Meningitis

Introduction - Meningitis is an inflammatory disease of the leptomeninges, the tissues surrounding the brain and spinal cord, and is defined by an abnormal number of white blood cells in the cerebrospinal fluid.

Clinical Manifestations - Patients with bacterial meningitis are often so ill that they will present soon after symptom onset. The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status. The headache is another common symptom and is usually worse than the patients usual headache. Nuchal rigidity can be demonstrated by the following physcial examiniation techniques.

• Brudzinski sign (figure B) - spontaneous flexion of the hips during attempted passive flexion of the neck.
•  Kernig sign (figure A) - inability or reluctance to allow full extension of the knee when the hip is flexed 90 degrees.

Aseptic meningitis often has a similar presentation to bacterial meningitis (eg, fever, headache, altered mental status, stiff neck, photophobia), which can be a life-threatening illness. However, in contrast to bacterial meningitis, the majority of patients with aseptic meningitis have a self-limited course that will resolve without specific therapy. In my experience, patients with bacterial meningitis are very sick and will seek medical attention quickly after the onset of symptoms.

Diagnosis - Lumbar puncture!!! Examination of the cerebrospinal fluid is crucial for establishing the diagnosis of bacterial meningitis. There are situations where you need to get a CT of the head before you get an LP. CT of the head is indicated if the patient has one or more of the following...

• Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation)
• History of central nervous system (CNS) disease (mass lesion, stroke, or focal infection)
• New onset seizure (within one week of presentation)
• Papilledema or any signs of raised intracranial pressure
• Abnormal level of consciousness
• Focal neurologic deficit

If LP is delayed needs to be delayed while the patient is getting a CT of the head, blood cultures should be obtained and antimicrobial therapy should be administered empirically before the patient goes for the CT and the LP should be done as soon as possible when the patient is cleared from the CT of the head. Dexamethasone may be given before or at the same time as the antimicrobials if the labs and clinical picture is highly suspicious of bacterial meningitis. Empiric antibiotics will not effect the cytology of the CSF but it may effect the gram stain and culture.

CSF Analysis

Opening pressure -The opening pressure is typically elevated in patients with bacterial meningitis (>200 mmH2O).

False-positives - It is important to note that a false-positive elevation of the CSF white blood cell count can be found after traumatic lumbar puncture or in patients with intracerebral or subarachnoid hemorrhage in which both red blood cells and white blood cells are introduced into the subarachnoid space. Generalized seizures may also induce a transient CSF pleocytosis mainly neutrophils.
A Gram stain of the CSF should be obtained whenever there is suspicion of bacterial meningitis. It has the advantage of suggesting the bacterial etiology one day or more before culture results are available .

•  Gram-positive diplococci suggest pneumococcal infection
• Gram-negative diplococci suggest meningococcal infection
• Small pleomorphic gram-negative coccobacilli suggest Haemophilus influenzae infection
• Gram-positive rods and coccobacilli suggest Listeria infection

 Treatment

If the patient has no immunodeficiency

Ceftriaxone or Cefotaxime - 2 g IV every 12 hours

PLUS

Vancomycin - 15 to 20 mg/kg IV every 8 to 12 hours

PLUS

Ampicillin (in adults greater than 50yrs of age) - 2 g IV every four hours

If the patient has an immunodeficiency

Vancomycin - 15 to 20 mg/kg IV every 8 to 12 hours

PLUS

Ampicillin - 2 g IV every four hours

PLUS

Cefepime/Meropenem - 2 g IV every eight hours


If the patient is allergic to Beta-Lactams

Vancomycin - 15 to 20 mg/kg IV every 8 to 12 hours

PLUS

Moxifloxacin -  400 mg IV once daily

PLUS

Trimethroprim-Sulfamethoxazole (if the patient is older than 50 years of age and needs covereage for Listeria) - 5 mg/kg IV every 6 to 12 hours

Transverse Myelitis

Introduction - Acute transverse myelitis is a spinal cord disorder that may present with the rapid onset of weakness, sensory alterations, and bowel or bladder dysfunction. TM can occur as an independent entity, most often a postinfectious complication, but TM may occur along with neuro-inflammatory disorders such as acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica. It is important in the evaluation of patients with acute myelopathies to exclude compressive and noninflammatory causes of myelopathy because the treatment options will vary depending on the etiology. Compressive etiology may require urgent neurosurgery!

Differentiating TM from acute inflammatory demyelinating polyneuropathy (AIDP) - Patients with acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barre syndrome) may also present with progressive sensory and motor dysfunction. There are several features that may be used to rapidly discriminate patients with AIDP from those with acute myelopathies.

• Patients who have AIDP often have both upper and lower extremity involvement. In contrast, patients with myelopathy will have dysfunction that is specific to the level of myelopathy. 
• Patients with myelopathy are more likely to have urinary or bowel urgency or retention, while those with AIDP are more likely to have cardiovascular instability. 
• A sensory level is often definable in patients with acute myelopathy but is never present in AIDP. 
• Cerebrospinal fluid analysis in AIDP usually shows an elevated protein with few white cells (this is known as cyto-albuminologic dissociation) whereas patients with TM may have an inflammatory cerebrospinal fluid with an elevated number of white blood cells and IgG index. 
• Spinal MRI imaging often shows a discrete lesion in myelopathy, whereas spinal MRI is normal in AIDP. 
• Electrodiagnostic studies may show conduction block or slowed conduction of peripheral nerves in AIDP and are usually normal in myelopathies.

Etiology

In 30 to 60 percent of the idiopathic TM cases, there is an antecedent respiratory, gastrointestinal, or systemic illness. In parainfectious TM, the injury may be associated with direct microbial infection of the central nervous system, or with the systemic response to infection by a variety of agents such as varicella zoster virus, herpes virus, and Listeria. TM may be associated with central nervous system vasculitis or infarction/ischemia of the spinal cord.  Alternatively, TM can be directly associated with infectious, systemic inflammatory, or multifocal central nervous system disease.

Although idiopathic TM usually occurs as a postinfectious complication that appears to result from an autoimmune process, TM can be directly associated with infectious, systemic inflammatory, or multifocal central nervous system disease.
Acquired central nervous system autoimmune disorders that can cause TM include multiple sclerosis, neuromyelitis optica, and acute disseminated encephalomyelitis.

• Multiple Sclerosis - TM can occur as part of the spectrum of multiple sclerosis. 
• Neuromyelitis Optica - TM manifesting as a longitudinally extensive spinal cord lesion spanning three or more vertebral segments is one of the characteristic findings of neuromyelitis optica. NMO antibodies may be ordered if this is suspected. 
• Disseminated Encephalomyelitis - TM may be seen in patients with acute disseminated encephalomyelitis, a demyelinating disease of the central nervous system.

Other central nervous system conditions that can cause TM are as follows:
- Infections including but not limited to West Nile virus, herpes viruses, HIV, HTLV-1, Lyme, Mycoplasma, Syphilis, Paraneoplastic syndromes and Neurosarcoidosis

 Systemic inflammatory autoimmune disorders that are associated with TM include the following:
-Ankylosing spondylitis
-Antiphospholipid antibody syndrome
-Behcet disease
-Mixed connective tissue disease
-Rheumatoid arthritis
-Scleroderma
-Sjogren syndrome
-Systemic lupus erythematosus

CLINICAL FEATURES — The onset of TM is characterized by motor, sensory and/or autonomic dysfunction (bowel, bladder, and sexual dysfunction). Motor symptoms include a rapidly progressing paraparesis with initial flaccidity followed by spasticity. The patient may describe sensory symptoms such as pain, dysesthesia, and paresthesia. Autonomic symptoms include increased urinary urgency, bladder and bowel incontinence, difficulty or inability to void, constipation, and sexual dysfunction.

MRI of the spinal cord typically shows a gadolinium-enhancing signal abnormality (seen in the image below), usually extending over one or more cord segments. The cord often appears swollen at the affected levels.



-Cerebrospinal fluid (CSF) is abnormal in approximately one-half of patients, with a moderate lymphocytosis and an elevated protein level

The diagnosis of TM is suspected when there are acute or subacute signs and symptoms of motor, sensory and/or autonomic dysfunction that localize to one or more contiguous spinal cord segments in patients with no evidence of a compressive cord lesion. Thus, the diagnosis of TM requires exclusion of a compressive cord lesion, usually by MRI, and confirmation of inflammation by either gadolinium-enhanced MRI or lumbar puncture.


