Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not αB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with αB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and αB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.     

Autosomal dominant leukodystrophy with axonal spheroids and pigmented glia: clinical and neuropathological characteristics

We report two autopsy cases of siblings with adult-onset autosomal dominant leukodystrophy characterized by destruction of cerebral white matter, large numbers of axonal spheroids and pigmented glia in the fronto-temporal lobes. Both patients presented with motor and cognitive symptoms and aphasia, 2–3 years before death. At autopsy, the brain showed brown coloration and decreased volume of white matter in the frontal and temporal lobes as well as corpus callosum. Microscopically, marked loss of myelin and axons and abundant axonal spheroids without apparent neuronal loss were observed in the frontal and temporal lobes, which was consistent with hereditary diffuse leukodystrophy with spheroids (HDLS). In addition, glial cells, most consistent with macrophages and containing pigments that were stained by Sudan III and PAS, were found in the white matter lesions. The present cases showed overlapping features with HDLS and pigmentary type of orthochromatic leukodystrophy, suggesting that the pathomechanisms of these two diseases are closely related.     

Adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia: report of a family,historical perspective,and review of the literature

We present a two-generation family consisting of a father and two daughters, who had an adult-onset leukodystrophy characterized by widespread destruction of cerebral white matter with neuroaxonal spheroids. The mode of inheritance appears to be autosomal dominant. All three patients presented with a variety of motor and cognitive symptoms, including frontal lobe signs, 4–7 years before death. Each followed a chronic course until death at ages 39, 46, and 51. At autopsy, the white matter loss was widespread but most prominent in the cerebrum with descending corticospinal tract degeneration and relative sparing of subcortical U-fibers. Pigmented glial cells were present, most of which appear to be macrophages, but inconstantly Prussian blue-positive. This disease is consistent with published reports of hereditary diffuse leukoencephalopathy with spheroids (HDLS). However, a review of the literature and a personal review of the neuropathology of the original case of the pigmentary type of orthochromatic leukodystrophy (POLD) reveal overlapping clinical and neuropathologic features between these two previously distinct entities, suggesting a common pathogenetic and perhaps etiological relationship between the two.     

Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18–71) and the mean disease duration was approximately six years (range, 3–11).We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.     

Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids

OBJECTIVE: To provide clinical, MRI, and histopathologic findings in a rare white matter disorder with autosomal dominant inheritance, so-called hereditary diffuse leukoencephalopathy with spheroids (HDLS). BACKGROUND: Progressive leukoencephalopathies often constitute a diagnostic dilemma in both children and adults. In some cases, histopathologic examination of brain tissue is required for a classifying diagnosis. METHODS: Clinical history, MRI, and autopsy findings were reviewed in three patients with HDLS: a father, his daughter, and an unrelated patient. RESULTS: Clinical history consisted of an adult-onset neurologic deterioration with signs of frontal lobe dysfunction, epilepsy, spasticity, ataxia, and mild extrapyramidal disturbances. MRI findings included cerebral atrophy and patchy white matter changes, most pronounced in the frontal and frontoparietal area with extension through the posterior limb of the internal capsule into the pyramidal tracts of the brainstem. Autopsy in two patients revealed a leukoencephalopathy with frontoparietal and frontal preponderance and numerous neuroaxonal spheroids in the abnormal white matter. The pyramidal tracts were affected throughout the brainstem. CONCLUSION: Similar clinical and histopathologic findings have been reported in members of a Swedish pedigree. The homogeneity of the findings strongly suggests that HDLS is a distinct disease entity. In the absence of a biochemical or genetic marker, a definitive diagnosis requires histopathologic confirmation in one of the affected family members. Neuroaxonal spheroids.     

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.     

CSF1R mutation presenting as dementia with Lewy bodies

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant leukoencephalopathy resulting from mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 protein (encoded by CSF1R). The clinical phenotypes reported with CSF1R mutations are variable. We present a case of a patient with a pathogenic variant in the CSF1R gene with clinical and imaging features suggestive of Dementia with Lewy Bodies (DLB). This case expands the known clinical presentations associated with CSF1R mutations.     

