than distal musculature. Both upper and lower extremities are involved, although the legs are usually affected more severely. Deep tendon reflexes are absent or depressed. Neck flexor weakness distinguishes CIDP from most other neuropathies. Sensory findings are typically mild and often include impaired touch and vibratory sensation, with less involvement of small-fiber sensation (pain and temperature). Pure motor or sensory forms do exist. Deterioration over > 8 weeks is a distinguishing criterion from GBS. Cranial nerves (diplopia, dysphagia, facial or masticatory muscles, papilledema) are affected in about 15% of patients. A coarse, irregular action tremor, often seen in paraproteinemic neuropathy, may occur and may be related to a CNS equivalent mimicking neuroradiologically MS. Albuminocytologic dissociation (elevated CSF protein >45 mg/dl in the absence of a high cell count <10) is characteristic of CIDP. An elevated IgG index and IgG synthesis rate is consistent with the immune-related nature of CIDP. An elevated Q-albumin shows an impairment of the blood-brain barrier, which in CIDP is at the level of the inflammed nerve root sheaths within the thecal sac. The hallmark of the disorder is: 1) reduction of in NCV in >2 nerves  (<75% of normal); 2) partial conduction block (<15% change in duration between proximal and distal sites) or abnormal temporal dispersion (>15% change in duration between proximal and distal sites) in > 1 nerve; prolonged distal motor latencies in >2 nerves  (>130% of normal); absent or prolonged F-wave latencies in >2 nerves. In addition, distal CMAP duration > 9 msec for any of four motor nerves (ulnar, median tibial or peroneal nerve) increases the diagnostic sensitivity. SNAP are usually reduced or absent. Despite these criteria diagnostic difficulties may arise with borderline cases. CSF protein is normal or elevated (> 100 mg/dl). MRI findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy include enhancement (hypertrophy) of cervical roots, brachial plexus or the cauda equina, and may enhance after the administration of gadolinium. Sural nerve rarely adds to the diagnosis. A proven diagnosis of CIDP is an excellent chance of recovery with immunosuppressive therapy. CIDP can be associated with a variety of underlying disorders including: malignancies (lymphoma, Castleman disease, carcinoma), autoimmune disorders (SLE, temporal arteritis, RA, MCTD, amyloidosis etc.), infections (HIV infection before developing AIDS, hepatitis C), renal disorders or endocrine disorders (diabetes, thyroid disorders).  Suspicion of such relation should be raised when; (1) the neuropathy evolves rapidly with unusual features (e.g. extensive cranial nerve involvement or neuropathic pain), (2) deterioration continues despite immunosuppressive therapy. A useful differential diagnostic tool between MMN and CIDP is the presence in MMN of  GM1 ganglioside antibodies (in 40-80%), normal CSF protein levels, and sometimes IgM monoclonal gammopathy. Furthermore MMN and pure motor forms of CIDP differentiate from CIDP by the lack of response to steroids and even clinical deterioration. Treatment (oral steroids, plasma exchange, iv immunoglobulin) should not be postponed until it is clear whether a patient suffers from GBS or CIDP. Prednisolone is given as 60-120 mg (1 to 1.5 mg/kg/d) for 2-4 weeks and then switched to a single dose on alternate days after 2-3 months in patients who respond favorably and then continued until clinical improvement plateaus. Then prednisolone is tapered by 5-10 mg every 2-4 weeks. When deterioration occurs IV immunoglobulin therapy or azathioprine should be added. After starting steroid therapy, there may be a lag time from the onset of therapy to first signs of clinical improvement of 1-4 weeks, occasionally up to 5 months. IV immunoglobulin infusions (starting dose 0.4 g/kg for 5 days, maintenance dose commonly tapered to total of 0.4 g/kg) are as effective as steroids or plasmapheresis, but their cost and their short-lived response (commonly 2-8 weeks) make them to an disadvantage. Azathioprine (3 mg/kg) in a single dose can be considered when previous measures fail. CBC count and liver function tests should be evaluated before and during this treatment. The drug has a steroid-sparing effect in steroid-responsive patients. Without therapy, CIDP is fatal in up to 10% of patients. Although 95% of patients will show initial improvement following immunosuppressive therapy, the relapse rate is high. 64% improved and are able to return to work and 11% become bedridden or wheelchair bound.

Subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, Leigh syndrome and necrotizing encephalomyelopathy of Leigh. Adult-onset forms of SNE are sporadic, or inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial trait. To complicate matters even more several different types of genetically determined enzyme defects can cause SNE. As with other mitochondrial disorders, the onset of neurologic symptoms present from the 1st - 6th decade with acute or subacute onset, often precipitated by surgical intervention or febrile illness. The disease can present with a variety of symptoms such as brainstem dysfunction (central respiratory failure, intermittent oculomotor palsy, cranial nerve dysfunction including deafness, optic atrophy or Wernicke-like syndrome), ataxia, or extrapyramidal (dystonia) symptoms, global cognitive dysfunction (dementia or mental retardation (30%)), spastic paresis, myoclonic jerks and seizures, peripheral demyelinating polyneuropathy, motor decline and unconsciousness with lactic acidosis. In addition, insulin-resistant diabetes mellitus, muscular weakness, intractable nausea and vomiting, and anemia can occur. The disease can be intermittent progressive or remitting/relapsing. CSF protein may be increased. Brain MRI shows abnormal high intensities in basal ganglia, particularly putamen, on T2 weighted images, bilateral medial regions of the thalamus, brainstem and periaqueductal gray matters. Proton MRS may show elevated lactate level in involved regions of the brain. Ragged red fibers can be found on muscle biopsy with increased succinic dehydrogenase activity and cytochrome oxidase negative fibers in almost 90% of cases. Pre- and postprandial serum and CSF lactate and pyruvate are useful in the diagnosis. Serum lactate is increased in 50% of patients but is less sensitive than CSF lactate. Pyruvate dehydrogenase deficiency (or Lactic and Pyruvate Acidemia with Episodic Ataxia and Weakness) presents with episodic ataxia, seizures, and hypoglycemic episodes and may mimic SNE. Serum and urine amino acid analyses reveal hyperalaninemia. Treatment for SNE is empirical but the administration of thiamine, coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.

Cat-scratch fever: B. henselae is the most common cause of chronic benign adenopathy in children in the United States. More than 80% of cases occur in those under 21 years of age, and 75% of cases occur between September and March. Approximately 90% of cases have a history of cat exposure, and 75% of patients report scratches. Skin pustules ("inoculation" pustules) occur 3-10 days after the injury at the sight of the scratch or bite. Regional tender lymphadenopathy, most commonly of the head and neck, can persist for 2-4 months. Fever, malaise, fatigue, headache, and sore throat are also common. Rash occurs frequently and can appear as maculopapular, petechial, or erythema multiforme or nodosum. Hepatosplenomegaly can occur as well as osteolytic lesions. Neurologic symptoms are relatively uncommon, but, if present, usually occur 3-8 weeks after animal contact. Neuroretinitis occurs 1-2 weeks after symptom onset and is usually unilateral and associated with a loss of visual acuity. Mild aseptic meningitis are the more typical manifestation with mild lymphocytic pleocytosis and slightly elevated protein. Rarely, acute life-threatening encephalitis and seizures (or status epilepticus) occur. Radiculitis, myelitis, cognitive deficits, and (rare) cranial neuropathy (oculomotor and facial palsy) may also occur. Brain MRI is often normal, but findings may also be consistent with cerebral edema and, rarely, multifocal white matter lesions can be seen. The indirect fluorescent antibody test is highly sensitive and specific for Bartonella species. A titer > 1:64 indicates infection. More recently, the enzyme immunoassay has been used which appears to be more sensitive for detecting this bacterium than the IFA. Culture of the organism remains very difficult. Detection of the organism by PCR or silver staining from excised lymph node is diagnostic.