Diagnostic criteria
Sensory, motor or autonomic dysfunction attributable to the spinal cord
Bilateral signs and/or symptoms
Clearly defined sensory level
No evidence of compressive cord lesion
Inflammation defined by cerebrospinal fluid pleocytosis or elevated IgG index or gadolinium enhancement



Treatment
Steroids
IVIG
Plasmapharesis

Wernike-Korsakoff syndrome - or Wernicke's encepatholopathy and Korsakoff's syndrome

 

I am now on the General Neurology service which has been very interesting compared to the stroke service. I had a patient with transverse myelitis and another with Wernike-Korsakoff syndrome today! Pretty interesting for my first day!

 

Introduction - Wernicke-Korsakoff syndrome is the best known neurologic complication of thiamine/vitamin B1 deficiency. The term is a combination of two different syndromes, each representing a different stage of the disease. Wernicke's encephalopathy is the acute syndrome which requires emergent treatment (thiamine and glucose) to prevent death and neurologic morbidity. Korsakoff's syndrome refers to a chronic neurologic condition that usually occurs as a consequence of WE.

 

Etiology - Although Wernike-Korsakoff is most often associated with chronic alcoholism, it can also occur in the setting of poor nutrition caused by malabsorption, poor dietary intake, increased metabolic requirement (cancer or systemic illness/inflammation) or increased loss of the water-soluble vitamin thiamine (eg, in renal dialysis). My patient has both a history of chronic ETOH abuse as well as a gastric bypass 8 years ago. Causes of Wernike-Korsakoff are listed below.

 

-Chronic alcoholism

-Anorexia nervosa or dieting

-Hyperemesis of pregnancy

-Prolonged intravenous feeding without proper supplementation

-Prolonged fasting or starvation, or unbalanced nutrition, especially with refeeding

-Gastrointestinal surgery (including bariatric surgery)

-Systemic malignancy

-Transplantation

-Hemodialysis or peritoneal dialysis

-Acquired immunodeficiency syndrome

 

Pathophysiology - It is unclear how thiamine deficiency causes brain lesions. Thiamine is a cofactor for several key enzymes important in energy metabolism such as transketolase, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase (You need to give thiamine before you give glucose in these patients). Because of its role in cerebral energy utilization, it has been proposed that its deficiency initiates neuronal injury by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover. 

 

Pathology - Acute lesions are characterized by vascular congestion, microglial proliferation, and petechial hemorrhages. In chronic cases, there is demyelination and gliosis. You will see neuronal loss most prominently in the unmeylinated areas of the medial thalamus. Necrosis/Atrophy of the mamillary bodies is a highly specific finding in chronic WE and Korsakoff syndrome and is present in up to 80 percent of cases. The lesions of WE occur in a characteristic, symmetrical distribution in structures surrounding the third ventricle, aqueduct, and fourth ventricle.

 

Clinical Manifestations

 

The classic triad of WE is encepthalopathy, gait ataxia and oculomotor dysfunction.

 

- Encepathopathy - characterized by profound disorientation, indifference, and inattentiveness. If these are less severe and permit higher cognitive testing, impaired memory and learning are also evident. My patient was attentive but didn't know where she was exactly and didn't have any insight as to why she was in the hospital. She seemed to think it was about 20 years ago when she still lived with her mom and dad (who had passed 15 years ago).

 

-Oculomotor dysfunction - Nystagmus, lateral rectus palsy, and conjugate gaze palsies reflect lesions of the oculomotor, abducens, and vestibular nuclei. Nystagmus is the most common finding and is typically evoked by horizontal gaze to both sides. My patient had horizontal nystagmus that was evident when she looked both to the right and to the left.

 

-Gait ataxia - When the WE is severe, walking is impossible. Less affected patients walk with a wide-based gait and slow, short-spaced steps. The portion of the cerebellum often affected is the vermis so you will see more truncal ataxia and less ataxia of the arms and the legs.

 

Treatment

 

Immediate parenteral administration of thiamine is the course of treatment in any patient that has suspected WE. A recommended regimen is 500 mg of thiamine intravenously, infused over 30 minutes, three times daily for two consecutive days and 500 mg intravenously or intramuscularly once daily for an additional five days, in combination with other B vitamins. Daily oral administration of 100 mg of thiamine should be continued after the completion of parenteral treatment and after discharge from the hospital until patients are no longer considered at risk. My patient has finished her IV thiamine and is now on 100mg PO daily. She will continue this regimen as an outpatient. 

Multiple sclerosis

Multiple sclerosis is the most common autoimmune inflammatory demyelinating disease of the central nervous system. It tends to affect women of the Northern European descent in their 20-40s. The pathologic feature of MS is multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring as well as axonal injury.

Diagnosis - MS is a clinical diagnosis. The typical patient is a young adult with either focal or multifocal neurologic deficit that often follow a relapsing remitting pattern. There are no distinct symptoms that are only seen with MS but there are classic clinical findings listed below.

Optic neuritis - is the most common type of involvement of the visual pathways. It usually presents as acute or subacute unilateral eye pain that is accentuated by movement of the eye. This is followed by a variable degree of visual loss affecting mainly central vision. Physical examination of patients with Optic Neuritis reveals a relative afferent pupillary defect (Marcus Gunn pupil). Desaturation of color (particularily red) is a common finding as well.

Internuclear ophthalmoplegia -  Internuclear ophthalmoplegia refers to abnormal horizontal ocular movements with lost or delayed adduction and horizontal nystagmus of the abducting eye. It is caused by a lesion of the medial longitudinal fasciculus on the side of diminished adduction. Convergence is preserved.

Sensory symptoms - Sensory symptoms are a common in MS. Symptoms are commonly described as numbness, tingling, pins-and-needles, tightness, coldness, or swelling of the limbs or trunk. Radicular pains also can be present, particularly in the low thoracic and abdominal regions. An intensely itching sensation, especially in the cervical dermatomes and usually unilateral, is suggestive of MS.

Lehermitte Phenomenon - Described as transient sensory/pain symptom that can be described as radiating down the spine or into the limbs with flexion of the neck and is commonly seen in MS

Vertigo - Vertigo is a reported symptom in 30 to 50 percent of patients with MS.

Motor symptoms - Paraparesis or paraplegia is more common than significant upper extremity weakness in patients with MS due to the lesions in the descending motor tracts of the spinal cord. Severe spasticity can occur when attempts to move the extremities occurs such as getting out of bed or a chair.

Coordination - Gait imbalance, difficulty in performing coordinated actions with the arms, and slurred speech may occur as a result of impairment of cerebellar pathways. Physical examination typically reveals dysmetria, decomposition of complex movements, and hypotonia, most often observed in the upper extremities. An intention tremor may be noted in the limbs and in the head. Walking is impaired by truncal ataxia.

Bowel/bladder/sexual function - Bowel, bladder, and sexual dysfunction are common in MS. The extent of sphincter and sexual dysfunction often parallels the degree of motor impairment in the lower extremities. The most common urinary complaint is urgency. Urinary incontinence becomes more common as the disease progresses, and an atonic dilated bladder that empties by overflow can be the end result.

Fatigue - Fatigue is a characteristic finding in MS, usually described as physical exhaustion that is unrelated to the amount of activity performed. Many patients complain of feeling exhausted on waking, even if they have slept soundly. Fatigue can also occur during the day but may be partially or completely relieved by rest. In addition, there appears to be a correlation between fatigue and disrupted sleep in MS patients.

Depression - depression is the most affective disturbance in MS. Depression may be more common in patients with MS than in others with chronic medical conditions. It is not known whether depression in MS patients reflects a comorbid association with bipolar illness or an effect of frontal or subcortical white matter disease.

Epilepsy - Epilepsy is more common in patients with MS than in the general population, occurring in 2 to 3 percent of patients. Convulsions may be either tonic-clonic in nature or partial complex.


McDonald criteria - The McDonald criteria can only be applied after careful clinical evaluation of the patient. The core requirement of the diagnosis is the objective demonstration of dissemination of central nervous system (CNS) lesions in both space and time, based upon either clinical findings alone or a combination of clinical and MRI findings.

• Dissemination in space - demonstrated on MRI by one or more T2 lesions in at least two of four MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) or by the development of a further clinical attack implicating a different central nervous system site. For patients with brainstem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count.

• Dissemination in time - demonstrated on MRI by the simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time, or a new T2 and/or gadolinium-enhancing lesion on follow-up MRI, irrespective of its timing with reference to a baseline scan, or by the development of a second clinical attack.