An autopsy case of hereditary diffuse leukoencephalopathy with spheroids,clinically suspected of Alzheimer’s disease

We report here a case of orthochromatic leukodystrophy with spheroids. A 40-year-old woman developed forgetfulness. About 1 year after the onset, clinical examination confirmed global intellectual deterioration with amnesia, spatiotemporal disorientation, and impairment of judgment. At age 43, she experienced tonic-clonic convulsions several times, and died of pneumonia at the age of 44. Alzheimers disease was suspected clinically. Pathologically, there was severe diffuse demyelination of the deep white matter of the frontal, parietal and occipital lobes with relative preservation of the subcortical U fibers. In the central demyelinated areas, myelin loss was severe with diffuse gliosis, moderate loss of axons, and many axonal spheroids. At the periphery of the severely degenerated regions, there were a lot of macrophages and most had non-metachromatic lipid granules. The cerebral cortex was intact. The neuropathological findings of this case are consistent with hereditary diffuse leukoencephalopathy with spheroids (HDLS). Ten cases of HDLS were reviewed and presented many findings in common. The gray matter was intact and U fibers were well preserved in most cases. In white matter lesions, severe loss of myelin, moderate to severe axonal loss, much axonal swelling, and the presence of macrophages and hypertrophic astrocytes were common findings. In some cases with HDLS, dementia appeared without obvious neurological manifestations in the early stage. We should remember that some cases with HDLS show clinical symptoms similar to Alzheimers disease, especially in the early stage.     

Impact of cladribine on soluble adhesion molecules in multiple sclerosis

Mitosek‐Szewczyk K, Stelmasiak Z, Bartosik‐Psujek H, Belniak E. Impact of cladribine on soluble adhesion molecules in multiple sclerosis.
Acta Neurol Scand: 2010: 122: 409–413.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background – Soluble forms of vascular cell adhesion molecule‐1 (VCAM‐1), intracellular adhesion molecule‐1 (ICAM‐1) and E‐Selectin play a role in the regulation of blood–brain barrier damage and represent markers of the clinical course of multiple sclerosis (MS) and magnetic resonance imaging activity. We determined sICAM, sVCAM and sE‐Selectin concentrations in the cerebrospinal fluid (CSF) and serum of patients with remitting–relapsing multiple sclerosis before and after cladribine treatment as well as in a control group. Methods – We examined 17 patients diagnosed according to McDonald’s criteria. Thirteen healthy age‐matched subjects served as controls. The ELISA method was used to measure sICAM‐1, sVCAM‐1 and sE‐Selectin. Results – The concentration of sICAM and sE‐Selectin decreased in sera (difference between patients and controls was statistically significant, in the former P < 0.04, in the latter P < 0.0003) but not in the CSF of MS patients after cladribine treatment. Conclusions – The reduction in sICAM and sE‐Selectin concentrations after cladribine treatment indicates an immuno‐suppressive effect of the drug. The changes in levels of sICAM and sE‐Selectin after cladribine treatment reflect disease activity and indicate a reduction in the inflammatory reaction.     

In vitro neurotoxic properties and excitatory aminoacids concentration in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Relationship with the degree of certainty of disease diagnoses

Fiszman ML, Ricart KC, Latini A, Rodríguez G, Sica REP. In vitro neurotoxic properties and excitatory aminoacids concentration in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Relationship with the degree of certainty of disease diagnoses.
Acta Neurol Scand: 2010: 121: 120–126.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To determine glutamate and aspartate levels in the cerebrospinal fluid (CSF) in patients with sporadic amyotrophic lateral sclerosis (SALS) grouped according to El Escorial diagnostic criteria, and to perform an in vitro assessment of the neurotoxicity of the CSF in murine cortical neurons. Methods – SALS patients were sorted according to El Escorial diagnostic criteria. Glutamate and aspartate were measured in the CSF using high performance liquid chromatography. Cultured cortical neuron viability was determined after exposure to CSF for 24 h. Results – Glutamate levels were elevated in 28 out of the 29 patients with definite, probable or possible SALS. There were no differences in glutamate concentrations when the three clinical forms of the disease were compared; neither there were significant variation across disease duration and clinical presentation. In agreement with previous reports, we concluded that CSF‐SALS‐induced in vitro neurotoxicity is mediated by ionotropic glutamate receptors. We found no relationship between the degree of in vitro neurotoxicity and glutamate concentration in the CSF. Conclusions – Glutamate but not aspartate CSF levels may contribute to ALS pathogenesis. However, glutamate levels may not influence the degree of diagnosis certainty or lesion extension.     

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis

Verbeek MM, Notting EA, Faas B, Claessens‐Linskens R, Jongen PJH. Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
Acta Neurol Scand: 2010: 121: 309–314.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. Materials and methods – We studied 80 patients with relapsing–remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. Results – CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 ± 0.21; SPMS, 0.10 ± 0.15; controls, 0.021 ± 0.020), but not in PPMS (0.061 ± 0.052). CTTS index was higher in MS patients with elevated MNC or CSF‐restricted oligoclonal IgG bands than in MS patients without these CSF findings. Conclusions – CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.     

Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings (“spheroids”). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25–83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.     

Remarkable behavioural signs and progressive non‐fluent aphasia in a patient with adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia

Adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, mainly the frontal subcortical areas and the corpus callosum. Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease‐related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural symptoms and non‐fluent aphasia, which are found in patients with frontotemporal lobar degeneration. However, behavioural symptoms and non‐fluent aphasia in a patient with ALSP have rarely reported in detail. Here, we describe a patient with ALSP who initially presented with remarkable behavioural signs and non‐fluent primary progressive aphasia, which resembled symptoms of frontotemporal lobar degeneration. The present case suggests that ALSP should be included in the differential diagnosis for frontotemporal lobar degeneration.     

Diagnostic significance of CSF spectrophotometry in cerebrovascular diseases

Different spectrophotometric “patterns” of xanthochromic compounds in the CSF may be found in cerebrovascular diseases. In about 1000 such cases the CSF was examined spectrophotometrically. Specific clinical diagnoses of thrombo-embolic or haemorrhagic disorders were verified (autopsy, operation or radiological examinations) or diagnosed with a high degree of probability on clinical grounds (excluding the CSF signs) in only about 20% of the cases.The diagnoses in these cases (about 200) corresponded extremely well with the spectrophotometric patterns found. It must be specially emphasized that this examination performed at a time interval of between 24 hr to 7 days after the onset of symptoms reveals a haemorrhagic component in nearly 100% of cases, as judged by cases with verified or highly probable CNS haemorrhage. A few cases had normal CSF spectra, obviously since the lumbar puncture had been performed too late or too early after the ictus.The times of appearance and disappearance of the pathological CSF patterns, and the optimal test times were also studied. Difficulties in the interpretation of CSF spectrophotometry and methods of overcoming them are described.In conclusion, direct spectrophotometry of the CSF is a simple, fast and extremely sensitive method, which in our opinion should be used routinely in the diagnosis of suspected vascular diseases of the CNS. CSF spectrophotometry may well provide a valuable guide for the clinician in the rational therapy of cerebrovascular disorders.     

Calcitonin gene-related peptide immunoreactivity in spinal spheroids in motor neuron disease

Summary The spinal cords from seven autopsy cases of sporadic motor neuron disease (MND) and two controls were immunohistochemically examined using anti-bodies directed to calcitonin gene-related peptide (CGRP) and to neurofilament proteins (Nf). CGRP immunoreactivity was observed in the posterior horns, especially in the laminae I and II, of all the spinal cords examined. In MND cases in addition, a considerable number of spheroids in the anterior horns were labelled with the antibody. In some spheroids, their entire area was homogeneously immunostained, whereas in others the immunoreactivity was confined to a focal area(s) within the profile of the spheroids and between these two forms of staining several variations of the staining patterns were seen. The anti-Nf intensely and homogeneously labelled all spheroids and there was no appreciable difference in the Nf-immunoreactive pattern, between CGRP-posittive and-negative spheroids. It is possible that the accumulation of CGRP in spheroids may result from entrapment of CGRP during the anterograde axonal transport causing loss of CGRP at the neuromuscular junction and producing weakness and atrophy of the muscles.Supported in part by the Grant-in-Aid for Encouragement of Young Scientists (the Ministry of Education, Science and Culture, Japan) and in part by the Amyotrophic Lateral Sclerosis Society (USA)     

Rapidly fatal neuropathies and an ALS clinical presentation

Venizelos AP, Brown HG, Fisher MA. Rapidly fatal neuropathies and an ALS clinical presentation.
Acta Neurol Scand: 2011: 124: 282–289.
© 2011 John Wiley & Sons A/S. Objectives – The objective of this report is to describe patients with an unusually severe, rapidly fatal acquired polyneuropathy. Methods – The clinical, electrodiagnostic (EDX), laboratory, and pathological findings in three patients with a distinctive form of neuropathic illness are discussed. Results – Three patients, ages 67, 54, and 50, had clinical findings that met accepted clinical criteria for amyotrophic lateral sclerosis (ALS) – definite in two and probable in one. The EDX studies in these patients had abnormalities that would be highly atypical for ALS. There were features consistent with an asymmetrical, non‐length‐dependent process as well findings consistent with demyelination – features consistent with a chronic acquired polyneuropathy. All patients had a rapidly progressive course with death because of respiratory failure in 4–30 months. The patients did not respond to immunomodulating therapies. Extensive evaluations in these patients did not reveal a cause for the patients’ neuropathies. Postmortem examination in two of the patients did not reveal evidence for ALS. In one of these patients, there were pathological findings thought possibly consistent with an immunologically mediated process. Conclusion – This report emphasizes the importance of considering other diagnoses in patients who clinically appear to have ALS and raise the specter of an as of yet poorly understood, severe neuropathic illness.     