Idiopathic hypertrophic cranial pachymeningitis (IHCPM): This chronic disease is characterized by headache, loss of vision, diplopia, ataxia and cranial nerve palsies (particularly VIIIth cranial nerve). Obstructive hydrocephalus may occur. Some patients have concomitant systemic fibrosis including: myocarditis, episcleritis and sclerosing cholangitis. There are no pulmonary abnormalities and ESR is raised in almost 50% of cases. CSF shows increased protein and lymphocytic pleocytosis. Cranial gadolinium MRI shows invariably abnormal dural enhancement of sphenoid wing dura mater and diffuse linear dural enhancement, including the falx cerebri, which gives an egg-shell appearance surrounding the brain). Biopsy of the dural lesion should be considered and is recommended if the patient clinically deteriorates or the neuroimaging worsens despite treatment. Steroids (prednisolone 60 - 80 mg/day) may result in complete resolution of pachymeningeal inflammation. However methotrexate or azathioprine may need to be added to steroid therapy. Venous sinus thrombosis and cerebral edema can complicate this disease process. Differential diagnosis of pachymeningeal lesions include infectious disease (TB, Lyme disease, syphilis, cat-scratch fever, candidiasis, aspergillosis, epidural abscess), noninfectious inflammatory disorders (neurosarcoidosis, autoimmune disorders (RA, Wegener granulomatosis), intracranial hypotension, neoplastic disease (benign or malignant forms), polyclonal plasma cell hyperplasia, plasmacytoma, meningeal carcinomatosis and metastatic (lung and breast carcinoma, lymphoma, leukemia, melanoma, colorectal cancer).

Central European Encephalitis (CEE): Louping ill virus, Far Eastern tick born encephalitis (FEE) and CEE are distinct viruses. CEE is an arbovirus and is contracted by tick bite in endemic areas in southern Germany or Austria. Incubation period is 1 - 3 weeks giving way to an influenza-like syndrome, then followed by: either meningoencephalitis syndrome or pseudo-poliomyelitis syndrome with rapid-onset or progressive weakness of pontomesencephalic or caudal cranial nerves with early progressive respiratory failure. The weakness is mostly proximal, and arm muscles are more involved and leg muscles (cervicothoracic radiculomyelitis) without sensory deficit. No or few signs of meningoencephalitis. Serology of CEE is positive in serum and CSF. CSF shows lymphomononuclear (20 – 60%) and polymorphonuclear (40 – 80%) pleocytosis with cell counts ranging from 63 - 2,133/mL and CSF protein from 110 - 240 g/L at initial presentation. Electrophysiological studies show LMN damage. Most patients recover completely. Fatality rates range from 0.5-5%. Prognostic factors for unfavorable outcome: rapid progression and severe paralysis at disease onset, age, respiratory failure, and concomitant involvement of cranial nerves. Differential diagnosis include: enterovirus, neuroborreliosis, axonal form of GBS, acute motor neuropathies, MG and epidural and spinal abscesses.