Lesion characteristics - The characteristic lesion demonstrated on MRI is the cerebral or spinal plaque. Histological examination of active plaques reveals perivascular infiltration of lymphocytes and macrophages.

Cerebrospinal fluid analysis -  Qualitative assessment of cerebrospinal fluid for oligoclonal IgG bands using electrophoresis is an important diagnostic CSF study when determining a diagnosis of MS. The immunoglobulin increase is predominantly IgG.

Treatment - A number of medications are available as disease modifying therapy which includes interferon beta drugs, glatiramer acetate, fingolimod, teriflunomide, mitoxantrone. Natalizumab  is approved as monotherapy only.

Imaging in stroke setting

CT without contrast- the large benefit of ordering this test is that it is very fast at determining if there was any intracranial hemorrhage which is important because the management of a stroke secondary to intracranial hemorrhage is very different than the management of an ischemic stroke. CT angiography and CT perfusion study has been added to the work up of stroke and has been shown to improve the detection of an acute infarction than using CT without contrast alone. In addition, the CTA and CTP may indicate the status of the vasculature and may show an occlusion in the vessel.

CT angiography — CT angiography (CTA) is performed by administering a bolus of standard intravenous CT contrast. The helical CT scan is timed to capture the arrival of dye into the brain. For the detection of intracranial large vessel stenosis and occlusion, CTA in various studies had sensitivities of 92 to 100 percent and specificities of 82 to 100 percent when compared with conventional angiography.

MRI - Has the advantage for further categorizing the stroke patients that may benefit from TPA and intravascular treatments. Studies that combines conventional MRI with diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI) can reliably diagnose both acute ischemic stroke and acute hemorrhagic stroke in emergency settings

Diffusion-weighted imaging (DWI)— DWI is based upon the capacity of fast MRI to detect a signal related to the movement of water molecules and  can detect abnormalities due to ischemia within 3 to 30 minutes of onset. In acute stroke, swelling of the ischemic brain parenchymal cells follows failure of the energy-dependent Na+/K + – ATPase pumps and is believed to increase the ratio of intracellular to extracellular volume fractions which will cause the DWI to detect abnomalities.

Perfusion Weighted Image - Diffusion-weighted imaging reveals evidence of ischemic injury, not ischemia itself which PWI will aid in. Perfusion-weighted imaging (PWI) uses fast MRI techniques to quantify the amount of MR contrast agent reaching the brain tissue after a fast intravenous bolus. Integration of the amount of gadolinium entering the brain on first pass allows construction of maps of cerebral blood volume as well as the transit time that it takes for the dye to reach and wash out of the tissue.

MR Angiogram - MR angiography (MRA) to detect vascular stenosis or occlusion is done at many centers as part of a fast MRI protocol for acute ischemic stroke. Results from a case series showed that the combined use of DWI with MRA within 24 hours of hospitalization substantially improved the early diagnostic accuracy of ischemic stroke subtypes. Most of my patients on the stroke service will get a MRA of the head and neck.

Peripheral Neuropathy

Definition - A disease process affecting many peripheral nerves (nerves outside the CNS), with the distal nerves affected most prominently. The clinical presentation is typically characterized by symmetric distal sensory loss, burning, or weakness.

Etiology - The peripheral nerves are susceptible to a variety of toxic, inflammatory, hereditary, infectious, and parainfectious factors that can impair their function, leading to polyneuropathy. 

• Diabetic - Poor glycemic control leads to the accumulation of advanced glycosolation products which, simply, produce an inflammatory state and can cause damage to blood vessels, organs nerves (peripheral nerve in the case of diabetic peripheral neuropathy)
• Uremia
• Long-standing HIV infection
• Amyloidosis 
• Vitamin deficiency such as B12 and folate 
• Long-standing hypothyroidism
• Lyme Disease
• Guillian-Barre Syndrome -  an acute neuropathy, usually provoked by a preceding infection. The preceding infection causes autoantibodies to form and are directed towards the myelin sheath or axon of the peripheral nerves causing inflammation and damage. 
• Toxic exposure - history of chemotherapy, alcoholism or heavy toxic metals
• Hereditary - Charcot-Marie-Tooth is an X linked genetic disorder causing demyelination of the peripheral nerves. Other genetic diseases include metabolic diseases of childhood, such as Krabbe's disease, metachromatic leukodystrophy, and adrenoleukodystrophy
• Environmental - prolonged cold exposure and hypoxemia
• Idiopathic

History of Illness

• Chronic Polyneuropathies are slow in progression. Injury tends to be related to axon length. The longer axons are affected first, resulting in symptoms that begin in the lower extremities. Sensory symptoms usually precede motor symptoms. Patients will present with progressive sensory loss and complain of  numbness, a burning sensation and pain in the feet. As the syndrome progresses, the motor function begins to be affected and the patient will complain of mild weakness of the lower legs and hand.
• Acute Polyneuropathies - usually secondary to toxic exposures such as metals and pophyrias. The predominant symptom is pain over numbness and tingling and the symptoms are more fulminant and rapidly progressive 2-3 weeks often followed by a period of recovery follows in a few months. 

Physical Examination

Motor and sensory deficits will predominate depending on if the neuropathy is secondary to axonal damage or demyelination. In patients with axonal neuropathy, there may be intrinsic muscle wasting of the hands and feet as well as decreased sensation to light touch, pinprick, vibration and proprioception. In the case of neuropathy secondary to demyelination, generalized weakness is the more common physical exam finding and the distal muscles are more commonly affected. 

Diagnosis

EMG or nerve conduction studies are a good first diagnostic test in patients where there is not a clear etiology. Lab tests such as A1C, thyroid and B12/Folate are useful. Nerve biopsy is reserved for patients in the situation where it is difficult to diagnose whether the disease is demyelinating versus axonal. 

Seizure

This is a very large topic and an important one! I am currently on the stroke service right now but will be starting the general neurology service in one week so I wanted to attempt to get a solid foundation of seizures before jumping in.

Definition - A seizure is a sudden change in behavior that is the consequence of brain dysfunction. Seizures can be divided into different categories…

-Epileptic Seizures - result from electrical hyper synchronization of neurons in the cerebral cortex. There are different classes of epileptic seizures and are named according to how they present such as simple partial (consciousness not impaired), complex partial (consciousness impaired) and generalized (involving the entire cortex). Epilepsy the disease is characterized by recurrent epileptic seizures due to a genetically determined or acquired brain disorder. Approximately 0.5 to 1 percent of the population has epilepsy.

-Provoked seizures - some seizures are provoked and occur secondary to alcohol or drug withdrawl, metabolic derangements, strokes or encephalitis. These patients are not considered to have epilepsy because the seizure would not occur in the absence of any of the above situations.

-Nonepileptic seizures - sudden changes in behavior that appear to be epileptic in nature (epileptic imitators) but are not associated with the same neurophysiologic changes seen in epilepsy

After looking at the groupings of seizures, one can see that a primary goal when assessing the cause of the patient’s seizure, is to understand whether it occurred secondary to a treatable systemic process (provoked) or if this is secondary to a true dysfunction of the neuronal network (epilepsy). If it is due to a dysfunction of the CNS, the nest step would be to figure out the underlying brain pathology. These are all important steps when decided the treatment plan.

Etiologies

Epilepsy

-Head trauma

-Brain tumors

-intracranial infection

-cerebral degeneration

-stroke

-congenital malformation

-inborn errors of metabolism

Nonepileptic seizures (imitators or epileptic seizures) – etiologies divided into age groups

Neonates – apnea, jitterinus, hyperplexia and benign neonatal sleep myoclonus

Infants – breath holding spells, benign myoclonus of infancy, shuddering attacks, torticollis and rhythmic movement disorder.

Children - Breath-holding spells, Vasovagal syncope, Migraine, Benign paroxysmal vertigo, Staring spells, Tic disorders and stereotypies, Rhythmic movement disorder, Parasomnias

Adolesence - Vasovagal syncope, Narcolepsy, Periodic limb movements of sleep, Sleep starts, Paroxysmal dyskinesia, Tic disorders, Hemifacial spasm, Stiff person syndrome, Migraine, Psychogenic nonepileptic pseudoseizures, Hallucinations

Adults - Cardiogenic syncope, Transient ischemic attack, Drop attacks, Transient global amnesia, Delirium or toxic-metabolic encephalopathy, Rapid eye movement sleep disorder

Clinical Features

As always, a good history and physical is important to formulate a diagnosis. Questions to ask…

Triggers?  Strong emotions, intense exercise, loud music or flashing lights? Interestingly, in 1997 the cartoon Pokemon caused in Japan 685 children out of 7 million viewers to seek medical attention for neurological symptoms and about 80% of the cases were diagnosed as seizures. Three fourths of the cases included first time seizure activity. The stimuli that caused these photic-induced seizures appear to be identifiable because the British and Japanese government have guidelines restricting the use of certain signals on television.