Comorbidity of psychiatric diagnoses in anorexia nervosa

The comorbidity of psychiatric diagnoses was examined with the Diagnostic Interview Schedule in 62 women who participated in a 10-year follow-up study of anorexia nervosa. Sixty-two age- and sex-matched controls, their parents, and parents of the anorectic probands were also interviewed with the Diagnostic Interview Schedule. There was a statistically significant comorbidity of the affective and anxiety disorders with anorexia nervosa. The first-degree relatives of the anorectic probands had significantly more alcoholism and total number of psychiatric diagnoses compared with the first-degree relatives of controls. There were two mothers with bulimia nervosa, two cases of anorexia nervosa and two of bulimia nervosa in other first-degree relatives of anorectic probands, and no cases of eating disorders in the first-degree relatives of controls.     

White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings

Sundal C, Ekholm S, Andersen O. White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings.
Acta Neurol Scand: 2010: 121: 328–337.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Leukoencephalopathies are a heterogeneous group of severe encephalopathy syndromes with myelin, axonal or vascular pathology, typically with extensive white matter lesions on MRI T2‐FSE and/or ‐FLAIR sequences. Objectives – This review is restricted to leukoencephalopathies with onset in adult age and a dominant inheritance. These diseases are generally severe and often lethal and present with an exacerbating or insidiously progressive course. Material and methods – The focus is on four syndromes with pure leukoencephalopathies, however, leukoencephalopathies with associated clinical features are included. Results – T2 weighted MR imaging often show features common for leukoencephalopathies, yet shows distinguishing features in transthyretin amyloidosis. Conclusion – The diagnosis within the group of leukoencephalopathies thus characterized by MRI relies mainly upon clinical and genetic analysis. The differential diagnosis against treatable leukoencephalopathies is increasingly relevant.     

Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson’s disease

Ishibashi K, Kanemaru K, Saito Y, Murayama S, Oda K, Ishiwata K, Mizusawa H, Ishii K. Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson’s disease.
Acta Neurol Scand: 2010: 122: 46–51.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – To evaluate the association between cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations and nigrostriatal dopaminergic function assessed by positron emission tomography (PET) imaging with carbon‐11‐labeled 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)‐tropane (¹¹C‐CFT), which can measure the dopamine transporter (DAT) density, in Parkinson’s disease (PD). Methods – ¹¹C‐CFT PET scans and CSF examinations were performed on 21 patients with PD, and six patients with non‐parkinsonian syndromes (NPS) as a control group. Results – In the PD group, CSF HVA concentrations were significantly correlated with the striatal uptake of ¹¹C‐CFT (r = 0.76, P < 0.01). However, in the NPS group, two indices were within the normal range. Conclusions – In PD, CSF HVA concentrations correlate with nigrostriatal dopaminergic function. Therefore, CSF HVA concentrations may be an additional surrogate marker for estimating the remaining nigrostriatal dopaminergic function in case that DAT imaging is unavailable.     

Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases

Hoevenaren IA, de Vries LC, Rijnders RJP, Lotgering FK. Delivery of healthy babies after natalizumab use for multiple sclerosis: a report of two cases.
Acta Neurol Scand: 2011: 123: 430–433.
© 2010 John Wiley & Sons A/S. Background – In current literature, no data on safety in pregnancy for new drugs in the treatment of multiple sclerosis (MS) like natalizumab (Tysabri^®), a humanized monoclonal antibody against α4 integrins, are yet available. In the management of MS, natalizumab is the first monoclonal antibody approved to the market. Methods – We describe the pregnancy and outcome in two women with MS using natalizumab. The first patient used it in the periconceptional period, and the second patient used it in both the periconceptional period and throughout gestation. Results – The antenatal course of the first patient was complicated by an exacerbation of MS. The second patient did not experience MS relapses during pregnancy, while still using natalizumab. The newborns did not show any abnormalities postnatal and at 6 weeks’ follow‐up. Conclusions – This is the first detailed report on pregnancy and delivery of two babies after maternal treatment of MS with natalizumab. From the small number of cases on the usage of natalizumab during pregnancy in literature, we cannot conclude whether the use of natalizumab is safe, and long‐term effects are not known. Further research is needed to establish the exact effects on pregnancy and intrauterine development as well as the long‐term effects. Prenatal counseling with thorough explanation of the risks and careful decision making is advisable.