Differential Diagnosis in Neurology

10.13. Neuropathies Associated with Infection

• General features:
  • Leprosy 10 million cases world wide
  • HIV-1 major new epidemic greater than 50 million people affected with neuropathy worldwide in and of itself and secondary to drug treatments
  • Herpes Zoster affects the aging population

Neuropathies of Viral Origin

Cytomegalovirus

• General features:
  • Encountered most frequently in terminal HIV patients
  • Associated with retinitis
• Clinical presentation:
  • Polyradiculitis
  • Motor cauda equina syndrome; asymmetric muscle involvement of these roots (L1–S5)
  • Bowel and bladder incontinence
  • All modality sensory loss
  • Painful cauda equina syndrome
  • Areflexia
  • Rapidly progressive and often fatal
• EMG:
  • Widespread denervation of affected muscles
  • Absent F waves
• Laboratory:
  • Polymorphonuclear pleocytosis
  • PCR positive
• MRI:
  • May demonstrate gadolinium enhancement of the cauda equina

Herpes Simplex

• General features:
  • Latent infection initiated at an early age
  • Latent in trigeminal and dorsal root ganglion
  • Travels down V1 innervation of the fifth nerve to reach the meninges
  • Environmental stress, tooth extraction ultraviolet light
  • Operations for tic douloureux may induce active infection
• Clinical presentation:
  • Cutaneous grouped vesicular eruption
  • Contiguous pain and secondary hyperalgesia around the skin lesions; may involve a much larger area than that involved by the eruption (on extremities or trunk)
  • Possible etiology for Bell's palsy
  • Recurrent aphthous ulcers
• Laboratory evaluation:
  • CSF-RBC's, sugar of 30–40 mg/dL
  • Slightly elevated protein
• MRI:
  • Bitemporal increased signal on T2 weighted images
  • Insular cortex involved; frontal lobe involved; occasionally one lobe of brain alone is involved

Herpes Zoster

• General features:
  • Latent dorsal root ganglion or Vth nerve infection initiated during childhood; reactivated with immune deficiency
  • 95% of the US population is infected
  • Transmission is respiratory or direct contact
  • Hz causes deep dermal invasion with infarctive necrosis
  • Recurrence is common in HIV patients and patients undergoing chemotherapy
  • Virus migrates from sensory nerve fibers that originate in the dorsal root ganglia to invade the skin and subcutaneous tissue in a dermatomal distribution
  • Patients with motor involvement may have an increased incidence of malignancy
  • Incidence increases with age:
    • May be generalized (infancy and HIV patients)
• Clinical presentation:
  • Radicular distribution of severe lancinating pain:
    • Decreased threshold to primary modalities of cold and pin prick in affected dermatome
    • Mechano dynamic and static allodynia of the affected dermatome
    • Secondary hyperalgesia at times in the dermatome above and below the affected one
    • Motor weakness may accompany the sensory symptoms
    • Cranial nerve involvement infrequent; ophthalmoplegia rare; IIIrd nerve involvement occurs: V1 involvement is often associated with meningoencephalitis
    • Sensory symptoms (usually burning pain) may occur prior to the skin eruption; possibly greater than six months; herpes sin herpete
    • Differential diagnosis of radicular pain without rash on the thorax includes: cancer of the lung, lymphoma, and diabetic radiculopathy
    • Rarely optic neuritis; VII nerve and the VII–VIII involvement of Ramsay-Hunt syndrome (Vesicles noted in the external auditory canal)
    • Central features included transverse myelitis and delayed MCA stroke often after V1 involvement
• Laboratory:
  • Cerebral spinal fluid:
    • RRC seen (40–50 RBC/mm³); increased protein in 50% of patients with a normal glucose
    • Rarely glucose is <40 mg/dL
    • PCR for VZV DNA is positive
• MRI:
  • Meningoencephalitis of V1 involved with dural enhancement
  • MCA stroke (if V1 involved)
• EMG:
  • Segmental denervation of involved dermatomes

Hepatitis C

• General features:
  • Common in association with HIV or drug abuse
  • Often asymptomatic liver involvement with persistently elevated enzymes
  • Associated vasculitis or vasculopathy
• Clinical presentation:
  • Asymptomatic polyneuropathy
  • Small fiber neuropathy
  • Cryoglobulins are common and are thought to cause the neuropathy
  • Mononeuritis multiplex
  • Rare encephalitis
• Laboratory:
  • Hepatitis C serology
  • PCR is positive