Auras? An aura (sound, light, smell and sensation distortion) is something that occurs when enough of the brain has been affected to cause it but not affected enough to cause loss of consioucness. Auras fall under the category of simple-partial seizures.

Loss of Consciousness? Loss of consciousness occurs in complex partial seizures and generalized seizures. Complex partial seizures are the most common type of seizure in epileptic adults. Patients often appear to be awake but are not consciousness. They often seem to stare into space and either remain motionless or engage in repetitive behaviors, called automatisms, such as facial grimacing, gesturing, chewing, lip smacking, snapping fingers, repeating words or phrases, walking, running, or undressing. Patients may become hostile or aggressive if physically restrained during complex partial seizures. Generalized seizures involve more than one portion of the brain rather than a focal portion and include absence seizures and generalized tonic-clonic seizures. Absence seizures can cause impaired consicouness along with staring spells. They occur in clusters, are short in duration (usually less than 10 seconds) and can happen multiple times a day. Tonic clonic siezures are the most dramatic type of seizure. They being with an abrupt loss of consciousness often in conjunction with a scream or a shriek. All of the muscles of the arms and legs as well as the chest and back then become stiff which is considered to be the tonic phase. After approximately one minute, the muscles begin to jerk and twitch for an additional one to two minutes. During this clonic phase the tongue can be bitten, and frothy and bloody sputum may be seen coming out of the mouth. The postictal phase begins once the twitching movements end. In the post-ictal state, the patient returns to consciousness and is groggy, confused and may have some residual aphasia or sensory loss.

Other questions to ask…

Medication history?

Family history of neurologic disease?

Drug or alcohol use?

History of head trauma?

History of intracranial infection?

Acute management of seizure

Most seizures do not need medical intervention and remit on their own. If the seizures are lasting 5-10 minutes or are occurring in close enough proximity and prevent the patient from returning to interictal baseline, then benzos or anti-epileptic drug (AED) is warranted. The first episode of a seizure, especially if it was provoked, is not enough to consider starting an AED. After the second seizure, AED is usually started. 

All of this research came from UptoDate

Toxic-Metabolic Encephalopathy

Acute toxic-metabolic encephalopathy (TME) is an acute condition of global cerebral dysfunction in the absence of primary structural brain disease.  There are many canuses of TME, however, it is usually secondary to a systemic illness. Most TME is reversible, making prompt recognition and treatment important because there are specific metabolic encephalopathies, such as thiamine deficiency (Wernicke's encephalopathy), that may result in permanent structural brain damage if untreated. Alcohol withdrawal syndromes must be excluded in patients with suspected TME

 

Pathology - All the etiologies of acute toxic-metabolic encephalopathy (TME) interfere in some way with the function of the ascending reticular activating system and/or its projections to the cerebral cortex which then causes a problem with the patient's consciousness/awareness. The pathophysiology behind the TME differs depending on the underlying etiology such as...

 

- Cerebral edema occurs in the setting of acute fulminant hepatic encephalopathy and hypoossmolar encephalopathies.

 

- Disruption of the balance of neurotransmitters (dopamine, serotonin, GABA and acetylcholine) can cause drug-induced delirium.

 

-Neuronal death can occur from nutritional disorders which can impair normal cellular metabolism

 

-Exogenous toxins such as CO and CN can lead to impairment of mitochrondrial function and decrease delivery of O2 to the brain.

 

-Increased blood-brain barrier permeability may lead to an increase in systemic toxins leading to impariement in neuronal function. Patients who have increased permeability in the BBB may have a larger amount of protein in the CSF fluid.

 

Clinical Manifestations - The manifestations are varied and generalized depending on the etiology. The symptoms can be broken down into categories.

 

-Mental status - impaired attention and fluctuation in attention, disturbed sleep-wake cycle, decreased alertness, hypervigilance, hallucinations, sensory misperceptions, impaired memory,apathy, mania and disorientation

 

-Seizures - usually are generalized clonic-tonic but can also be focal, multifocal or partial complex

 

-Cranial nerve examination - Almost all the causes of TME will leave the patient with intact pupillary function except in the cases of anticholinergic or glutethimide ingestion. Other brainstem reflexes such as gag, oculocephalic or corneal reflex typically remain intact and are only affected in severe TME

 

-Motor examination - a variety of motor abnormalities can be see in TME such as tremor, as

terixis, multifocal myoclonus, primitive reflexes, brinsk deep tendon reflexes and extensor plantar reflexes.

 

-Autonomic instability such as tachycardia, hypertension, fever, diaphoresis is characteristic in delirium

Specific Etiologies

-Septic Encephalopathy - This is THE MOST COMMON CAUSE of acute TME

 

-Hepatic encephalopathy - normal ammonia levels does not exclude the diagnosis

 

-Uremic encephalopathy

 

-Hyponatremia - Hypernatremia

 

-Hypoglycemia

 

-Hyperosmolar hyperglycemia and diabetic ketoacidosis

 

-Wernicke's Encephalopathy - secondary to a thiamine deficiency and may see the classic triad of confusion, ataxia and opthalmoplegia

 

-Hypoxic-ischemic encephalopathy - Hypoxic-ischemic encephalopathy is usually a straightforward diagnosis that follows an obvious precipitating event such as cardiac arrest with prolonged resuscitation efforts

 

-Post-transplantation encephalopathy - Encephalopathy following transplantation may be due to underlying conditions, operative procedures, immunosuppressive medications, cranial radiation, or opportunistic infections

 

Medications - Most immunosuppressant medications used following transplantation are capable of producing encephalopathy: Cyclosporin, steroids, tacrolimus.

 

Diagnsosis - TME is a diagnosiss of exclusion. Tests that would be helpful would be...

 

Laboratory studies - complete blood count, coagulation studies, electrolyte panel, and examination of calcium, magnesium, phosphate, glucose, blood urea nitrogen, creatinine, bilirubin, liver enzymes, ammonia, serum osmolality, and arterial blood gases, toxicologic screening should be performed for suspected intoxications, and blood and CSF cultures obtained if infection appears present. Thyroid function tests, vitamin B12 and serum cortisol concentrations should be assessed if endocrinopathy is in the differential diagonosis.  

 

Neuroimaging - CT or MRI of the head is indicated when focal signs are present on physical examination or when subdural hematoma is suggested by the history.

 

Electroencephalography — The electroencephalogram (EEG) can both confirm global cerebral dysfunction and exclude subclinical seizures with greater sensitivity than clinical examination alone

 

Treatment - the best treatment is to treat the underlying cause of the TME. A thourough check of the medication list would be helpful. Give thiamine for patient's suspicious of wernickes encephalopathy as well as patients on hemodialysis, malnutrition, cancer and hyperemesis gravidarum. Can give haloperidol for agitation but avoid halopaeridol in cases of alcohol withdrawal, anticholinergic toxicity, and benzodiazepine withdrawal, and also in patients with parkinsonism

Cerebral Amyloid Angiopathy

In the Neuro ICU, cerebral amyloid angiopathy (CAA) gets blamed a lot in elderly patients as a cause of their hemorrhagic stroke. Although I am familiar with the disease, I thought I should revisit it.

 CAA is characterized by amyloid beta peptide deposits in the blood vessels of the brain. The deposits weaken the blood vessel wall and makes it prone to bleeding.  It can occur as a sporadic disorder, in association with Alzheimer’s disease or as a familial syndrome. CAA can cause intracerebral hemorrhage, transient neurological symptoms, hemosiderosis, incidental microhemorrhages or cognitive impairment.

 Epidemiology – the incidence is largely age dependent and is uncommon at ages younger than 60-65.


Pathogenesis – The vascular deposits in CAA consist of an amyloid beta-peptide. There has been an APP mutation identified which has been shown to cause AD CAA. Other side effects of the mutated APP is producing an amyloid protein that is unable to be degraded by proteasomes or producing an amyloid protein that has more of a toxic effect on the vascular wall. There is growing evidence from studies that support a link between CAA and the alleles of the Apolipoprotein E gene. Patients who carry the APO epsilon 2 or epsilon 4 allele correlate with a higher risk for CAA. Other factors likely contributing to CAA include pt’s who over express cytokines such as TGF.


Presenting Features – The most common presenting feature of CAA is spontaneous lobar hemorrhage which is located in the cortex and subcortical white matter and sparing of the areas that are affected more by hypertensive hemorrhages such (basal ganglia, thalamus or the pons).  Spontaneous hemorrhage secondary to CAA is more likely to happen in the posterior portion of the brain. A reason for this particular deposition of the amyloid proteins in the posterior circulation is unknown, but may be due to an undiscovered characteristic of the posterior circulation that would decrease the elimination of the beta amyloid deposits. Other clinical manifestations include seizure, headache, hemiplegia and depressed consciousness. Patients may also complain of transient symptoms such  as a recurrent, brief (about 10 minutes) episodes of weakness, numbness or paresthesias.


Diagnostic criteria – CAA should be suspected in patients over the age of 60 who have multiple lobar hemorrhages in the absence of an obvious cause. The true diagnosis can only be definitive with a post-mortem autopsy but there are two approaches to give a probable diagnosis during life such as a gradient-echo MRI and an examination of the tissue (brain biopsy which is rarely done). A gradient-echo MRI will accentuate the signal dropout caused specifically by iron-containing deposits left by old hemorrhages.


Treatment – similar to the treatment of other acute intracerebral hemorrhages by paying attention to the ICP and controlling the blood pressure and surgical hematoma resection.  After diagnosis, patients are to avoid anticoagulation medication such as Warfarin and Aspirin.


Other bits I learned today…

 -Primary Lateral Sclerosis (PLS) is similar to ALS but only involves the upper motor neuron and survival is better than ALS

 - A Jannetta procedure is something that can be done for trigeminal neuralgia. It involves a craniotomy and the removal or separation of various vascular structures, often an ectatic superior cerebellar artery, away from the trigeminal nerve.

Amaurosis Fugax

I love that word, Amaurosis Fugax. It comes from the Greek word "amaurosis" which means dark and the Latin word "fugax" which means fleeting (an appropriate name for someone experiencing transient vision loss. It is not on my Neurology wish list of topics to cover but I had a patient with this today and thought it would be a good little topic. Neurology has been going well so far but has very long hours and assigned readings. I am exhausted by the end of the day and am afraid that this one new topic a day may be every other day instead. I will do my best!

A brief case description of my patient today. She is a 68 yo female with a Pmhx of HLD and hypothyroidism who presented to the ED with a cc of right intermittent monocular visual loss. It started 4 days ago when was paying bills that the patient had a sudden painless loss of vision or "graying" as she described it. Pt had no HA, stroke-like symptoms, nausea, vomiting, tremors or loss of conciousness. The episode lasted about one minute and vision fully resolved. Pt again experienced a similar episode later that day that lasted longer but her vision returned to normal. She went to work the next day and while sitting at the computer she had a similar episode which only caused visual loss in her right lower and temporal visual field and didn't fully resolve. She went to an opthomologist who did a fundoscopic exam and they found a few Hollenhorst plaques in the right retinal artery. She came to the ED and was admitted to our service for treatment and r/o of stroke as well as temporal arteritis. CT of the head and neck was negative, CTA showed mild atherosclerosis of the right internal carotid, MRI was normal, EKG showed NRS, TTE bubble study was pending and SED rate and CRP were negative. 

 Questions to ask the patient

• Was the vision loss monocular or binocular? It is important to establish whether the visual loss was monocular or binocular. Transient monocular visual loss points to pathology anterior to the optic chiasm (eye, optic nerve, optic artery) which could be a disease of the eye itself or ischemia secondary to atherosclerosis of the ipsilateral internal carotid. Transient binocular visual loss suggests a more posterior process, involving the optic chiasm, tracts, or radiations, or the visual cortex. Patients with homonymous visual field defects often report monocular visual loss and attribute it to the eye with the temporal field cut. 
• How long did the episode last? Episodes lasting seconds can be caused by papilledema. Episodes lasting 1-15 minutes is more consistent with thromboembolic disease (this is what the patient was experiencing). Episodes lasting 30 minutes or longer with headache points more towards a migraine with aura. 
• Description of the visual symptoms - Transient visual loss secondary to any cause can be described as blurring or fogging (I think of how my patient described it as a "graying") to complete blackness and it can involve the entire visual field or just parts of it. The description of the loss of vision as field of vision as a curtain being pulled down over eye is highly suggestive of retinal ischemia. Positive visual phenomena, such as photopsias or scintillations that march across the visual field, suggest migraine as the most likely diagnosis. Seizures affecting visual cortex often involve positive visual symptoms, but are typically maximal at onset and lack the evolution or build-up characteristic of migraine. Patients who experience viual loss due to hemorrhage of the anterior chamber may describe that the visual field appears red (erythropsia) during the episodes. 

Causes of Amaurosis Fugax

Monocular

• Ischemia - The end result of all the following disorders is ischemia to the retina, the optic nerve, or both. The disease include Large artery occlusive disease (atherothrombosis, embolus, dissection), small artery occlusive disease (anterior ischemic optic neuropathy, vasculitis), venous disease, cardiac disease, hypercoagulable disorders, and systemic hypoperfusion. 
• Retinal Vein occlusion - Occlusion or thrombosis of the central retinal vein is associated with chronic glaucoma, atherosclerotic risk factors, hyperviscosity, and coagulopathy. The cause of retinal vein occlusion is often unknown.
• Optic Neuropathy - Patients with a chronic optic neuropathy may experience episodes of transient loss or blurring of vision, usually in association with elevation of body temperature such as exersise or a hot shower (interesting!). Episodes typically last several minutes or until the body temperature returns to normal. It is classically associated with multiple sclerosis. 
• Papilledema
• Optic nerve compression

Binocular

• Migraine
• Seizure
• Vertibrobasilar Ischemia

Tests to Order

• Opthamologic evaluation
• ESR
• Carotid Dopplers
• Cardiac evaluation - TTE and bubble study, 12 lead EKG possible Holter moniter 
• MRI of brain
• Hypercoagulability
• EEG - if pt's hx suggests seizures

Our team still has a few tests to run on the patient. We ordered a Neuro-Opthamology consult and the TTE was still pending. Eventhough her right internal carotid had mild atherosclerosis, my attending said it wasn't really enough to be the cause. I may update this blog when we get a better understanding of what the etiology is. 

Neurology Topic Wish List

 I am starting my Neurology rotation tomorrow and am very excited to be back on the inpatient floor and out of the OR! Instead of writing a blog entry today, I wanted to compose a Neurology wish list of topics I would like to cover while on this rotation. I doubt that I will get through them all but I hope that by the end of four weeks, I will have seen most of these problems and have a better understanding of the patho-physiology and treatment. I will keep coming back to this list and checking off topics as I go. Some I have already covered!

Topics that I hope to cover...

Disorders of consciousness

• Mental status and/or behavioral changes  X
• Memory complaints 
• Pain in the head, neck, and back
• Numbness, paresthesias, and neuropathic pain 
• Weakness and clumsiness 
• Dizziness and vertigo
• Disorders of language
• Neurogenic bladder and bowel
• Vision loss and diplopia
• Dysarthria and dysphagia
• Abnormal movements
• Sleep-related complaints

Understand the patho-physiology and treatments for the following neurological conditions:

•  Ischemic stroke  X
• Hemorrhagic stroke  X
•  Subarachnoid hemorrhage X
• Subdural and epidural hemorrhage
•  Structural coma
• Metabolic encephalopathies X
• Neuro-toxicology and vitamin deficiencies
• Meningitis and encephalitis
•  Dementia and memory disorders
•  Seizures and epilepsy (including status epilepticus) X
•  Syncope
• Vertigo
•  Headache disorders (Migraine, cluster, tension, analgesia-overuse, neuralgias)
•  Neck and back pain
•  Myelopathies
•  Radiculopathies (including cauda equina syndrome)
• Nerve compression
• Neuropathies
• Multiple Sclerosis and other immunologic diseases (sarcoid, SLE, paraneoplastic disorders
•  Movement disorders (Parkinson’s disease, essential tremor, Huntington’s disease, tics, medication-induced dyskinesias)
• Neuromuscular disorders (Myasthenia, Lambert-Eaton, botulism)
•  Myopathies
•  Brain tumors
•  Head trauma

I am excited and nervous to begin!! It has been awhile since I have done a full physical exam on a patient (Anesthesiology for the past month...need I say more?) and I am especially concerned about doing a thorough Neuro exam. I hope to get back on board, learn some new skills, strengthen some old ones and overall grow in my medical knowledge this month so I will be a better intern this June!

Polyarteritis Nodosa

The NEJM released a recent study about Polyarteritis Nodosa, which is a vasculitis of the medium size vessels, and identified a mutant ADA2 (Adenosine Deanimase 2) as a possible cause. Normal ADA 2 will degrade adenosine into inosine. Adenosine will suppress inflammation in acute events such as ischemia or infection but if it is chronically elevated, adenosine can actually promote inflammation. If the enzyme ADA2 is mutated, there will be chronically elevated levels of adenosine around and this supports the possible connection of ADA2 to vasculitits. It was an interesting article to read as Rheumatology is a strong interest of mine and I felt the need to brush up on Polyarteritis Nodosa.

Etiology

Most cases are idiopathic however Hepatitis B and C as well as Hairy Cell Leukemia are among the infections that can cause Polyarteritis Nodosa.

Pathology

Polyarteritis nodosa is a systemic segmental transmural necrotizing vasculitis that typically affects medium-sized muscular arteries (spares the veins), with occasional involvement of small muscular arteries. Unfortunately, the pathogenesis of the disease is poorly understood and thought to be autoimmune related although the NEJM article mentioned above postulates a mutation in ADA2 as a possible cause. Polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (ANCA) which sets it apart from granulomatous with polyangitis (Wegner's) and microscopic polyangitis.

Symptoms

Patients typically present with systemic symptoms and commonly affects the kidneys, skin, muscles, nerves, coronary arteries and gastrointestinal tract tendency to spare the lungs.

• Renal - renal insufficiency, hypertension, perirenal anerurysms, infarction, glomerulonephritis is typically not present and more consistent with the ANCA vasculitis
• Skin - tender erythematous nodules, purpura, raynauds, livedo reticularis, ulcers, and bullous or vesicular eruption. Skin lesions may be focal or diffuse and often more marked over the lower extremities. If the skin involvement progresses there can be infarction and gangrene of the fingers, toes, or other areas and ulceration extending into the subcutaneous tissue. 
• Muscles - The muscles are commonly involved and symptoms include myalgia and muscle weakness. Serum creatinine kinase levels may be elevated but not as elevated as a inflammatory myopathy.
• Nerves - A mononeuropathy multiplex, also known as asymmetric polyneuropathy, is one of the most common symptoms in polyarteritis nodosa affecting about 70% of patients. It typically affects the radial, ulnar and peroneal nerves and can present with both motor and sensory deficits. The neuropathy is typically asymmetric at the onset of the disease but can progress and involve multiple nerve branches causing a symmetric polyneuropathy.
• Gastrointestinal - May present as nausea, vomiting, melena, bloody or nonbloody diarrhea or life-threatening gastrointestinal bleeding. Mesenteric arteritis may present as post prandial abdominal pain and may lead to weight loss from fear of pain after eating. 
• Coronary arteries - Myocardial ischemia or heart failure from either vasculitis of the coronary arteries or from uncontrolled hypertension from renal insufficiency. 

Diagnosis 

Vasculitis should be considered in patients who present with systemic symptoms (fatigue, weakness, fever and arthralgias) in addition to single and/or multiorgan dysfunction (abdominal pain, renal insufficiency/failure). As with all of the other vasculitidies, you ultimately need a biopsy for an accurate diagnosis. The biopsy can be done anywhere where there is disease such as the sural nerve or an ulcer. If a biopsy cannot be done, you can do an arteriogram to look for aneuryms. The American College of Rheumatology has a list of criteria for the classification of PAN with a sensitivity of 82% and specificity of 87%.  To fit the classification of PAN, patient must have 3/10 of the following criteria 

• Otherwise unexplained weight loss >4 kg (about 9lbs or more)
• Livedo reticularis
• Testicular pain or tenderness
• Myalgias (excluding the shoulder and hip girdle), weakness, or polyneuropathy
• Mononeuropathy or polyneuropathy
• New onset diastolic blood pressure >90 mmHg
• Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 mcmol/L)
• Evidence of hepatitis B virus infection via serum antibody or antigen serology
• Characteristic arteriographic abnormalities (microaneurysms) not resulting from noninflammatory disease processes or occlusions of visceral arteries
• A biopsy of medium- or small-sized artery containing polymorphonuclear cells

Treatment

Without treatment, the prognosis of PAN is quite poor. Remission may be induced in about 50% of cases treated with glucocorticoids. The other cases need cyclophosphamide in addition to glucocorticoids. If the patient's PAN is secondary to Hep B or C infection, you may not treat the patient with cyclophosphamide. Once the patient is in remission, cyclophosphamide may be replaced with Methotrexate or azathioprine. 

Community Acquired Pneumonia: an Evaluation of Diagnosis and Treatment by NEJM

The NEJM released an article yesterday addressing a very common clinical problem, Community Acquired Pneumonia, and evaluates the guidelines currently in place and offers recommendations. It starts off with a vignette.

A 67-year-old woman with mild Alzheimer's disease who has a 2-day history of productive cough, fever, and increased confusion is transferred from a nursing home to the emergency department. According to the transfer records, she has had no recent hospitalizations or recent use of antibiotic agents. Her temperature is 38.4°C (101°F), the blood pressure is 145/85 mm Hg, the respiratory rate is 30 breaths per minute, the heart rate is 120 beats per minute, and the oxygen saturation is 91% while she is breathing ambient air. Crackles are heard in both lower lung fields. She is oriented to person only. The white-cell count is 4000 per cubic millimeter, the serum sodium level is 130 mmol per liter, and the blood urea nitrogen is 25 mg per deciliter (9.0 mmol per liter). A radiograph of the chest shows infiltrates in both lower lobes. How and where should this patient be treated?


The World Heath Organization (WHO) estimates that pneumonia is the most common infectious cause of death worldwide and the third most common cause of death overall. Community acquired pneumonia that is severe enough to warrant hospitalization is associated with an increase in mortality as well as increased costs, especially if the patient needs to be admitted to the ICU. Because of the mortality associated with severe community acquired pneumonia and the costs associated with admission, this article focuses on the interventions and guidelines to reduce mortality and costs.


Diagnosis of CAP

 Evidence of infection (fever/chills, leukocytosis), respiratory symptoms (cough, sputum production, SOB, chest pain and abnormal respiratory physical exam) and a new or changed infiltrate on the chest x-ray usually identifies patients with community acquired pneumonia. This diagnosis is not as straight forward in patient who has lung cancer, heart failure or underlying infiltrative lung disease. Atypical presentations, such as confusion, may delay the diagnosis. Human error can play a role as a Radiologist may miss an infiltrate on an x-ray.


Initial Management

 Once CAP is diagnosed, three decisions must be made: what type of antibiotics should be used, what type of testing should be used to determine the cause of the pneumonia and where should the patient be treated (home, inpt or the ICU)?

What type of antibiotics should be used? Appropriate therapy for CAP requires adequate coverage of Streptococcus pneumonia and the atypical bacterial pathogens such as mycoplasma, chlamydia, and legionella. For outpatient treatment, atypical coverage is important and the most appropriate therapy choices are Macrolides, Flouroquinolones and Doxycycline. For patients who will be admitted to the hospital or the ICU, the current recommendations (based on inpatient data that shows a decrease in mortality and length of hospital stay) advise first-line treatment with a flouroquinoline that is effective against the respiratory system (Levofloxacin or Moxifloxacin) or a combination of a second or third generation of a cephalosporin plus a macrolide. It is recommended that the timing of the first antibiotic be given within 6 hours of the initial presentation. It was shown that mortality decreased if the antibiotic was given in the first 4 hours of presentation but this increased the inappropriate use of antibiotics and the side effects such as C. Diff. An exception is made for patients who present with shock and states that the antibiotics should be given within 1 hour of hypotension. The duration of antibiotic treatment is 5-7 days and there has been no evidence of decreased mortality in extended the therapy beyond 7 days.  Health care acquired pneumonia (HAP) is a different beast and you need to treat with antibiotics that will cover MRSA and Pseudomonas Aeruginosa.  The criteria to diagnose HAP is detailed below.

Hospitalization for ≥2 days during the previous 90 days

Residence in a nursing home or extended-care facility

Long-term use of infusion therapy at home, including antibiotics

Hemodialysis during the previous 30 days

Home wound care

Family member with multidrug-resistant pathogen

Immunosuppressive disease or therapy

There is a strain of MRSA that is increasing in the previously healthy population and causing community acquired pneumonia and produces an exotoxin. The article recommends treatment against the MRSA (vancomycin) plus treatment against the exotoxin (linezolid or clindamycin).

Diagnostic testing

Blood culture – strongly recommended in CAP if the patient is hypotensive or has been transferred from the general medical floor to the ICU, in HAP, if the patient has cirrhosis or asplenia. The antibiotic treatment will change depending on the blood culture result.

Respiratory tract culture – strongly recommended if the aspirate in an intubated patient or a productive cough in a non-intubated patient. Antibiotic therapy may change if the sputum culture warrants.
Influenza test during influenza season – recommended in all cases (CAP and HAP) and if tested positive add or continue Oseltamivir.

Test for Urinary Pneumococcal Antigen – Recommended in both CAP and HAP

Test for Urinary Legionella Antigen – Recommended in both CAP, HAP (if the patient comes from a nursing home) and if the patient has travelled recently

Pleural-Fluid Culture – Strongly recommended in both CAP and HAP

Site of Care

Currently, the decision to admit to the medical floor can be objectively determined by the CURB-65 score which assigns 1 point for each. A score of 3 or greater indicates hospitalization. I have seen physicians use this but not stick by it which is understandable because not included in the score are results such as low O2 saturation or if they know that the patient will be non-compliant with medication as an outpatient.

C – Confusion
U – Uremia BUN > 20mg/deciliter
R – Respiratory Rate > 30 breaths/min
B – Blood Pressure Systolic < 90 or diastolic < 60
65 – Age > 65 years

ICU admission may be considered if the patient has  3 or more of the nine criteria: hypotension, tachypnea, confusion, elevated BUN, multilobar infiltrates seen on chest x ray, hypoxemia, thrombocytopenia, hypothermia, leukopenia.
The article states that if these criteria are rigidly followed, more inappropriate ICU admissions occur. The article recommends that much of the decision making about placement will occur in the ED and patients who fit the criteria for ICU admission should be first given the following interventions such as fluid resuscitation, antibiotics, inhalers/bronchodilator treatment and measurement of ABG and then reassess the patient’s disposition.

So, the woman in the vignette at the beginning of my post has a CURB-65 score of 4 (confusion, respiratory rate, BUN and age). She has four minor criteria (confusion, resp rate, BUN and multilobar infiltrates) that would suggest she should be admitted to the ICU but first, she would benefit from further evaluation in the ED such as fluid resuscitation and measuring ABG. She is a nursing home resident which places at risk for HAP however, she does not have any risk factors for MDR so it would be appropriate to treat for severe CAP with a macrolide and a second or third generation cephalosporin. Blood cultures would not be necessary and I would get sputum cultures because he cough was productive (the article doesn't recommend this?). The article does not mention whether to do urine antigen testing but I would based on their previous recommendations. If it was influenza season, I would do an influenza test on the patient.

Eosinophilia

The New England Journal of Medicine published an interesting case report this past week (http://www.nejm.org/doi/pdf/10.1056/NEJMcpc1302331) from Massachusetts General Hospital about a 27 yo male that presented with diarrhea, fatigue and eosinophilia. I was humbled while going through the differential diagnosis and therefore, I wanted to write a blog post on to refresh myself on the topic of Eosinophilia. 

A wide variety of medical conditions can cause eosinophilia. The level of eosinophils in the blood will be different depending on the medical condition. As a result, it has been difficult to establish solid parameters that will define eosinophilia but uptodate states the following measurements

• Mild eosinophilia - 500-1500 cells/microL
• Moderate - 1500-5000 cells/microL
• Severe - >5000 cells/microL

Uptodate also defines the following

• Hypereosinophilia - eosinophils > 1500 cells/microL and can cause tissue and organ damage regardless of the cause
• Hypereosinophilia syndrome - eosinophils > 1500 in the absence of a discernable cause such as allergy, drug, parasite and HIV

Categories of Eosinophilia

• Primary - when eosinophilia occurs due to a problem with the progenitor cells/bone marrow and there is evidence of clonal expansion (lymphoid leukemias, myeloid leukemias)
• Secondary - when eosinophilia occurs due to a problem outside the progenitor/bone marrow cells such as parasites, drug sensitivity, allergies, autoimmune disease, metastatic cancer, Hodgkin's lymphoma and endocrine disease (adrenal insufficiency)

H & P 

• Medications both recent and current list?
• Recent travel? Where?
• Constitutional symptoms - fevers, chills, night sweats and weight loss
• Diarrhea? 
• Rash?
• Hx of allergies?
• Hx of autoimmune disorder?

Causes of Eosinophilia 

• Atopic Dermatitis
• Asthma
• Allergic rhinitis
• Esophagitis
• Gastritis
• Colitis
• Medications - eosinophilia alone is not enough to stop the medication unless there is evidence of end organ damage (most commonly involved are the lungs, kidneys and heart)
• Parasites - Strongyloides stercoralis, hookworm, filariae, and Toxocara canis and schistosomes Note: In contrast to infections with multicellular helminthic parasites, infections with single-celled protozoan parasites (Giardia lamblia and Entamoeba histolytica) do NOT characteristically elicit blood eosinophilia. The only exception is Dientamoeba fragilis and Isospora belli. 
• Fungal - Aspergillosis and coccidiodomycosis
• HIV - usually due to one of the following reasons and not the actual virus itself
• Leukopenia - may lead to percentage of eosinophils and not absolute increase in eosinophil
• Medications - pt may have reaction with medication against opportunist infections
• Adrenal insufficiency - occurring from cytomegalovirus causing adrenal failure
• Eosinophilic folliculitis - can be seen in pt with HIV
• Hematologic and Neoplastic Disorders
• Mastocytosis - characterized by proliferation of mast cells in various organs such as the skin, liver, spleen, bone marrow, and lymph nodes
• Leukemia - AML has a subtype called Acute eosinophilic leukemia
• Tumors - non-keratinizing cervical tumors, lung carcinomas, squamous carcinomas of the vagina, penis, skin, and nasopharynx, adenocarcinomas of the stomach, large bowel and uterine body, and transitional cell bladder carcinoma can all cause eosinophilia
• Rheumatic Disease 
•  eosinophilia-myalgia syndrome 
• idiopathic eosinophilic synovitis
• vasculitis - churg strauss
• Adrenal Insufficiency - glucocorticoids will exert eosinopenic effects by causing apoptosis. When there is adrenal insufficiency, there is a decrease in glucocorticoids which will cause an increase in eosinophils
• Immunodeficiency states - hyper IgE

Delirium

All too often on my Emergency Medicine rotation, we would hear on the EMS about a patient in route for altered mental status/confusion/delirium. Sometimes, these cases where fairly straightforward (a relatively healthy 88 yo female with sudden confusion and urosepsis) but more often we would have patients who had multiple problems, were on multiple medications, had baseline dementia or had no history at all! These cases could prove very challenging!

Delirium – The DSM IV lists four key features that characterize delirium

• Disturbance of consciousness with reduced ability to focus, sustain, or shift attention. Distractibility is the key work here!
• A change in cognition or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia.
• The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. Fluctuate is another key word!
• There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a medical condition, substance intoxication, or medication side effect.

Unfortunately, the pathogenesis of delirium is poorly understood. The biologic basis is difficult to assess in part because it is not practical to run conventional tests on acutely ill patients and it is often difficult to separate delirium from other illnesses or medication side effects. However, uptodate reports some data on the pathogenesis and risk factors for developing delirium.

 Pathogenesis

• Cortical dysfunction – On EEG, there is a correlation with the slowing of the dominant posterior alpha waves and the appearance of abnormal slow-wave activity with a decreased level in consciousness (excluding causes of delirium such as drug and alcohol withdrawl).
• Subcortical dysfunction – Evoked potential studies as well as neuroimaging studies have shown that there is a connection with delirium and subcortical function. This research correlates with the finding that patients who have a dysfunction to the subcortical area (Parkinson’s and stroke patients) are more susceptible to delirium
• Neurotransmitter imbalance – Acetylcholine imbalance has been long known to have a part in delirium. When healthy patients are given anticholinergics, delirium can ensue. The role of acetylcholine is further supported by the fact that events precipitating delirium (hypoxia, hypoglycemia and thiamine deficiency) can all decrease the amount of acetylcholine synthesis in the body. It is modern practice to avoid anticholinergic medication in the elderly population which can be difficult (especially if the patient is post-op as the patient will received anticholinergics to prevent the muscarinic side effects when the patient is given an anticholinesterase inhibitor.) Other neurotransmitters thought to be involved include interleukins and tumor necrosis factor which would account for the high risk of delirium in patients with inflammatory conditions and sepsis.

