When a disease can cause multiple neurological deficits it more important to identify the site of the deficits than to just diagnose the disease as in multiple sclerosis.
Case 1. A 28 year old patient comes in to the hospital complaining of blurring of vision. He is known to have had an episode of paraplegia 5 years ago, diagnosed as multiple sclerosis. What is happening now and what is the lesion?
Case 2. A 43 year old woman who had recently been taken off disease modifying drugs for multiple sclerosis reports to her doctor with double vision on looking to the left. She says her left eye becomes wobbly whenever she looks to the left. What is the lesion?
Case 3. A 20 year old woman reports to her doctor with weakness in the left leg for several hours. Her doctor examines her and finds 3/5 weakness in the left lower limb, hypertonia, increased reflexes and an up going planter. There is no pain or sensory loss. What has happened?
Clinically isolated syndromes suggestive of MS such as optic neuritis, long tract symptoms/signs (eg, numbness, paresthesia, or weakness), a brainstem syndrome (eg, internuclear ophthalmoplegia), or a spinal cord syndrome (eg, transverse myelitis) are common presentations. Please remember that UMN lesions of one or more limbs are caused by demyelination of the long tracts which, after a crossover in the medulla oblongata go down on the contralateral side of the spinal cord. Hence monocrural or brachial monoplegia or a paraplegia or quadriplegia are caused by demyelinating lesions in the spinal cord.
What happens when the cerebral cortex (specially the motor cortex) is damaged? Not a simple UMN lesion but some or all of the following:
- Limb rigidity, not spasticity
- Bradykinesia or clumsy limb
- Postural instability
- Abnormal gait
- Axial rigidity
- Limb dystonia
- Cognitive decline is a prominent feature
- Dysarthria is prominent and usually an early feature of motor cortex damage. Characteristics are mixed and varied. Approximately one-third of patients have the hypokinetic form, similar to the type seen in idiopathic Parkinson disease, that is characterized by reduced volume, monotone pitch, fluctuating speech articulation, shallow inhalations, and a slow rate of speech punctuated with rapid burst.
- Aphasia and limb alienation are 2 other features.
In a particular exam students thought that this is 20 year old woman had lesions in her periventricular white matter. Periventricular leukomalacia occurs in lesions in premature infants, cerebral palsy and in adults in normal pressure hydrocephalus and vascular dementia. Small periventricular white matter lesions may occur in aggressive MS when a likely diagnosis of PML is more accurate.
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system. PML is caused by reactivation of the polyomavirus JC. PML was initially described in patients with lymphoproliferative and myeloproliferative diseases such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma. Malignancy is the most common predisposing condition among PML cases. PML is also seen in HIV, organ transplant and after the use of immunomodulatory therapy as in MS.
PML usually manifests with subacute neurologic deficits including altered mental status, motor deficits (hemiparesis or monoparesis), limb ataxia, gait ataxia, and visual symptoms such as hemianopia and diplopia. PML typically spares the optic nerves and the spinal cord.
In patients with multiple sclerosis (MS), particularly those being treated with natalizumab, who are therefore at increased risk for PML, it may be difficult to distinguish recurrent attacks of MS from PML based upon clinical and radiologic findings. However, certain neuroimaging features may be useful in this regard:
- PML lesions after natalizumab therapy are usually unifocal if detected early on MRI, located at the gray-white junction of the frontal and parieto-occipital lobes, and are larger than typical foci of demyelination in MS. In contrast, MS lesions are more often small, multifocal, and predominate in the periventricular white matter.
- MS lesions usually have an ovoid shape and are oriented perpendicular to the corpus callosum (the abutting calloso-septal margin) or long axis on the lateral ventricles (Dawson finger pattern); PML lesions do not follow this pattern.
- PML lesions may be hyperintense on trace diffusion-weighted MRI, whereas MS lesions are usually not.
Optic neuritis usually presents as acute or subacute unilateral eye pain that is accentuated by ocular movements. There may be a scotoma, usually in the center of the field of vision. What will the optic disc look like? If the lesion is retrobulbar the disc may look normal or there may be edema resembling papillitis or there may be optic atrophy. A bitemporal or binasal homonymous field defect is rare in MS and should suggest a mass lesion pressing down on the optic pathways. In optic neuritis site recovers in a few weeks though some dimness and reduction in the brightness of red color may persist. A number of studies have found that reduced axial diffusivity on diffusion tensor MRI (DTI) correlates with prolonged latency of visual evoked potentials and worse visual outcome on follow-up.
There is a 35% chance of recurrence in 10 years in one or both eyes. Treatment is with IV glucocorticoids. Oral steroids are not used. Alternative treatments used for acute neuro-immunologic disease include intravenous immune globulin (IVIG) and plasma exchange. These do not have established efficacy in the treatment of optic neuritis.
Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, may improve axonal function in patients with demyelinating disease. In one randomized crossover study in 20 patients with optic neuritis of at least six months duration, five weeks of treatment with 4-aminopyridine was associated with improved measures on visual evoked potentials.
All patients with a CIS who meet diagnostic criteria for MS should be started on a DMT. The recombinant human interferon beta agents or glatiramer acetate are first-line choices for high-risk patients with a CIS. Glatiramer acetate, administered by subcutaneous injection, is dosed at 20 mg daily or 40 mg three times a week. Teriflunomide is an alternative for patients who prefer oral therapy, but its use is contraindicated for women who are pregnant or trying to conceive because of the risk of teratogenicity, and frequent monitoring is required due to the risk of hepatoxicity.
Transverse myelitis is an inflammatory disorder that presents with acute or subacute spinal cord dysfunction resulting in weakness, sensory alterations, and autonomic impairment (eg, bowel, bladder, and sexual dysfunction) below the level of the lesion. Transverse myelitis can occur as an independent entity, usually as a postinfectious complication, but transverse myelitis also exists on a continuum of neuro-inflammatory disorders:
- Transverse myelitis can occur as part of the spectrum of MS
- Transverse myelitis manifesting as a longitudinally extensive spinal cord lesion spanning three or more vertebral segments is one of the characteristic manifestations, along with bilateral optic neuritis, of NMOSD. ( “Neuromyelitis optica spectrum disorder).
- Transverse myelitis may be seen in patients with acute disseminated encephalomyelitis. (ADEM) which follows a viral infection or vaccination.
Eye movement abnormalities in MS.
Abnormalities of voluntary gaze (very common) and include internuclear ophthalmoplegia, ocular dysmetria and gaze impersistence, horizontal gaze palsy, one-and-a-half syndrome, dorsal midbrain syndrome, skew deviation. Nystagmus (very common) which may be horizontal and vertical or pendular, periodic alternating.
Abnormalities of slow phase eye movements (common) such as disordered smooth pursuit: paroxysmal disorders of eye movements (less common) such as ocular flutter, square wave jerks, opsoclonus
Isolated ocular motor nerve palsies are uncommon.
Internuclear ophthalmoplegia (INO) refers to abnormal horizontal ocular movements with lost or delayed adduction and horizontal nystagmus of the abducting eye. INO is caused by a lesion of the medial longitudinal fasciculus in the brainstem on the side of diminished adduction. Convergence is typically preserved.
In patients with MS, paraparesis or paraplegia are more common than isolated upper extremity weakness due to the frequent occurrence of lesions in the descending motor tracts of the spinal cord. Severe spasticity can occur, such that extensor spasms of the legs and sometimes the trunk may be provoked by active or passive attempts to rise from a bed or wheelchair.
Physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes are exaggerated, sustained clonus may be elicited, and extensor plantar responses are observed. All of these manifestations are commonly asymmetrical.
Occasionally, deep tendon reflexes are decreased due to lesions interrupting the reflex arc at a segmental level, and an inverted triceps reflex may be observed. In it, the triceps contraction is lost and the efferent component is represented by a contraction of the biceps muscle. The Achilles reflex can be absent due to lesions of the sacral segments of the spinal cord, with or without concomitant sphincter and sexual problems. Occasionally, reduced reflexes reflect hypotonia resulting from cerebellar pathway lesions.
Gait imbalance, difficulty in performing coordinated actions with the arms and hands, and slurred speech often occur as a result of impairment of cerebellar pathways. Cerebellar signs are usually mixed with pyramidal (corticospinal) tract signs.
I hope some of this information helps to clarify why and when neurological signs appear in MS and closely related diseases in which demyelination occurs in the CNS.