Hepatitis B

• General features:
  • Incidence not determined
• Clinical presentation:
  • GBS
  • Mononeuritis multiplex
  • Sensorimotor polyneuropathy
  • Transverse myelitis
• Pathology (nerve biopsy):
  • Immune complex on nerves
  • Vasculitis

Human Immunodeficiency Virus-1 (HIV-1)

• General features:
  • Approximately 1/3 of HIV patients have a peripheral neuropathy from the disease or its treatment
  • Wasting syndromes; aphthous ulcers; dementia; chronic diarrhea (possibly inflammatory cytokine mediated) are characteristic when neuropathy supervenes
  • IL-6, IL-1 and TNF infinity found in dorsal root ganglion cells; nucleic acid of HIV-1 is found in approximately 1/3 of DRG
  • Glycoprotein gp 120 from the HIV cell may activate cytotoxic T lymphocytes with consequent inflammatory cytokine expression
  • Apoptosis of sensory neurons demonstrated
  • Possible participation of immunoglobulins in HIV neuropathy
  • Neurotoxic drugs include:
    • All used in these infected patients cause concomitant neuropathy
    • Deoxyadenosine (ddI)
    • Zaltidine (ddC)
    • Stavudine (d4T)
    • Thalidomide
    • Dapsone
    • Isoniazid
    • Pyridoxine
    • Metronidazole
    • Vincristine
    • Etoposide
    • Chloramphenicol
    • Ethambutol
  • Approximately 10% of patients taking Deoxyadenosine (ddI) for 10 months develop neuropathy (partly reversible ). Zaltidine (ddC) incidence of neuropathy is 25–66%.
  • History of neuropathy, immunosuppression and low hemoglobulin associated with HAART therapy
  • B12 deficiency may occur in wasted malnourished demented patients
  • Autoimmune mediated neuropathies particularly AIDP and mononeuritis multiplex may occur early in the course of the illness
  • CMV DNA is detected by PCR in the cerebral spinal fluid of mononeuritis multiplex patients in advanced HIV; autopsy frequently demonstrates CMV in peripheral neurons; CMV lumbosacral polyradiculitis is well characterized
• Clinical presentation:
  • Distal symmetric polyneuropathy
  • Occurs in 30% of HIV patients
  • Large and small fiber modalities, painful, stocking and glove neuropathy occurs;
    • Legs earlier and more severe than arms; or reflexa
    • Allodynia and hyperalgesia are common
    • Joint position sense only slightly affected
    • Minimal distal muscle weakness and atrophy
• Inflammatory Demyelinating Polyneuropathy:
  • AIDP and CIDP patterns occur most often in asymptomatic infection; CIDP may occur with seroconversion
  • AIDP weakness much greater than sensory loss; facial diplegia occurs; monophasic with progression over four weeks.
    • Diaphragmatic weakness and autonomic instability may be prominent
  • CIDP:
    • Greater sensory loss
    • Relapsing remitting course
    • Distal weakness
    • Generalized depressed reflexes
    • Rare ataxic neuropathy similar to tropical ataxic neuropathy of HTLV-1
• Mononeuritis Multiplex:
  • Weakness and sensory loss in cutaneous and mixed nerves as well as nerve roots
  • Depressed reflexes
  • Concomitant involvement of cranial nerves
  • Self limited with some recovery if it occurs early in the illness
• Progressive Polyradiculopathy:
  • Rapidly progressive cauda equina syndrome
  • Leg weakness with difficulty walking
  • Bowel and bladder dysfunction
  • Back pain with radicular paresthesias
  • Evolves into areflexic paraparesis with large and small fiber sensory loss
  • S4 and S5 dermatome involvement occurs in 10% of patients
  • Arms and cranial nerve involvement occur late with severe immunocompromise
  • CMV most often causative; syphilis and lymphomatous infiltration occur rarely
• Cranial Nerve Involvement in HIV patients:
  • Occur in approximately 5% of patients
  • Differential diagnosis includes:
    • CMV encephalitis
    • Cryptococcus (particularly if II is involved)
    • Central nervous system lymphoma
    • Non-Hodgkin's lymphoma
    • Rare brainstem lymphoma
• Autonomic Dysregulation:
  • Orthostatic hypotension
  • Approximately 50% of patients have abnormal sympathetic and parasympathetic functional testing
  • Occurs in the course of HIV infection
  • Poor prognosis
• Diffuse Infiltrative Lymphocytosis Syndrome:
  • Painful distal neuropathy
  • Acute onset
  • Motor involvement
  • May be asymmetric and restricted to the arms
  • Possibly HIV immune dysregulation is causative
• Differential Diagnosis of HIV distal sensory polyneuropathy
  • Concomitant disease:
    • Diabetes
    • Uremia
    • Drug abuse (ethanol)
    • Standard HAART therapy
    • B12 deficiency
    • Diffuse infiltrative lymphocytosis syndrome
• Differential Diagnosis of Polyradiculopathy:
  • CMV
  • Mechanical bone and disc compression of the cauda equina
  • Lymphomatosis of the meninges
  • Syphilis
• Differential Diagnosis of Late HIV Infection:
  • CMV:
    • Patients not responding to therapy
    • Rapidly progressive course
    • CD4 counts less than 200 lymphocytes/mm³
  • Diffuse infiltrative lymphocytosis syndrome
  • Lymphomatosis
  • Vasculitic neuropathy
• EMG:
  • Reduced or absent SNAPs in sural nerve (DSP); mNCV mildly reduced compared to amplitude
  • Reduced median and ulnar motor and sensory NCVs
  • Prolongation of F-wave and H-reflexes
  • NCS of inflammatory polyneuropathy similar to chase of non-HIV patients
  • Mononeuritis multiplex; reduced CMAP, SNAPs and mild decrease of m and s NCVs.
  • Needle EMG rules out myopathy
• Laboratory:
  • Cerebral spinal fluid:
    • Lymphocytic pleocytosis is present in greater than 50% of asymptomatic HIV patients; usually up to 50 cells/mm³ in seropositive patients
    • Cerebral spinal fluid protein elevated in both seronegative and positive patients (50–80 mg/dL )
    • DSP and MM (mononeuritis multiplex) patients may demonstrate a mild mononuclear pleocytosis
    • Low glucose (30–40 mg/dL ), high PMN pleocytosis (as high as 2000 cells/mm³); high protein up to 1 gram/dl has been reported in CMV lumbosacral plexitis
    • Lymphomatous in filtration less than 200/mm³ monocytes is usually found
    • CSF glucose is normal in HIV patients
    • CMV detection of DNA by PCR is most important; culture is only positive in 50% of patients
• MRI:
  • Enhancement of lumbosacral roots in CMV lumbosacral plexitis
  • Meningeal enhancement occurs in lymphomatosis
• Pathology of nerve (sural nerve biopsy)
  • DSP:
    • Axonal pathology of both myelinated and unmyelinated fibers
    • No segmental demyelination
    • Epineurial and endoneurial mononuclear inflammation
  • CMV inclusion bodies have been documented in some patients with MM
  • Necrotizing arteries occurs in progressive sensory motor neuropathy