Risk factors

• Factors that increase vulnerability – stroke, parkinson’s disease and dementia
• Factors that precipitate delirium – polypharmacy, dehydration, malnutrition, immobility and infection

Differential Diagnosis – I learned a helpful acronym when thinking of causes of delirium…MOVE STUPID

Metabolic – B12 or thiamine deficiency, serotonin syndrome
Oxygen – hypoxemia (cardiac, pulmonary or anemia) or hypercarbnia
Vascular – Hypertensive emergency, CVA, vasculitis and MI
Electrolytes  and Endocrine
Seizures
Toxins – lead, mercury and CO, trauma, tumor and temperature
Uremia from renal or hepatic dysfunction
Psychiatric or Porphyria
Infection
Drugs – anticholinergics, antipsychotics and withdrawl from drugs

Labs to order - should include serum electrolytes, creatinine, glucose, calcium, complete blood count, and urinalysis and urine culture. Drug levels, toxicology screen, liver function testing, and arterial blood gas should follow if the cause remains obscure. Neuroimaging or EEG should be further down the list of test when a cause continues to remain obscure.

Treatment - involves correcting the underlying factor and maintaining an environment that will not further precipitate the delirium. Recommendations from uptodate are below. When I rotated at a hospital in MN, this was part of an order set which I though was awesome!! I think that every hospital should have delirium prevention protocol order sets.

• Orientation protocol and cognitive stimulation for patients with cognitive impairment
• Environmental modification and nonpharmacologic sleep aids for patients with insomnia
• Early mobilization and minimizing use of physical restraints for patients with limited mobility
• Visual and hearing aids for patients with these impairments
• Early volume repletion for patients with dehydration

Tumors of the Nervous System

All of the different types of primary (not metastasis) nervous system tumors can be challenging to remember. I really have not interacted with the material since I studied for STEP 2 until this past week while on Neurosurgery. We had several cases for resections of brain tumors and so it seemed appropriate to refresh and revisit tumors of the nervous system. 

Quick Facts From NIH

• 18,000 patients in the USA are diagnosed with a brain tumor every year
• Nervous system tumors are the second most common cause of cancer in pediatrics (Leukemia is first)
• Nervous system tumors are not as common in adults but come in 7th in the order of Lung, Colon, Breast, Pancreas, Prostate, Leukemia and then Brain/Nervous system
• Metastatic tumors are more common than primary, so when you see a brain tumor on a CT, it is more often metastasis from a different site
• Primary Brain tumors more common in men, except for meningiomas
• Brain tumors in adults are 70% located in the supratentorial and 30% infratentorial
• Brain tumors in Peds are 70% infratentorial and 30% supratentorial

Symptoms of Brain Tumors - often persistent and progressive (tumor stays and grows over time)

• Worsening, constant headache, headache wakes them up at night
• Seizures
• Focal neurologic deficits - visual loss, arm or leg weakness, facial drooping
• Personality changes
• Altered mental status

CT scan is the initial test. If a brain tumor is suspected, an MRI and brain biopsy would be the next step. 

Gliomas - the most common primary brain tumor and the term "glioma" is used for these tumors because they have histology representative of glial cells (astrocytes, oligodendrocytes and ependymal cells)

1. Astrocytomas (also referred to as gliomas). The cell of origin is an astrocyte. There are four I-IV and are graded on a scale of severity. Most common brain cell tumor. 

• Grade I - known as pilocytic glioma/astrocytoma. More common in children. Surgical resection is often curative.
• Grade II - known as low-grade astrocytoma. Surgical resection is usually not enough and need additional therapy such as chemo and radiation. 
• Grade III - known as anaplastic glioma/astrocytoma
• Grade IV - known as glioblastoma multiform. More common in adults. Prognosis is dismal. Tumor can be resected but will not be curative. Pt will have chemo (tamezolamide and carnustine) and radiation treatment in addition. Can see "butterflying" when the tumor crosses the corpus callosum

2. Oligodendroglioma - less common and more often seen in adults. Most often found in the frontal lobe. 

• Treatment will be PVC chemo (procarbazine, vincristine and CeeNU/lamustine), radiation and surgical resection
• Tends to recur and become more treatment resistant

3. Ependymoma -Ependymal cells are cells that line the ventricles so the most common location will be inside the ventricles.

• Risk factor is Neurofibromatosis type 1
• A symptom could be cauda equina symptoms or hydrocephalus
• treatment is surgical resection, radiation and chemotherapy

Meningioma - origin is menigial cells of the dura mater. 

• Sometimes, can see a dural tail connecting the tumor to the dura mater. 
• Can extend into the epithelial cells
• Primarily see these in adults and are usually benign

Medullablastoma - origin unknown but will arise in the medulla

• Mostly seen in children
• Tends to block the fourth ventricle since and can cause obstructive hydrocephalus
• Gait issues are a common symptom
• Diplopia from impingement on CN VI
• Treatment is surgical resection, chemo and radiation

Schwannoma - originates from schwann cells which are myelinating cells of the peripheral nervous system.

• Risk NF-1 and NF-2 (bilateral acoustic neuromas) 
• Commonly affects CN VIII and can see sensorineural hearing loss and vestibular symptoms
• Treatment is surgical resection and prognosis is good

Hemangioblastomas

• seen on the cerebellum
• Assoc with von Hipple-Lindau 

Craniopharyngiomas

• more common in children
• arises from the pituitary stalk
• can have endocrine abnormalities and panhypopituitarism, bitemporal hemianopsia from compression of the optic chiasm

 Brain Metastases

• most common cause of brain tumors
• Mets will come from commonly from these locations - lung, skin and breast

Fluid Management in Neurosurgery

I have been spending a lot of time in neurosurgery rooms this last week. Yesterday, I watched a craniotomy for a resection and removal of a supratentorial brain tumor. I noted how many different types of fluids (keppra, mannitol and 3% saline) we had hanging for the patient which I rarely see in other surgical procedures. I thought fluid management in Neurosurgery would be a good, brief topic. 

Mannitol

Mannitol, a sugar alcohol, accomplishes the goal of decreasing intracranial pressure (ICP) in two ways: an immediate effect due to plasma expansion from simply adding the mannitol and a delayed effect secondary to osmosis (mannitol is hypertonic). The early plasma expansion reduces blood viscosity which will increase the intravascular volume and cardiac output. Together, these effects result in an increase of cerebral blood flow and compensatory cerebral vasoconstriction of the cerebral arteries (autoregulation), resulting in a reduction in ICP. Mannitol also establishes an osmotic gradient between plasma and brain cells, drawing water from the cerebral space into the intravascular space, causing a decrease in cerebral swelling and a reduction in ICP. A side affect of mannitol, however, is osmotic diuresis. Mannitol is freely filtered by the kidney tubules but not reabsorbed and so, through osmosis, free fluid is pulled into the tubules and lost in the urine. 

3% Saline

Hypertonic saline will reduce ICP in a similar way that mannitol does through osmosis and expanding the intravascular volume, but it has recently been found to have some extra beneficial effects. In addition to an osmotic action, hypertonic saline has autoregulatory effects. In particular, hypertonic saline relaxes arteriolar vascular smooth muscle and will improve cerebral microcirculatory flow. Another added benefit is that hypertonic saline does not cause an osmotic diuresis but it can, however, cause hypernatremia. 

Keppra

Antiseizure medications may be given before neurosurgery to prevent seizures post-operatively. I found that there is an interesting discussion going on in the neurosurgery world currently about whether keppra is superior to the traditional phenytoin for supratentorial craniotomies. I read an article from the American Epilepsy Society that found both medications to have similar efficacy in reducing post op seizures and epilepsy but keppra was associated with fewer adverse effects than phenytoin. This study was a retrospective study and the article admitted that a randomized controlled trial with a placebo would be more informative but concluded that, "Until a definitive study is performed, it may be reasonable to use levetiracetam (keppra) instead of phenytoin for seizure prophylaxis after supratentorial craniotomy—if the practitioner chooses to use AED prophylaxis at all in this setting."(Efficacy and Tolerability of Levetiracetam Versus Phenytoin after Supratentorial Neurosurgery Milligan TA, Hurwitz S, Bromfield EB.)