Myasthenia gravis: The prevalence of MG in the general population is around 0.1‰. MG is a heterogeneous autoimmune disorder with regard to age of onset of disease, serum titers of anti-AchR antibodies, and severity of clinical symptoms. The disease predominates in women (affected twice as much as men) and most commonly peaks in the 2nd - 3rd decades, while the peak age in man occurs at later age 5th - 6th decade. In 5% of patients, MG is associated with other autoimmune diseases such as autoimmune thyroiditis, RA, SLE and pernicious anemia. In a large majority of patients (80‑90%) suffering from MG, these autoantibodies are found in the serum. MG is a monophasic illness, which begins relatively acutely in most patients (often following surgery, trauma, infection or pregnancy). The hallmark of MG is fluctuating weakness and muscle fatigability, particularly of ocular muscles (initially 40% and eventually 85%). Bulbar symptoms (dysphagia or dysarthria), leg weakness and generalized weakness with fatigue and muscle pain (low back pain) are found each in about 10% of patients. The pure ocular form of MG is observed in 15‑20% of patients. About 10-15% of MG patients have a thymoma. Two tests are of immediate diagnostic help in MG: the most direct confirmatory study is the edrophonium (Tensilon) test (sensitivity 80‑90%) and the repetitive supramaximal nerve stimulation (3 Hz) of the median nerve, which reveals a decremental response of the CMAP amplitude: in about 50% of MG patients a decrement (>10% decrease in CMAP amplitude of the 5th potential vs. 1st potential) to repetitive nerve stimulation is found. However in patients with pure ocular or mild generalized weakness the test is less likely to be positive. With regards to the edrophonium test, one or preferably two reliable endpoints (ptosis, dysconjugate gaze,...) must be taken as reference. Anti-AchR antibodies are found in 70-85% of all patients with generalized MG and around 50% of patients with the ocular form. The levels of the anti-AchR antibodies do not predict the severity or clinical course of the patient. Anti-AchR antibodies are almost invariable found in patients with both MG and associated thymoma. Patients with thymoma-associated MG, late age at disease onset (mean 65 years) and with intermediate titers of anti-AchR antibodies have high prevalence (55%) of anti-titin antibodies and anti-muscle-specific tyrosine kinase. Ryanodine receptor and anti-titin antibodies present in 70% and 95% of thymoma and 14% and 58% of late onset MG, respectively. The long‑term natural course of MG is highly variable. Generalization usually develops within the first year of the disease while spontaneous long-lasting remission occurs in 10‑15% of cases, usually in the first two years of the disease. Thymectomy is generally recommended for thymoma, moderate to severe MG inadequately controlled with pyridostigmine, and those patients <55 years. An estimated 75% of MG patients will benefit from thymectomy, and the intervention appears to be most efficient the first two years of the disease. Thymectomy is classically a long-term therapy and its effect may not be apparent until after 1 year. Thymectomy appears to increase the likelihood of long-term remission and possibly reduces the long-term exposure to immunosuppressive drugs. 80% of patients will respond favorable response to steroids. Corticosteroids (1mg/kg/d in 3 divided doses e.g. 20 mg tid or 120 mg alternate days) are used in patients with moderate to severe disabling symptoms that are refractory to pyridostigmine and require hospitalization due to risk of early exacerbation (first few days of therapy and lasting about 3-4 days or 2 weeks). However transient initial severe exacerbation (10% of patients) requiring mechanical ventilation or tube feeding may occur after 1 - 3 weeks. Maximum dose should be maintained until complete remission is accomplished (about 3 months), than tapering (5-10%/month) can begin. Steroid sparing can be envisaged with azathioprine (initially 1 mg/kg/day to a maintenance dose of 2-3 mg/kg/day). Short-term effects (1-2 months) are achieved with plasmapheresis and IVIg. Improvement starts within a few days after the onset of the treatment and is meaningful after 14 days, persisting at 1 month. Mostly patients with severe disease benefit from IVIg. In patients with Osserman classification grade > 2 plasmapheresis (5 sessions on alternate day basis over 1 week, each session removing 2.5-4 L of plasma to be replaced by 5% albumin in saline (ml/ml) including 1 L of fresh frozen plasma pre-thymectomy)) is indicated pre-thymectomy. Parameters such as fibrinogen, coagulation factors, calcemia should be monitored. Anticholinergic therapy should be continued tilt the morning of the intervention (1 mg iv or im neostigmine = 30 mg pyridostigmine po, e.g 1 mg iv q4h). Prednisolone 20 mg w or w/o cyclophosphamide 50 mg can be added if required pre-thymectomy. The post-operative dose of pyridostigmine is generally 25-50% of the pre-operative dose.  In acute cases, monitoring should be done by respiratory rate, pulse oximetry, FVC (intubation if FVC<15 ml/kg), arterial blood gases every 2 hours. Cranial neuropathies (diabetes and botulism, mitochondrial disorders, hypothyroidism, myopathies or MND), Wernicke encephalopathy, MFS, ALS, SMA, LEMS and drug-induced MG need to be excluded in the differential diagnosis. Congenital MG should always be considered in patients with seronegative MG, as in those cases there is a high prevalence of autoimmune conditions like thyroid disease, polymyositis, SLE, RA and pernicious anemia.