Lyme Neuropathy (Borrelia Burgdorferi)

• General features:
  • Treponema-like spirochete
  • Ixodes tick, I. scapularis, I. pacificus; feeds from white footed mouse and large mammals
  • Molecular mimicry and B-cell induced cytokine response are possible mechanisms
  • Incubation ranges from 3 to 30 days
• Clinical presentation
  • Stage I:
    • Erythema chronicum migrans, rash develops at the inoculating site
    • Three to four weeks of fatigue and constitutional symptoms
  • Stage II (early)
    • Lymphocytic meningitis and meningoradiculitis:
      • Waxing and waning symptoms
      • 50% of patients have unilateral or bilateral VIIth nerve neuropathy (Bannsworth Syndrome)
      • Rare II, III, V and VIIIth nerve involvement
  • Stage II (late)
    • Peripheral neuropathy:
      • Distal symmetrical motor sensory neuropathy
      • Lasts for weeks to months
      • Sensory neuropathy occurs in untreated patients:
      • a) Minimal weakness
      • b) Little objective sensory loss
      • c) Preserved deep tendon reflexes
  • Stage III:
    • Asymmetric arthritis
    • Cardiac involvement (CHF)
    • Subacute encephalitis
    • Demyelinating disease (large plaques on MRI)
    • Cognitive dysfunction/dementia
    • Spastic paraparesis
    • Cerebral vasculitis with stroke
    • Myositis
• Laboratory evaluation:
  • Intrathecal spirochetal antibody production (oligoclonal bands)
  • Immunoglobulin G and M index
  • Cerebrospinal fluid:
    • Lymphocytic pleocytosis
    • Moderately elevated protein (50–80%)
    • Elevated immunoglobulin
    • Specific PCR greater than 90%
• EMG:
  • Axonal neuropathy

Myobacterium Leprae (Leprosy)

• General features:
  • Estimated 10–20 million patients' affected world wide
  • USA patients are from southwest border states; illegal aliens; most patients world wide are from Asia, Africa, South America and Southern Russia
  • Reproduces at 26–30 degree centigrade; predilection for nose, testes, anterior portions of the eye, superficial nerves (cold body parts)
  • Gram positive obligate intracellular bacillus
  • Lepromatous form:
    • Abnormal cell-mediated immunity
    • Disseminates hematogenously
  • Tuberculoid form:
    • Presence of cell mediated immunity
    • No disease dissemination
  • Lepromatous form
• Clinical Presentation:
  • Individual macules, papules or nodular skin lesions
  • Symmetric rash of the face, forearms or buttocks and knees
  • Loss of pain and temperature in dorsum of feet, ears, lateral leg and forearm
  • Perforating skin ulcers at pressure points
  • Leonine faces
  • Evolves to hoarseness, respiratory strider and hypotension
  • Sensory loss due to intracutaneous loss of unmyelinated and thinly myelinated fibers
  • Enlarged nerves: greater auricular, supraclavicular; ulnar and median; patchy sensory loss in the face, extremities and trunk
  • Peripheral nerves in cooler areas of the body are involved symmetrically
  • Increased size of C-fibers in the cornea
• Pathology:
  • Early stages:
    • Infection of Schwann cells of myelinated fibers; minimal inflammatory response
  • Advanced disease:
    • Extensive inflammatory response
    • Hypertrophy of peripheral nerves; repeated episodes of remyelination
    • Increased levels of IL-4 and IL-10 found in lepromatous lesions

Tuberculoid Forms

• Anesthetic skin plaques; central hypopigmentation with erythematous borders in extensor surfaces
• Pathology:
  • Elevation of IL-2 and gamma interferon are found in lepromatous lesions
  • Disruption of nerve architecture
  • Intense inflammatory granulomatous reaction

Borderline Form

• Intermediate between lepromatous and tuberculoid:
  • Poorly defined skin lesions that evolve to a confluent rash
• Hypertrophic nerve lesions; anesthetic patches
• Laboratory evaluation:
  • Lepromin skin test; skin responses: the Mitsuda reaction seen at the injection site in 3–4 weeks; lepromatous form there is a minimal or slight reaction; reaction of greater than 5 mm is seen in tuberculoid or borderline forms
• EMG:
  • Axonal degeneration and segmental demyelination in affected areas
  • Slow NCVs; decreased SNAPs and evidence of denervation of affected muscles
• Pathology:
  • Skin biopsy demonstrate granulomas in skin with or without bacilli
  • Fite stain reveals bacilli in nasal smears

Corynebacterium Diphtheria (Diphtheria)

• General features:
  • Rare in USA; increasing incidence in the former republics of the USSR
  • Oropharyngeal and diaphragmatic weakness are seen 5–7 weeks after the infection
  • Neuropathy occurs in 20% of patients
  • Bacteria toxin mediates demyelination
• Clinical presentation:
  • Associated with circulatory and myocardial failure; sore throat and hoarseness; thick pharyngeal exudate
  • Cranial neuropathy of IX and X
  • Demyelinating sensorimotor neuropathy that involves the extremities and trunk occurs two to three months after infection
  • Diaphragmatic weakness with decreased pulmonary function is common
• EMG:
  • Demyelinating characteristics
• Laboratory evaluation:
  • Positive culture for C. diphtheriae

Brucella (suis, melitensis, abortus)

• General features:
  • Seen in countries with unpasteurized milk
  • Lymphadenopathy with remittent fevers and severe night sweats is characteristic
  • Blood borne infection
• Clinical presentation:
  • Cranial neuropathy
  • Radiculopathies; L5 frequently involved
  • Paraparesis
• Laboratory:
  • Positive serum and CSF culture
• Pathology:
  • Granulomatous meningeal reaction

Tuberculosis

• General features:
  • Incidence increasing due to HIV co-infection
  • CNS strokes associated (conducting cortical vessels)
  • Inappropriate ADH often occurs with inflammatory chest disease
  • Tuberculomas occurs anywhere in the neuraxis
• Clinical presentation:
  • Headache, meningismus, low grade meningitis
  • Lower cranial nerves involvement from basilar meningitis; cranial III, VI and VII most often involved; may involve II
  • Papilledema from CSF obstruction
  • Ethambutol causes green color blindness; streptomycin, VIIIth nerve dysfunction
  • In HIV infected patients – tumoricidal radiculopathy
• Laboratory evaluation:
  • Purified protein derivative skin test greater than 5–10 mm (intermediate strength)
  • Chest X-ray is positive in disseminated disease
  • CSF:
    • Cold coagulum forms overnight in refrigerated material
    • CSF lymphocytic pleocytosis (30–50 lymphocytes/mm³)
    • Protein 80–150 mg/dL
    • Sugar 30–40 mg/dL
    • Difficult to identify organisms by acid fast stain
    • Positive culture in most patients
  • Low serum sodium (120–130 meq/dl)

Botulism (Clostridium Botulinum) Toxin

• General features:
  • Specific types due to circumstances:
    • Contaminated fish
    • Infantile form (from bottle feeding; honey often added)
    • High altitude (low boiling point that does not kill organism during canning process; Colorado)
• Clinical presentation:
  • Diarrhea and vomiting (12–36 hours after ingestion)
  • May take three days to develop neurologic symptoms
  • Diplopia
  • Fixed dilated pupils
  • Bulbar involvement
  • Late in course there is extremity and respiratory weakness
  • Autonomic dysfunction:
    • Decreased salivation
    • Ileus and constipation
    • Urinary retention
    • Orthostatic hypotension
• EMG:
  • Low or absent CMAP
  • Mild disease: facilitation of the CMAP with tetanic repetitive stimulation
• Laboratory:
  • Toxin identified in blood stool. Gastric contents with food; bioassay in mice
• Differential Diagnosis:
  • Anticholinergic intoxication:
    • Atropine
    • Jimson Weed
    • Mushroom poisoning
  • Autonomic form of GBS
  • Streptococcal pharyngitis (early drying and redness of the oral mucosa

Syphilis (Treponema Pallidum)

• General features:
  • General resurgence due to HIV infection
  • All stages are compressed in HIV comorbidity "telescoped"
• Clinical presentation:
  • Stage I – chance to one year with no neurological symptoms; infection of paraaortic lymph nodes, meninges, coronary arteries during this time:
    • Infection to chance (six weeks); painless skin lesion with raised margins
  • Stage II (meningitis form):
    • Proliferative endarteritis; small brainstem strokes (most of the named brainstem syndrome are syphilitic infection; Heubner's arteritis)
    • Meningitis
      • Lymphocytic pleocytosis; may be neutrophilic early
      • Normal sugar
      • Protein of 60–120 mg/dl
      • IgM increased in acute infection; FTA always positive as is VDRL in CSF
  • Stage III:
    • Latent stage
    • Argyll–Robertson pupils; optic atrophy is common
    • Dorsal column involvement:
      • Hitzig spots on the skin (short segmental branches from the dorsal root that innervates the skin; anesthetic oval depigmented areas on the trunk)
      • Proprioceptive sensory ataxia
      • Stamping gait
      • Areflexia
      • Optic atrophy
      • VIIIth nerve involvement
      • Pachymeningitis cervicales
      • a) Compression of the cervical spinal cord from thickened dura
      • Mid face numbness
      • a) Destruction of the Vth nerve entry zone afferent fibers
      • Rare Gummas anywhere in the brain
      • Syphilitic dementia with expansive paranoid ideation; seizures; brainstem strokes
      • Tabetic gastric crisis
      • a) DRG induced lancinating pain of the abdomen
• Laboratory evaluation:
  • Cerebral spinal fluid:
    • 1–3 lymphocytes
    • Protein normal to minimally elevated
    • Sugar is normal
    • Increased IgG (in late infections)

Tick Paralysis (Dermacanter species)

• General features:
  • Ticks usually feed on cold areas of the body (hair line; ears)
• Clinical presentation:
  • Ascending paralysis
  • Loss of lower extremity deep tendon reflexes
  • Ataxia may be more prominent than weakness
  • Bulbar paralysis occurs in severe cases
• EMG:
  • CMAPs a single stimulus
  • Repetitive CMAPs after a single stimulus

Trypanosoma Cruzi (Chagas Disease)

• General features:
  • Central and South America
  • Infection by the protozoan trypanosoma cruzi
• Clinical presentation:
  • Cardiomyopathy
  • Esophageal dysmotility
  • Megacolon
  • Sensory motor neuropathy
• Laboratory:
  • Positive serological evaluation of blood and CSF