Intracranial hypotension: Intracranial hypotension is most commonly induced post-LP, or occur spontaneous, or in CSF shunt overdrainage or following trauma or surgery. The orthostatic headache is typical and relieved by recumbency. Post-LP headache is found in up to 40% of patients after diagnostic LP. The headache begins within 72 hours or can be delayed for as long as 14 days and persists for about 5 days. Nausea and neck stiffness, interscapular pain, changes in hearing, upper limb radicular symptoms are common associated findings. Cranial nerve palsies (abducens palsy) have been reported and tend to occur between 4 to 14 days after the procedure and resolve in 4 to 6 weeks. There is a clear relationship between the diameter of the needle used and the incidence of post-LP headache. In case of IHH not caused by LP, chronic postural headache may develop and the diagnosis is based besides the clinical findings on LP (with CSF analysis) and MRI. The opening pressure at LP is either normal or <60 mmH2O (normal 60-200 mmH2O). CSF analysis can be normal or demonstrate lymphocytic pleocytosis with elevated protein. Brain and spine MRI findings include diffuse symmetric dural gadolinium meningeal enhancement also called pachymeningitis (dural vasodilatation), subdural hematomas and hygromas (70%) and acquired Arnold-Chiari type I malformation (62%) can sometimes be found. Indium-labelled albumin injected into lumbar CSF with isotopic scan of the spinal canal taken 24-48 hours later may also be diagnostic. Differential diagnosis for isolated orthostatic headaches includes spontaneous intracranial hypotension, colloid cyst of the third ventricle and post-lumbar puncture headache.

Diphtheric polyneuropathy: Apparently 10% of adults vaccinated in childhood have insufficient residual immunity. Hence occasional outbreaks of diphtheria occur in these individuals. About 15% of patients diagnosed with diphtheria develop polyneuropathy. The disease presents in two waves first the bulbar phase and a second phase the polyneuropathy.  The earliest neurological symptom is always bulbar and consists of uni-or bilateral paralysis of the palate, appearing a median of 10 days after the onset of localized throat diphtheria (sore throat).  The voice becomes nasal, regurgitation of fluids through the nose on swallowing, the larynx becomes paralyzed, allowing inhalation and choking. 20% develop respiratory failure and will need intubation. Improvement of bulbar symptoms occurs at median 30 days from onset. Blurring of vision for near objects due to paralysis of accommodation with preserved pupillary reflexes and convergence. Facial and oculomotor paresis may occur. The second wave is characterized by an acute or subacute generalized sensorimotor demyelinating polyneuropathy affecting the limbs (limb weakness with paresthesias and distal loss of position sense and vibration) occurs in 90% at a median of 37 days from onset. 50% of patients may develop severe disability and being unable to walk and 30% develop impaired bladder control. Blood pressure swings or cardiac arrhythmias reflect either autonomic neuropathy or cardiomyopathy. Rarely, diphtheric hemiplegia (vascular or acute post-infective encephalitis) and spasmodic diphtheria (meningitis with opisthotonos) develop. The diagnosis is predominantly clinical and can be confirmed by throat cultures which are positive in 98%. CSF protein is usually elevated (50-200 mg/dl). The major differential diagnosis is GBS and MG. Survival has increased substantially. Limb symptoms persist in 80% of patients at 1 year. Diphtheric antitoxin given within 48h of the onset of the infection reduces the incidence and severity of the neuropathy. In addition antibiotherapy needs to be given, preferably erythromycin. Repeated culture (swabs) need to be taken until they are negative.

Critical illness polyneuropathy (CIP):

Acute quadriplegic myopathy:

Headache disorders: